Entrepreneur Dave Aspreys end-of-life plans are quite simple, really, even if some of his ambitions sound laughably optimistic to most of us.I want to die at a time and by a method of my own choosing, and keep doing awesome things until that day, he tells me. I dont think its outrageous to believe Ill make it to 180 years old. And if I run out of energy, itll just be because I did too much cool shit for my own good.

Asprey is strolling across his lush property in British Columbia, holding up his phone and pointing out the specimens in this years garden as we chat over Zoom in the midst of the global pandemic. Hes protecting his skin from the sun with a goofy Outdoor Research hat and wearing a long string of beads that he says are each over a hundred years old, from cultures around the world.

Asprey, 48, is the founder of the Bulletproof wellness empire and a vocal champion of the movement to extend human life expectancy beyond 100 years. Hes made millions by experimenting on his own body and packaging his home-brewed discoveries into books, a podcast, consulting services and consumer products (you may have even tried his butter-laced coffee). Asprey, who was a web-security executive before he became the Bulletproof Executive, is just one of a cadre of tech elite who have begun directing their attentionand truckloads of moneytoward the problem of life extension. Jeff Bezos, Peter Thiel, Sergey Brin, Larry Ellisonname a Silicon Valley A-lister and he or she is likely funding longevity research, experimenting with anti-aging interventions or both. These are the masters of the universe who see no reason they cant take the tech industrys optimization obsession and apply it to the ultimate challenge: conquering death itself.

And their efforts appear to be paying off: Thanks to a recent explosion of advances in longevity medicine, Aspreys vision of living healthfully into his second century might not be so crazy. In fact, for people in middle age right now, a handful of therapies in clinical trials have the potential, for the first time in human history, to radically transform what old age looks like. If the life extensionists are right, a person whos 40 today might reasonably expect to still be downhill skiing, running a 10K or playing singles tennis at 100.

Dave AspreyDave Asprey

If you do anti-aging right, Asprey insists, youll have a level of resilience and energy to fight what comes your way. If you get Covid-19, youre less likely to become very sick. The idea is that at a cellular level, youre making yourself very hard to kill.

The most extreme of the controversial interventions Asprey has undergone involved having stem cells extracted from his own bone marrow and fat and then injected into hundreds of locations on his body. Into every joint, between every vertebra and into my cerebrospinal fluid, face and sex organs, he tells me cheerfully. For what I spent on that, I could have bought a really nicely appointed Tesla.

He trots up a flight of stairs to his home office, which sits above a million-dollar lab filled with health gadgets, such as a cryochamber, a hypoxic trainer and an AI-enabled stationary bike. For a wealthy person, investing in your body should be a major part of your Im rich strategy, he explains. Personally, I think you should be spending at least 2 to 3 percent of your net worth on health and longevity. Get a personal chef who can cook you the right food. Its not that hard.

It might be an exaggeration to say BioViva CEO Liz Parrish believes death is optional, but for her, Aspreys goal of living to 180 shows a distinct lack of ambition. If you can reach homeostasis in the body, Parrish says, where its regenerating itself just a little bit faster than its degrading, then what do you die of? An accident or natural disaster, probably. Theres no expiration date at 90 or 100 years old.

Tall, blond and fit, Parrish cuts a strikingly youthful figure at 49one that might convince you to order whatever shes having. But, like Asprey, she has received criticism from the longevity research community for becoming patient zero in her own experimental drug trial, aimed at halting aging at the cellular level. In 2015, Parrish underwent telomerase and follistatin gene therapies in Bogota, Colombia. The procedures involved receiving around a hundred injections of a cocktail of genes and a virus modified to deliver those new genes into her bodys cells. The objective was to prevent age-related muscle loss and lengthen her telomeres: the caps at the end of our chromosomes. Scientists have identified their unraveling as not only a marker of aging but also a potential cause of age-related decline.

Liz ParrishLiz Parrish

Parrish told the media about her clandestine experiment and has published periodic updates on her condition in the five years since, and she reports that she has indeed increased her muscle mass and lengthened her telomeres. Parrishs punk-rock approach stems from her conviction that the medical-research communityboth the Food and Drug Administration (FDA) and researchers who arent business-mindedis moving too slowly, with too much red tape, when it comes to advancing aging therapeutics. But gene therapy is a relatively new area of medicine that brings with it a host of new risks, including cancer, severe immune reactions and infections caused by the viral vector used to deliver the drug.

Parrish downplays such worries. There may be risks, she tells Robb Report. But the known risk is that youre 100 percent likely to die. So you have to decide for yourself if the potential benefit outweighs that.

Humans have always aspired to find the fountain of youth, so people might be skeptical about the fact that anti-aging technologies are working now, says British investor and businessman Jim Mellon. But the fact is that this is finally happening, and we need to seize the moment. Mellon cofounded Juvenescence, a three-year-old pharmaceutical company thats investing in multiple technologies simultaneously to increase the odds of bringing winning products to market.

Mellon, 63, has made his fortune betting on well-timed investment opportunities, and he predicts that a new stock-market mania for life extension is just around the corner. This is like the internet dial-up phase of longevity biotech, he enthuses. If youd invested in the internet in the very early days, youd be one of the richest people on the planet. Were at that stage now, so the opportunity for investors is huge. According to a report by Bank of America Merrill Lynch, hes not wrong: The market for technologies to increase human life span is projected to grow sixfold to $610 billion in just the next five years.

When I talk to Mellon in the late spring, hes sequestered on the rugged coast of the Isle of Man, a tiny spit of land in the Irish Sea. Despite being what he describes as imprisoned there for 15 weeksand countingduring the Covid-19 shutdown, hes jovial and chatty and wants to make it clear that his interest in life extension is much more than financial. Working to extend life is an ethical cause, he says. If we can help people to live healthfully until the end of life, well transform the world completely. Well reduce a huge amount of pressure on failing health-care systems, and well have to reimagine pension and life insurance. This should be the number-one tick in anyones investment portfolio.

If youd like to get on board with this social-impact view of longevity, it helps to understand the trajectory of aging today. In Americas most affluent neighborhoods, the average life span is about 88 years. (Meanwhile, in this countrys poorest, it hovers around a meager 66 because of a raft of inequalities, such as diet, stress, smoking, pollution and health care.) For most people, health starts gradually diminishing in the last 15 years of life with the onset of chronic conditions, including arthritis, neurodegeneration and diabetes. If we could eliminate such diseases of aging, experts say, the US could save an estimated $7.1 trillion in health-care costs over the next 50 years. (Quite where all these sprightly centenarians might live on this already densely populated planet remains to be seen.)

Jim MellonEric Verdin

One of Mellons bets is on a class of drugs called senolytics, which destroy senescent cells: the so-called zombie cells that, for complex reasons, stop dividing as we age. Senescent cells harm the body by secreting compounds that cause inflammation in surrounding tissues. Many age-related conditionsarthritis, diabetes, Alzheimers, cancerhave an inflammatory component, and studies suggest that a buildup of senescent cells is a large part of the problem.

A number of biotech start-ups are devel- oping drugs that target cell senescence, but the furthest along is Unity Biotechnology, a company in South San Francisco that has three drugs in clinical trials to address aging conditions, starting with osteoar- thritis of the knee. Unity raised more than $200 million from such big names as Thiel and Bezos, who chipped in through their investment firms, before going public in 2018. Since then, Mellon has also bought a small stake.

The holy grail of senolytics will be the development of a preventive therapy to wipe out senescent cells in the body before they cause conditions of aging, theoretically extending life span. In June, a team from Sloan Kettering published new breakthrough research showing that CAR T cellstypically used for precision cancer therapycan also be used to target and kill senescent cells. Prescription senolytics for anti-aging therapy are still years away, but unsurprisingly, theres an audience of longevity enthusiasts who want to access such anti-aging miracles yesterdayand no shortage of FDA-unapproved ways to chase after them. For instance, after a few studies examined the senolytic effects of a chemotherapy drug called dasatinib, the website FightAging.org published a step-by-step guide to senolytic self-experimentation using chemotherapeutics.

It doesnt take a Ph.D. in biochemistry to guess that taking off-label chemo drugs might come with harmful side effects, but that hasnt stopped a zealous group of body-hackers from trying it themselves and chronicling their efforts online. The internet is littered with novice longevity adviceand sketchy anti-aging companies eager to separate the hopeful and desperate from their money, like the company that charges $8,000 for transfusions of plasma from the blood of teenagers and early-twentysomethings (yes, just like Gavin Belson on HBOs Silicon Valley). Many of these are at best ineffective and at worst deadly, since the same cellular systems that fuel growth in young people might cause cancer when tipped into overdrive. Imagine the tragic irony of paying tens of thousands for a therapy that promises to help you live longer but actually causes the cancer that kills you.

Adobe

Beyond the obvious red flags of repurposed chemo drugs and the bloodletting of teens, it can be difficult for a layperson to separate the world-changing longevity breakthroughs from the terrible ideas. Enter one of the worlds leading experts on longevity to help make sense of things.

Eric Verdin, 63, is president and CEO of the Buck Institute, a globally renowned center for aging research just outside San Francisco in Marin County. Verdin is bullish on the promise of living healthfully to at least 100. Today. But 180? Dont count on it. My prediction, based on everything we know today, is that getting to 120 is about the best we can do for the foreseeable future. Ill bet my house were not going to see anyone live to 180 for another 200 years, if ever, he says. But making everyone a healthy centenarian, this is something we can do today. And thats something to be excited about.

Verdins own lab at the Buck Institute studies the aging immune system and how its affected by lifestyle factors, such as nutrition and exercise. Informed by this research, Verdin follows a time-restricted diet in which he eats all of his meals in an eight-to-nine-hour window (similar to the Buchinger Wilhelmi process) and gets plenty of exercise mountain biking in Marins steep hills. The good news is that over 90 percent of what causes diseases of aging is environmental, and that means its within your control, he says.

But he emphasizes that responsible management of your health comes with limits, like avoiding experimental therapies. A group of people have decided to try some expensive and dangerous interventions, but there is zero evidence that any of these are going to help them live longer, he says. The problem, according to Verdin, is that the results of aging interventions in mouse trials can look very promising but rarely translate to success in humans. Theres a huge delta between the health of a stressed lab mouse and an optimally healthy mouse, Verdin says. So when you treat lab mice with longevity therapeutics, you see an outsized result that doesnt at all guarantee the same result in humans.

On the other hand, Verdin tells Robb Report, there are definitely new protocols worth getting excited about. Take, for instance, rapalogs, a class of drugs that interact with a protein called mTOR, which serves as a linchpin for multiple critical biological processes, including cell growth and metabolism. Rapalog drugs tamp down mTOR, possibly preventing age-related diseases such as diabetes, stroke and some cancers. The drug rapamycin, the most heavily studied formula, was approved in the US in 1999 to help prevent organ-transplant rejection. Last year the medical journal Aging published a rapturous opinion piece by oncologist Mikhail Blagosklonny in which he made the case that rapamycinin small or intermittent dosesis effective as a preventive treatment to ward off diseases of aging, and that, in the elderly, not taking rapamycin may be even more dangerous than smoking.

Eric VerdinJim Hughes Photography

Later this year, a biotech firm called resTORbio, which was spun out of the Swiss-based Big Pharma company Novartis in 2017, is expected to seek FDA approval for its rapalog RTB101, which clinical trials have shown to slow age-related decline of the immune system and improve immune response in elderly people by more than 20 percent, a key factor in protecting vulnerable aging populations from disease. (It is currently in trials on elderly patients with Covid-19.) This is the furthest-along program of anything in the aging field, Joan Mannick, cofounder and chief medical officer of resTORbio, told MIT Technology Review last year. If health authorities approve this drug well have a product for people to prevent age-related diseases. Not just in our lifetime, but in, you know, a few years.

One of the many effects of rapamycin is that it mimics the mechanisms of calorie restriction. As Verdins lab and others have shown, fasting provides a number of anti-aging benefits, including insulin regulation, reduced inflammation and, to put it colloquially, clearing out the gunky by-products of metabolismpart of the reason Twitter CEO Jack Dorsey and other tech titans eat just a few meals per week. For lesser mortals, fasting is extremely hard to commit to and not much fun, hence the huge interest in calorie-restriction mimetics like rapamycin, which provide all the benefits without the downer not-eating part.

Of all the calorie-restriction mimetics, the one sparking the most excitement among longevity researchers is already on the market: metformin, a decades-old diabetes drug. Metformin became a part of the Silicon Valley health regimen several years ago after an epidemiological study showed that Type 2 diabetics who took the drug lived longer than non-diabetics who didnt. Just about everyone in the longevity industry takes metformin, Verdin tells me. He takes it himself, and nearly everybody I interviewed is taking or has taken it, too.

In April, Nir Barzilai, the renowned endocrinologist who spearheaded research on the anti-aging properties of metformin, announced in an opinion piece he co-authored in the journal Cell Metabolism that his lab is launching a large clinical trial to investigate the anti-aging effects of the drug on non-diabetic populations. Barzilais goal is to prove to the FDA that aging itselfrather than conditions associated with it, like Alzheimers and arthritiscan be targeted as a disease. If Barzilai is successful and the FDA approves aging as a treatment indication, the process of bringing longevity therapies to market would accelerate rapidly.

Just as the FDA was able to move faster to bring Covid-19 therapies to market this year, we will reach a tipping point when public opinion pushes the FDA to approve aging as an indication, and the longevity-research field will make leaps as a result, Mellon says. He has contributed funding to Barzilais metformin research, which he believes will be instrumental in proving that there are compounds that can extend human life across the board.

The fact of the matter is that the US has the best regulatory system for new drug development in the world, Mellon says. Were in the first era ever when humans can be bioengineered to live longer. And in 10 years, well have solutions that are even better than today. Just wait, its coming.

Liz Parrish

Jim Mellon

Diet:Vegetarian.Mindfulness practice:Nightly meditation.

Exercise regimen:30 minutes of cardio and 10 minutes of weights,five days a week.

Anti-aging Rx:Regenerative gene therapies. Im certain most peoplewill take them in the next couple decades.

180th-birthday wish:Solving another critical issue.

Sleep routine:7.5 hours plus a 30-minute nap; in bed by 9 p.m.

Vitamins/supplements/ prescription meds:Vitamins D and B12, metformin.

Exercise regimen:Walk or run minimum 10,000 steps a day;weights three times week.

Anti-aging Rx:Green tea.

100th-birthday wish:Another 25 years.

Dave Asprey

Jim Hughes Photography

180th-birthday wish:Either a cruise to Mars or a 1970 Mustang Fastback,which by then will be 210 years old!

Sleep Routine:Avoid: coffee after 2 p.m., heavy workouts after 6 p.m.,alcohol during the week and heavy eating in the evening.

Vitamins/supplements:Vitamin D, omega fatty acids, NMN, citrus bioflavonoidcomplex, fiber supplement, prebiotic supplement.

Diet:Fasting-mimicking diet once every four to six months;roughly 16:8 intermittent fasting at other times.

Mindfulness practice:Daily meditation.

Anti-aging Rx:I love cooking and eating, so I do not restrict foodon the weekend. Happiness with friends and family is thesurest path to longevity.

100th-birthday wish:A bike tour across the US, from coast to coast.

Read more from the original source:
Why Silicon Valley Execs Are Investing Billions to Stay Young - Robb Report

Abstract

The emergence of several cell therapy candidates in the clinic is an encouraging sign for human diseases/disorders that currently have no effective treatment; however, scalable production of these cell therapies has become a bottleneck. To overcome this barrier, three-dimensional (3D) cell culture strategies have been considered for enhanced cell production. Here, we demonstrate a high-throughput 3D culture platform used to systematically screen 1200 culture conditions with varying doses, durations, dynamics, and combinations of signaling cues to derive oligodendrocyte progenitor cells and midbrain dopaminergic neurons from human pluripotent stem cells (hPSCs). Statistical models of the robust dataset reveal previously unidentified patterns about cell competence to Wnt, retinoic acid, and sonic hedgehog signals, and their interactions, which may offer insights into the combinatorial roles these signals play in human central nervous system development. These insights can be harnessed to optimize production of hPSC-derived cell replacement therapies for a range of neurological indications.

Stem cellsincluding adult and pluripotent subtypesoffer tremendous clinical promise for the treatment of a variety of degenerative diseases, as these cells have the capacity to self-renew indefinitely, mature into functional cell types, and thereby serve as a source of cell replacement therapies (CRTs). Human pluripotent stem cells (hPSCs) are of increasing interest for the development of CRTs due to their capacity to differentiate into all cell types in an adult, for which adult tissuespecific stem cells may, in some cases, not exist or may be difficult to isolate or propagate (1). For example, one potential CRT enabled by hPSCs is the treatment of spinal cord injury (SCI) with oligodendrocyte progenitor cells (OPCs). These hPSC-OPCs have recently advanced to a phase 2 clinical trial for the treatment of SCI (2) and are being considered for additional myelin-associated disorders in the central nervous system (CNS), including adrenoleukodystrophy, multiple sclerosis (3, 4), and radiation therapyinduced injury (5). In parallel, hPSC-derived midbrain dopaminergic (mDA) neurons are under consideration for Parkinsons disease therapy (6, 7).

The promise of hPSC-derived therapeutics such as hPSC-OPCs or mDA neurons motivates the development of manufacturing processes to accommodate the potential associated clinical need. For example, approximately 250,000 patients in the United States suffer from some form of SCI, with an estimated annual incidence of 15,000 new patients (8). Human clinical trials involving hPSC-OPCs have used dosages of 20 million cells per patient (9), such that the hypothetical demand would be over 1 trillion differentiated OPCs. It is therefore imperative to develop systems to enable discovery of efficient and scalable differentiation protocols for these therapies.

Differentiation protocols to direct hPSCs into functional OPCs (10, 11) have been developed to approximate the signaling environment at precise positions within the developing spinal cord. Positional identity of cells is guided patterning cues that form intersecting gradients along the dorsoventral axis, such as Sonic hedgehog (SHH), and rostrocaudal axis, such as retinoic acid (RA). In addition, certain cues are present along both axes, such as Wnts (1215). These signaling environments vary over time as the embryo develops (16, 17). However, translating this complex developmental biology to an in vitro culture requires optimization of a large combinatorial parameter space of signaling factor identities, doses, durations, dynamics, and combinations over many weeks to achieve efficient yield of the target cell type, and there remains open questions about the impact of cross-talk between patterning cues on the expression of cellular markers present in OPCs such as transcription factors Olig2 and Nkx2.2 (18). Strategies to derive OPCs and other potential CRTs from hPSCs have shown steady progress, especially with application of high-throughput screening technology (1921); however, current production systems for hPSC-derived CRTs involve two-dimensional (2D) culture formats that are challenging to scale (2228).

More recently, 3D culture systems have demonstrated strong potential for a larger scale and higher yield (29) of hPSC expansion and differentiation than 2D counterparts, as well as compatibility with good manufacturing practice (GMP) standards (3033). While high-throughput systems for screening 3D cell culture environments have been applied to basic biological studies of hPSC proliferation (34), we envision that this technology could additionally be applied toward systematically optimizing production strategies for CRTs to accelerate the pace of their discovery and development toward the clinic while simultaneously uncovering new interactions among signaling cues that affect cell fate. Here, we harness the powerful capabilities of a uniquely structured microculture platform (35, 36), to screen dosage, duration, dynamics, and combinations of several cellular signaling factors in 3D for hPSC differentiation (Fig. 1). The independent control of gel-encapsulated cells (on pillar chip) and media (in well chip) enables simultaneous media replenishment for more than 500 independent microcultures in a single chip. Furthermore, we use custom hPSC reporter cell lines (37) to enable live imaging of proliferation and differentiation of OPCs for over 80 days on the microculture chip. One thousand two hundred combinatorial culture conditions, amounting to 4800 independent samples, were screened while consuming less than 0.2% of the reagent volumes of a corresponding 96-well plate format. Furthermore, the robust dataset enabled statistical modeling to identify relative differentiation sensitivities to, and interactions between, various cell culture parameters in an unbiased manner. Last, we demonstrate the generalizability of the platform by applying it toward a screen for differentiation of tyrosine hydroxylaseexpressing dopaminergic neurons from hPSCs.

(A) A micropillar chip with cells suspended in a 3D hydrogel is stamped to a complementary microwell chip containing isolated media conditions to generate 532 independent microenvironments. One hundred nanoliters of hPSCs suspended in a hydrogel is automatically dispensed onto the micropillars, and 800 nl of media is automatically dispensed into the microwells by a robotic liquid handling robot programmed to dispense in custom patterns. The independent substrate for cells and media enables screens of combinations of soluble cues at various dosages and timings. Scale bar, 1 mm. (B) Timeline of exogenous signals for in vitro 3D OPC differentiation from hPSCs and anticipated cellular marker expression along various differentiation stages.

Initially, we assessed whether hPSCs could be dispensed in the microculture platform system uniformly and with high viability. Quantification of total, live, and dead cell counts across the microchip indicates uniform culture seeding and cell viability at the initiation of an experiment (fig. S1).

We then used a custom-made Nkx2.2-Cre H9 reporter line, which constitutively expresses DsRed protein but switches to green fluorescent protein (GFP) expression upon exposure to Cre recombinase, to longitudinally monitor proliferation and differentiation of hPSCs to Nkx2.2+ oligodendrocyte progenitors in 3D on the microchip platform. A small range of culture conditions from previously published protocols of OPC differentiation were selected for an initial, pilot differentiation experiment, and the GFP expression was quantified after 21 days of differentiation. Cell morphology changes accompanying neural lineage commitment and maturation were clearly observed at later stages in the 3D differentiation (movie S1 and fig. S2) as cultures were maintained and monitored for up to 80 days on the microchip. We then developed fluorescence image analysis pipelines for quantification of nuclear and cytoplasmic marker expression via immunocytochemistry for endpoint analyses at various times (fig. S3). Together, these results support the robust and long-term culture potential and cellular marker expression readout of this miniaturization methodology for hPSC differentiation screening.

hPSC seeding density. We first focused on parameters within the first week of 3D differentiation into OPCs (Fig. 2A). The importance of autocrine, paracrine, and juxtacrine signaling mechanisms among cells in many systems led us to anticipate that the density of cells at the start of differentiation could affect the early neural induction efficiency and, consequently, the efficiency of OPC differentiation. We therefore demonstrated the ability of this microculture platform to test a range of initial hPSC seeding densities on day 2 (fig. S1) and assessed the effect of seeding density on Olig2 expression. We observed notable differences in levels of cell-to-cell adhesion in hPSC cultures by day 0, 2 days after initial seeding (Fig. 2Bi). Then, after 15 days of differentiation, we observed a trend that lower hPSC seeding density, between 10 and 50 cells per pillar, increased OPC specification slightly (Fig. 2Bii).

(A) Timeline of key parameters in the early phase of OPC differentiation. (B) i. Bright-field images of 3D H9 microculture sites at day 0 seeded with varying cell densities and the immunocytochemistry images of Olig2 (red) expression at day 15. Scale bar, 100 microns. ii. Quantification of day 15 Olig2 expression with respect to seeding density and SAG dose. *P value < 0.05 using Tukeys Method for multiple comparisons. (C) i. Montage of 360 fluorescence confocal images representing 90 unique differentiation timelines on a single microchip stained for Hoechst (blue) and Olig2 (red) after 21 days of differentiation. ii. Trends in Olig2 expression at days 15 and 21 in various CHIR and RA concentrations and durations (short CHIR, days 0 to 1; long CHIR, days 0 to 3). Error bars represent 95% confidence intervals from four technical replicates.

Timing of SMAD inhibition relative to RA and Wnt signals. The formation of the neural tube in human development (12) results from cells in the epiblast being exposed to precisely timed developmental signals such as Wnt (38) and RA that then instruct neural subtype specification (39). This led us to hypothesize that the overall differentiation efficiency of hPSCs to OPCs in this 3D context in vitro would be sensitive to the timing at which RA and Wnt signals were introduced during neural induction. Therefore, we induced neuroectodermal differentiation of hPSCs via inhibition of bone morphogenetic protein (BMP) signaling using the dual SMAD inhibition approach (40), with LDN193189 (hereafter referred to as LDN) and SB431542 (hereafter referred to as SB), and tested a range of times (0, 2, and 4 days) at which RA and Wnt signals (by CHIR99021, hereafter referred to as CHIR) were introduced into the culture. We observed a strong correlation between early addition of RA/CHIR and OPC specification such that combined exposure of RA and CHIR signals with SMAD inhibition on day 0 resulted in up to sixfold higher Olig2 expression in some cases (fig. S4), potentially implicating an important role of synchronized exposure of RA and CHIR signals with SMAD inhibition for specifying Olig2+ progenitors. For subsequent experiments, we kept the timing of RA and CHIR addition at day 0 and evaluated how the dose and duration of these signals may affect Olig2+ specification.

Dose and duration of key signaling agonists. We examined the combinatorial and temporal effects of three signaling cues that form gradients across intersecting developmental axes in the neural tube to influence specification of oligodendrocyte progenitors: RA (present along the rostrocaudal axis of the CNS development), SHH (41) (a morphogen that patterns the dorsoventral axis of the developing CNS and is activated by smoothened agonist, hereafter referred to as SAG), and Wnt (present along both the rostrocaudal and dorsoventral axes). Because OPC specification is likely sensitive to the relative concentrations of these cues, for example, given the importance of morphogen gradients in oligodendrocyte differentiation in the developing neural tube (12), we assessed the Olig2 expression resulting from a full factorial combinatorial screen of these cues (fig. S5). Most notably, we observed positive correlations in Olig2 expression in response to increasing RA dose and increasing duration of CHIR exposure from days 0 to 4 of differentiation (Fig. 2C). Without CHIR, an increase in RA from 10 to 1000 nM resulted in a 10-fold increase of Olig2 expression by day 21. A similar 10-fold increase in Olig2 expression was observed at an RA concentration of 100 nM if CHIR was present for the first 3 days of differentiation (Fig. 2C). Analysis of variance (ANOVA) analysis revealed a strong effect size for RA when added early in the differentiation, as well as an interaction between RA dose and longer CHIR duration, in specifying Olig2+ cells in this 3D context (fig. S5), consistent with previous work conducted in 2D in vitro formats (19, 42).

In other developmental systems, the activity of the Wnt signaling pathway was observed to be biphasic (43), whereby activation of the pathway initially enhances cardiac development but later represses it. As this complex signaling profile has been applied to enhance cardiomyocyte differentiation protocols in vitro (44), we analogously investigated whether adding antagonists of key signaling pathways after pathway activation could further enhance the OPC differentiation efficiency by adjusting the dorsoventral and rostrocaudal positioning in vitro. Maintaining the 5 M CHIR for days 0 to 3 from the previous experiment, we used IWP-2 (an inhibitor of the Wnt pathway), GANTT61 (an antagonist of SHH signaling), and DAPT (a Notch pathway antagonist) (Fig. 3A) to inhibit endogenous autocrine/paracrine and/or basal signaling. We used a full factorial analysis of these cues to additionally probe for combinatorial interactions among the pathway inhibitors.

(A) Timing of addition for three inhibitory signaling cuesGANTT61, IWP-2, and DAPTin the OPC differentiation protocol. (B) i. Olig2+, Nkx2.2+, and the proportion of total Olig2+ that are Nkx2.2+/Olig2+ cells in at day 21 in response to full factorial combinations of selected novel signaling antagonists. ii. Immunocytochemistry images of costained Olig2 (red) and Nkx2.2 (green) cells. Scale bar, 100 m. Error bars represent 95% confidence intervals from four technical replicates.

To further refine the markers for OPC specification, we measured Nkx2.2 expression in addition to Olig2 and quantified the proportion of cells coexpressing both OPC markers. Most notably, a significant decrease in %Olig2 was observed in response to Notch inhibitor DAPT across all conditions tested (Fig. 3Bi). The same trend was not observed with respect to %Nkx2.2. This result could point to a role for Notch signaling in maintaining or promoting specification of Olig2+ progenitorsa hypothesis not previously examined to our knowledgeand serves as preliminary evidence to test Notch agonists such as DLL-4 in follow-up studies of OPC optimization. This effect may be mediated by an interaction with the SHH pathway (45).

A slight increase in %Olig2+ cells was detected with increasing Wnt inhibitor IWP-2 dose when no SHH inhibitor GANTT61 was present, as was a slight increase in %Nkx2.2+ cells as a function of increasing IWP-2 and GANTT61 dose, pointing to a potential interaction between these two cues in inducing Nkx2.2 expression. The highest proportion of Olig2+Nkx2.2+ cells was observed at the highest IWP-2 and GANTT61 doses and was not influenced by DAPT exposure (Fig. 3Bii). As CHIR was present between days 0 and 3 in the differentiation, it seems that the role of Wnt signaling changes during the 21-day differentiation window of hPSCs to OPCs in that initially (days 0 to 3) it promotes OPC differentiation but shifts to an inhibitory role at later stages (days 4 to 21). To examine the extent of reproducibility of these findings, we tested the effect of temporal modulation of Wnt signals in a human induced pluripotent stem cell (hiPSC) line, TCTF, and found that the general trend of activation followed by inactivation of Wnt signaling would increase the proportion of Olig2+ cells at day 21 (fig. S6).

Although the levels of key signaling cues may vary temporally within the natural developmental environment of certain target cell types, such as within the neural tube where a dynamic SHH gradient along the dorsoventral axis patterns pMN development (16, 17), the dosage of signaling cues in the media for in vitro stem cell differentiation protocols is often applied at a constant level throughout the culture period. On the basis of this discrepancy, we applied the micropillar/microwell chip to screen through numerous temporal profiles of SAG, as well as RA due to its analogous role along the rostrocaudal axis during spinal cord development, by dividing the signal window into early and late stages that were dosed independently to form constant, increasing, and decreasing dose profiles over time (Fig. 4A). To gain additional insights into OPC marker expression, we measured Tuj1 expression and calculated the proportion of Olig2+ cells that coexpressed Tuj1 to potentially identify any modulators of the balance between Olig2+ cells that proceed down a motor neuron fate (which are both Olig2+ and Tuj1+) versus an oligodendrocyte fate (Olig2+/Nkx2.2+).

(A) Timeline of early and late windows for RA and SAG exposure. (B) i. Hierarchical cluster analysis of standardized (z score) phenotypic responses to temporal changes in RA and SAG dose during OPC differentiation. ii. Representative immunocytochemistry images of each major category of endpoint population phenotype mix of Olig2 (red), Nkx2.2 (green), and Tuj1 (orange) expression. Scale bar, 100 m. iii. Olig2, Nkx2.2, and coexpression of Olig2+Nkx2.2+ and Olig2+Tuj1+ at day 15 in response to time-varying doses of SAG. Error bars represent 95% confidence intervals from four technical replicates. *P value < 0.05.

To consider all measured phenotypes simultaneously, we applied a hierarchical cluster analysis from which we were able to identify several patterns. A broad range of endpoint phenotype proportions of Olig2, Nkx2.2, and Tuj1 was found to result from varying the temporal dosing of only two signaling cues, RA and SAG, pointing to a very fine sensitivity to temporal changes in signal exposure in these populations. Four categories of the endpoint marker expression profiles were created to further interpret the cluster analysis. Categories 1 and 2 are composed of phenotypes ranking low on OPC progenitor fate (low Olig2 and/or Nkx2.2 expression), all of which shared the low dosing of RA at 0.1 M between days 2 and 21 of the differentiation, further emphasizing the strong impact of RA on OPC yield. In contrast, category 3composed of the highest Olig2 and Nkx2.2 expression as well as Olig2+Nkx2.2+ proportioncorrelated with the highest dose of early SAG but had negligible differences across doses of late SAG (Fig. 4Biii, and fig. S7). Last, category 4 points to a biphasic relationship of Nkx2.2 expression as a function of RA dosage, where a high dose of RA of 1 M in the late stage of differentiation resulted in lower Nkx2.2 expression (fig. S8) compared with a consistent RA of 0.5 M throughout the entire differentiation. It appears that Olig2 and Nkx2.2 undergo maxima under different RA dosage profiles (fig. S8), and therefore, the use of coexpressing Olig2+Nkx2.2+ cells as the main metric when optimizing OPC differentiation may be most suitable.

We sought a comprehensive, yet concise, analysis to describe individual and combinatorial effects of all 12 culture parameters (e.g., signal agonist and antagonist dosages and timings) on the results of the more than 1000 unique differentiation conditions involved in this study. To this end, we fit generalized linear models to correlate the expression and coexpression of Olig2, Nxk2.2, and Tuj1 to individual input parameters within the 12 culture parameters involved in this study, and the 132 pairwise interactions between them. First, we identified significant parameters of interest for each phenotype measured using a factorial ANOVA (fig. S9). After applying a Benjamini and Hochberg false discovery rate correction for multiple comparisons (46), we fit an ordinary least squares model of the statistically significant terms to the phenotype of interest. The parameter coefficients were analyzed as a measure of relative influence on the expression of a certain endpoint phenotype, such as Olig2+Nkx2.2+ cells, and could be interpreted as a sensitivity analysis of key parameters on the OPC specification process. The most significant parameters were then sorted by their effect magnitude (Fig. 5B).

(A) Identification of statistically significant culture parameters using a factorial ANOVA of all single and pairwise effects on Nkx2.2 expression subject to the Benjamini and Hochberg false discovery rate (B&H FDR) correction. (B) Effect magnitude of significant culture parameters for i. Nkx2.2 expression, ii. Olig2 expression, iii. and coexpression of Olig2 and Nkx2.2. (C) i. Diagram summarizing results and effect magnitude of significant culture parameters for Olig2 and Nkx2.2 coexpression within the Olig2+ population and ii. effect magnitude of significant culture parameters for Olig2 and Tuj1 coexpression within the Olig2+ population.

RA, a rostrocaudal patterning cue, was among the most impactful parameters in this study for Olig2 and Nkx2.2 expression (Fig. 5Bi and ii). In particular, a high RA dose (1 M) early in the differentiation (days 0 and 1) emerged as the most influential culture parameter in the acquisition of OPC fate (coexpression of Olig2 and Nkx2.2) (Fig. 5Bi to iii). In addition, the dose of SAG from days 4 to 10 of differentiation exerted a markedly more significant impact on OPC fate induction than from days 10 to 21 of differentiation, in line with the previous analysis (Fig. 4). IWP-2 and GANT were observed to correlate positively with coexpression of Olig2 and Nkx2.2 as well. Furthermore, this analysis identified two cases of culture parameters interacting in a synergistic manner to promote OPC differentiation. First, higher doses of RA during days 0 to 2 followed by SAG during days 4 to 10 were found to promote higher Nkx2.2 expression. In addition, longer CHIR duration (from days 0 to 4) along with higher GANT dose promoted coexpression of Nkx2.2 and Olig2.

We created a new differentiation protocol from the parameters isolated in this screen to have the most influence in specifying Olig2+Nkx2.2+ progenitors (Fig. 5Biii) and carried out the differentiation into the later stages of OPC maturation in a larger-scale format to assess the ability of this optimized protocol to create mature oligodendrocytes. The protocol was able to produce platelet-derived growth factor receptor (PDGFR)expressing cells by day 60 across multiple hPSC lines, as well as O4-expressing cells by day 75 and myelin basic protein (MBP) expressing cells and myelination ability at day 100 (fig. S10).

The OPC screening identified new conditions that affect cell differentiation, and we then sought to demonstrate the generalizability of this approach by conducting a different study. Specifically, we screened 90 unique hPSC differentiation protocols for tyrosine hydroxylase+ mDA neurons (Fig. 6). Exposure of CHIR was divided into three periods (early, middle, and late), and dosage for each period was varied independently. This screening strategy uncovered a key window of CHIR competence between days 3 and 7 (early), a negligible effect of CHIR between days 8 and 11 (middle), and an inhibitory effect of CHIR between days 12 and 25 (late) of mDA differentiation. These data further illustrate the existence of biphasic signaling activity during the differentiation process and underscore the need to improve the temporal dosing of several signaling agonists across a range of hPSC-derived CRTs.

(A) Timeline of small-molecule addition for differentiation of mDA neurons from hPSCs. (B) Montage of 90 unique differentiation timeline to test temporal profiles of CHIR dose stained for tyrosine hydroxylase (TH) and Tuj1. Scale bar, 1 mm. (C) Immunocytochemistry images of i. low, ii. medium, and ii. high proportions of TH+ (yellow) neurons (red) dependent on the temporal profile of CHIR exposure. Scale bar, 100 m.

The clinical emergence of several cell-based therapy candidates (47) is encouraging for human diseases/disorders that currently have no effective small molecule or biologic-based therapy. As research and development into CRT candidates continues to progress, cell production has emerged as a bottleneckas delivery vectors recently have in gene therapyand improved tools will be necessary to enable higher quality and yield in cell manufacturing. Although previous studies have reported ~90% hPSC differentiation efficiency into Olig2+ progenitors using 2D culture formats (19), the 2D culture format constrains the space in which cells can expand to the surface area of the culture plate that limits the overall cell yield that can be produced. The adoption of scalable 3D culture formats, which have demonstrated the ability to produce up to fivefold higher quantities of cells per culture volume, shows promise in surpassing limits of 2D cell expansion (2933) and could result in a higher overall production quantity of target cells even if differentiation efficiencies were lower than what has been reported in 2D. Therefore, the 3D screening and analysis strategy presented here is relevant for numerous emerging CRT candidates for which conversion of a stem or progenitor cell, such as a hPSCs (48), to a therapeutically relevant cell type requires searching through a large in vitro design space of doses, durations, dynamics, and combinations of signaling cues over several weeks of culture.

Notably, to emulate a ubiquitous and naturally occurring phenomenon in organismal development (16, 49), we dynamically varied key signaling cues in our screening strategy, tuning dosage over time. These analyses revealed new biological insights into the dynamic process by which cell competence to signals and fate are progressively specified (50). For example, by applying this platform to screen through several dynamic signaling levels simultaneously, we observed that the differentiation toward Nkx2.2+ progenitors is very sensitive to the dose of RA between days 0 and 1 and the dose of SAG between days 4 and 10. After these respective time windows, the effect of each respective signal in producing Nkx2.2+ progenitors is decreased, potentially pointing to a decrease in cellular competence to each of these signals over the course of OPC development. These cases of stage-specific responses to signaling cues, revealed by our screening platform, create a new dimension for future optimization of cell production.

To effectively navigate this enormous parameter space across doses, durations, dynamics, and combinations of signaling cues and resulting differentiation outcomes, we developed a robust sensitivity analysis strategy that can rank effect sizes to reveal which parameters should be the focus of optimization to modulate expression of target markers of interest (49) and, by contrast, which parameters exert minimal impact and can thus be neglected. For example, titration of RA dose will exert a significantly higher impact on differentiation efficiency than several other culture parameters combined. Furthermore, insights from this study could reduce the necessary quantity of SHH agonist by more than 50% to achieve similar levels of OPC differentiation. As these cell production processes translate from bench scale to industrial scale, awareness of key parameters that influence critical quality attributes (18) of the cell therapy product (such as expression of specific cellular markers) will be a necessary step in reliably producing these therapeutic cell types at scale for the clinic (51).

The wealth of combinatorial and temporal signaling patterns identified in this study can be analyzed in the context of CNS development as well. We observed a potential case of biphasic activity for the Wnt signaling pathway as both activation and inhibition appeared to increase expression of OPC markers Nkx2.2 and Olig2. In particular, this effect was seen with initial Wnt activation by CHIR during days 0 to 3 of OPC differentiation followed by inhibition by IWP-2 during days 4 to 21 of OPC differentiation. The Wnt pathway has shown stage-specific activity in cardiac and hematopoietic development (43, 44), which may thus be a conserved feature across several developmental systems. Wnt signals play an important role in the gastrulation of the embryo to form the primitive streak (38), yet in the subsequent stages of spinal cord development, Wnt signals induce a dorsalizing effect (52), whereas oligodendrocytes originate from the motor neuron domain on the ventral side. Therefore, suppressing endogenous Wnt signals in vitro after initial activation of Wnt may better recapitulate the natural developmental signaling environment of developing oligodendrocytes. Alternatively, as Wnt signals also play a role in rostrocaudal patterning of the CNS, these insights may further point toward a rostrocaudal region of the CNS during this developmental window that is optimal to recapitulate in vitro for OPC production. The oligodendrocytes created through this protocol, which expressed OTX2 at day 10 (fig. S2C), may resemble OPCs in the midbrain/hindbrain region. It is conceivable that exposure to the Wnt antagonist, IWP-2, induced a position rostral to the spinal cord during the differentiation window. This biphasic Wnt trend was seen again in our analysis of differentiation of mDA neurons, underscoring that stage-specific responses may be a conserved feature across several differentiation processes aiming to recapitulate a precise cellular position across several axes of patterning signals during natural development.

Furthermore, the statistical model identified an interaction between RA and SAG (an SHH agonist) in the early differentiation windows for specifying Nkx2.2+ progenitors (Fig. 5B), which has not been previously reported to our knowledge. In the developing CNS, RA signaling influences rostrocaudal positional identity, whereas SHH signaling specifies dorsoventral positional identity. Therefore, this statistical interaction found in the screen may represent intracellular cross-talk between the RA and SHH signaling pathways to integrate both patterning dimensions into Nkx2.2+ progenitor identity. This finding builds on what is known about RA and SHH signals for Olig2+ progenitor development in the spinal cord (53, 54).

Additionally, the 3D context of this screening platform enables high-throughput investigation into neurodevelopmental model systems that can offer unique perspectives beyond what is capable in 2D screening platforms, for example, by recapitulating cell-to-cell interactions, cytoskeletal arrangement, and multicellular patterning in 3D. The lumen structures that were observed during the neural induction period (fig. S2B and movie S1) in response to caudalizing conditions (high Wnt and RA) could be the basis of future organoid screening strategies to probe early multicellular arrangement and the effect of lumen size and shape on cell fate determination at various positions along the rostrocaudal and dorsoventral axes.

In conclusion, we demonstrate the versatile capabilities of a unique microculture platform for 3D differentiation screening and optimization of hPSC-derived cell therapies, whereby 1200 unique OPC differentiation timelines, and a total of over 4800 independent samples, were investigated using 0.2% of the reagent volumes required in a standard 96-well plate format. The dense dataset enabled subsequent statistical modeling for empirical optimization of the differentiation process and identified differential sensitivities to various culture parameters across time. These insights are important in developing strong process knowledge for manufacturing stem cell therapeutics as they continue to emerge in the clinic, and therefore, such screening strategies may accelerate the pace of discovery and development. Simultaneously, this combinatorial 3D hPSC differentiation screens may provide new insights on the basic biology of human development.

Human embryonic stem cells (H9s: National Institutes of Health Stem Cell Registry no. 0062) and hiPSCs (TCTFs: 8FLVY6C2, a gift from S. Li) were subcultured in monolayer format on a layer of 1% Matrigel and maintained in Essential 8 medium during expansion. At 80% confluency, H9s were passaged using Versene solution and replated at a 1:8 split.

H9s were dissociated into single cells using Accutase solution and resuspended in Essential 8 medium containing 10 M Y-27632 (ROCK Inhibitor). H9s were counted and resuspended at defined densities in 50% Matrigel solution on ice. While chilled, 100 nl of H9s in 50% Matrigel solution was deposited onto the micropillars at a density of 100 cells per pillar, unless otherwise noted, using a custom robotic liquid handling program and then incubated at 37C for 20 min to promote gelation of 3D cultures. The micropillar chip was then inverted and placed into a fresh microwell chip containing cell culture media (table S1). All liquid dispensing into the microculture platform was performed with a DIGILAB OmniGrid Micro liquid handler with customized programs for deposition patterns. Between days 2 and 0, cells were kept in E8 media supplemented with 10 M ROCK Inhibitor. Between days 0 and 10, cells were kept in differentiation media made of a base of 50% Dulbeccos Modified Eagles MediumF12, 50% Neurobasal, 0.5% penicillin/streptomycin (pen/strep), 1:100 GlutaMAX supplement, 1:50 B27 supplement, and 1:50 N2 supplement. Between days 10 and 21, cells were kept in differentiation media made of a base of 100% Neurobasal, 0.5% pen/strep, 1:100 GlutaMAX supplement, 1:50 B27 supplement, and 1:50 N2 supplement. After day 21, OPCs were transitioned to maturation media consisting of 100% Neurobasal, 0.5% pen/strep, 1:100 GlutaMAX supplement, 1:50 B27 supplement, 1:50 N2 supplement, insulin-like growth factor 1 (10 ng/ml), platelet-derived growth factor (PDGF)AA (10 ng/ml), NT-3 (10 ng/ml), and insulin (25 g/ml). Media were changed daily by transferring the micropillar chip into a microwell chip containing fresh media every other day using a custom-made mechanical Chip Swapper for consistent transfer. Technical replicates included two different dispensing patterns to average out positional effects across the microchip.

At the endpoint of the experiment, the micropillar chip was carefully removed from the microwell chip and placed in new microwell chip containing calcein AM, ethidium homodimer, and Hoechst diluted in sterile phosphate-buffered saline (PBS) (dilution details in table S1). The micropillar chip was incubated for 20 min and then transferred to a new microwell chip containing PBS, and individual microenvironments were imaged using fluorescence microscopy.

At the endpoint of the experiment, the micropillar chip was carefully removed from the wellchip and placed into a bath of 4% paraformaldehyde for 15 min to fix cell cultures. Then, the micropillar chip was washed twice in PBS for 5 min each and placed into a bath of 0.25% Triton X-100 + 5% donkey serum in PBS for 10 min to permeabilize cells. After permeabilization, the micropillar chip was washed five times in 5% donkey serum for 5 min each, transferred to a wellchip containing primary antibodies of interest diluted in PBS + donkey serum (dilution details in table S1), and stored overnight at 4C. After primary staining, the micropillar chip was washed twice in PBS for 5 min each, placed into a microwell chip containing the corresponding secondary antibodies (dilution details in table S1), and incubated at 37C for 2 hours. After secondary staining, the micropillar chip was washed twice in PBS for 5 min each and placed into a wellchip containing PBS; individual microenvironments were imaged using fluorescence confocal microscopy.

Stained micropillar chips were sealed with a polypropylene film (GeneMate T-2452-1) and imaged with a 20 objective using a Perkin Elmer Opera Phenix automated confocal fluorescence microscope available in the High-Throughput Screening Facility at University of California, Berkeley. Laser exposure time and power were kept constant for a fluorescence channel within an imaging set. Images were scored for marker expression depending on nuclear or cytoplasmic localization (fig. S3).

Fixed cultures on micropillars at day 15 were stained with 4,6-diamidino-2-phenylindole (DAPI) and imaged using an upright Olympus BX51WI microscope (Olympus Corporation) equipped with swept field confocal technology (Bruker) and a Ti:sapphire two-photon Chameleon Ultra II laser (Coherent) was used. The two-photon laser was set to 405 nm, and images were captured using an electron multiplying charge-coupled device camera (Photometrics). Prairie View Software (v. 5.3 U3, Bruker) was used to acquire images, and ImageJ software was used to create a video of the z-series.

Quantified image data were then imported into Python for statistical data analysis (55) and visualization. For comparisons between datasets acquired across different experimental sessions, raw data were scaled and centered by z score, and descriptive statistics were calculated from four technical replicates. Error bars represent 95% confidence intervals, unless otherwise specified. For the hierarchical cluster model, the Euclidean distance was used to measure pairwise distance between each observation, and the unweighted pair group method with arithmetic mean (UPGMA) algorithm was used to calculate the linkage pattern. A Benjamini and Hochberg false discovery rate correction was applied as needed to correct for multiple comparisons. Code is available upon request.

Acknowledgments: We thank M. West of the High-Throughput Screening Facility (HTSF) at UC Berkeley and E. Granlund of the College of Chemistry machine shop for machining custom parts. In addition, we are grateful to G. Rodrigues, M. Adil, and J. Zimmermann for participating in the discussions on the work. Funding: This research was supported by the California Institute for Regenerative Medicine (DISC-08982) and the NIH (R01-ES020903) and Instrumentation Grant (S10OD021828) that provided the Perkin Elmer Opera Phenix microscope. R.M. was supported in part by an NSF Graduate Research Fellowship. Author contributions: R.M., D.S.C., and D.V.S. conceived various parts of the project and supervised the study. R.M. designed the experiments and managed the project workflows. X.B. created Nkx2.2-Cre H9 reporter lines. R.M., E.T., and E.C. performed the experiments. R.M. conducted statistical modeling, and A.M. aided in statistical testing. R.M., D.S.C., and D.V.S. analyzed and interpreted the data. R.M. wrote the manuscript with revisions from J.S.D., D.S.C., and D.V.S. Competing interests: R.M., D.S.C., and D.V.S. are inventors on a U.S. patent pending related to this work filed by the University of California, Berkeley (PCT/US2020/029553, filed on 23 April 2020). D.V.S. is the inventor on two U.S. patent pendings related to this work filed by the University of California, Berkeley (PCT/US2016/055362, filed on 4 October 2016; no. PCT/US2016/055361, filed on 5 October 2015). All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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High-throughput 3D screening for differentiation of hPSC-derived cell therapy candidates - Science Advances

By David Bautz, PhD

NASDAQ:BCLI

READ THE FULL BCLI RESEARCH REPORT

Business Update

KOL Event for Alzheimers Program

On July 8, 2020, BrainStorm Cell Therapeutics, Inc. (NASDAQ:BCLI) conducted a Key Opinion Leader (KOL) webinar to discuss the companys upcoming Phase 2a clinical trial of NurOwn in patients with Alzheimers Disease (AD). The event included presentations by two of the lead investigators for the upcoming trial, Dr. Philip Scheltens, Professor of Cognitive Neurology and Director of the Alzheimer Centre at VU University Medical Center in Amsterdam, Netherlands, and Dr. Bruno Dubois, Professor of Neurology at the Neurological Institute of the Salptrire University Hospital in Paris, France. The presentation can be found here.

The companys Phase 2a trial (BCT-201-EU) is expected to enroll approximately 40 patients with prodromal to mild AD. It will be taking place at medical centers in France and the Netherlands. To be eligible for the trial, patients must have been diagnosed with prodromal to mild dementia at least six months prior to enrollment. In addition, patients must score between 20-30 on the Mini-Mental State Exam (MMSE) and have a Clinical Dementia Rating (CDR) global score of 0.5-1.0. The MMSE is a series of questions that are designed to assess a patients mental skills, with the maximum score being 30 points and a score of 20-24 suggesting mild dementia. The CDR is a scale used to characterize six domains of cognitive and functional performance with a score of 0.5 suggesting very mild dementia and a score of 1.0 suggesting mild dementia.

The primary objective of the trial is to assess the safety and tolerability of three intrathecal injections of NurOwn in AD patients. Following bone marrow aspiration during a 10-week run-in period, patients will be treated three times with NurOwn, with eight weeks between treatments. Follow-up visits will occur 12 and 26 weeks following the final injection of NurOwn for a total trial length of 52 weeks. The following figure gives an overview of the trial design.

Cerebrospinal fluid (CSF) and serum will be collected prior to treatment and again at Weeks 0, 8, and 16 to assess changes in various neurotropic, neurodegenerative, and inflammatory factors (e.g., VEGF, HGF, NfL, NfH, MCP-1, IL-6), markers associated with amyloid deposition (e.g., a40, a42), and markers of tau protein levels (e.g., p-tau, t-tau). Additional clinical outcome measures will be analyzed through administration of the following tests:

Clinical Dementia Rating ScaledSum of Boxes (CDR-SB)

Free and Cued Selective Reminding Test (FCSRT)

Neuropsychological Test Battery (NTB)

Delis-Kaplan Executive Function System (D-KEFS) subtests

Mini Mental State Examination(MMSE)

AmsterdamInstrumentalActivitiesofDailyLivingQuestionnaire-ShortVersion(A-IADL-Q-SV)

Alzheimers Disease

Alzheimers disease (AD) is the most common form of dementia in older adults. The disease is named after Dr. Alois Alzheimer, who identified the first case in a 50-year-old woman named Auguste Deter in 1902. Dr. Alzheimer followed her case until her death in 1906, at which point he first publicly reported on it (Alzheimer, 1907).

After Ms. Deters death, Dr. Alzheimer examined her brain and found many abnormal clumps (now known as amyloid plaques) and tangled bundles of fibers (now known as neurofibrillary tangles). Over the next five years, 11 similar cases were reported in the medical literature, with some of them already using the term Alzheimers disease (Berchtold et al., 1998).

The most common early symptom of AD is a gradually worsening ability to remember new information. This is due to neurons associated with forming new memories dying off first. As neurons in other parts of the brain die, individuals experience different symptoms, which include:

Memory loss that disrupts daily life

Inability to plan or solve problems

Difficulty completing familiar tasks

Confusion with location and time

Difficulty with visual images and spatial relationships

Problems with words in speaking or writing

Withdrawal from social activities

Changes in mood, including apathy and depression

Each person progresses through AD at a different rate, and little is known about how or why there is such a marked variation, thus predicting how it will affect someone is quite difficult. One thing that is common to everyone diagnosed with AD is that his or her cognitive and functional abilities will gradually decline. As the disease progresses symptoms can include confusion, irritability, aggression, mood swings, and long-term memory loss. In the final advanced stage of the disease, people need help with the basic activities of living (e.g., bathing, dressing, eating, and using the restroom), they lose the ability to communicate, fail to recognize loved ones, and eventually become bed bound and reliant on round-the-clock care (Frstl et al., 1999). The inability to move makes them more prone to infections, including pneumonia, which are often a contributing factor to the death of those with AD.

Competing Theories for the Cause of Alzheimers

The root cause of Alzheimers is still unknown; however, it is likely to involve a number of different factors as opposed to being due to one single cause. These factors are likely a combination of genetic, environmental, and lifestyle. There are a number of hypotheses that exist to explain the cause of the disease, with the two dominant hypotheses focused on amyloid and tau.

Amyloid hypothesis: This hypothesis proposes that extracellular beta-amyloid deposits are the fundamental cause of the disease (Hardy et al., 1991). Beta-amyloid is a fragment of the larger protein amyloid precursor protein (APP), mutations of which are known to cause FAD. Several lines of evidence support the amyloid hypothesis: 1) the location of APP is on chromosome 21, while those with Down Syndrome (trisomy 21) almost all show signs of AD by 40 years of age (Lott et al., 2005); 2) APOE4 is a major genetic risk factor for AD, and while apolipoproteins enhance the breakdown of beta-amyloid, some isoforms are less capable of performing this task than others, leading to more beta-amyloid buildup on the brain (Polvikoski et al., 1995); 3) mice that harbor a mutant form of APP develop amyloid plaques and Alzheimers-like pathology (Games et al., 1995). Lastly, amyloid plaques are readily identifiable by microscopy in the brains of AD patients (Tiraboschi et al., 2004). While the brains of many older individuals develop some plaques, the brains of AD patients show severe pathological changes specifically within the temporal neocortex (Bouras et al., 1994).

Tau hypothesis: Tau is a protein located mainly within the axonal compartment of neurons and is an important element in microtubule stabilization and neurite outgrowth. In AD, a proportion of tau protein becomes abnormally phosphorylated, dissociates from axonal microtubules, and accumulates in paired helical filaments inside the neuron (Goedert et al., 1991). When this occurs, the microtubules disintegrate causing the collapse of the neurons transport system (Igbal et al., 2005). Just as with beta-amyloid plaques, tau tangles are readily observable in the brains of those affected by AD.

In addition to amyloid and tau, inflammation has been an underappreciated and often overlooked mediator in patients with AD (Akiyama et al., 2000). A multitude of inflammatory markers are found in AD patients brains and a number of studies have shown a link between chronic inflammation and an increased risk of developing AD (Walker et al., 2017; Tao et al., 2018). Thus, a treatment such as NurOwn that can decrease inflammatory mediators could prove beneficial in AD patients.

On Track to Repot Topline Data from Phase 3 ALS Trial in 4Q20

On July 2, 2020, BrainStorm announced that all doses have been administered in the pivotal Phase 3 trial ofrecen NurOwn in patients with amyotrophic lateral sclerosis (ALS) and that it remains on track to report topline data in the fourth quarter of 2020.

The ongoing randomized, double blind, placebo controlled, multi-dose Phase 3 clinical trial is testing the ability of NurOwn to alter disease progression as measured by the ALSFRS-R (NCT03280056). Cells were extracted once from each patient prior to treatment, with all administrations of NurOwn derived from the same extraction of cells due to a cryopreservation process the company developed for long-term storage of mesenchymal stem cells (MSC). Just as with the companys prior studies, there was a 3-month run-in period prior to the first treatment with two additional NurOwn treatments occurring two and four months following the first treatment. The company is focusing the trial on faster-progressing ALS patients since those patients demonstrated superior outcomes in the Phase 2 trial of NurOwn.

BrainStorm Joins Russell 2000 and Russell 3000; Granted SME Status by EMA

On June 23, 2020, BrainStorm announced that its shares would be included in the Russell 2000 Index and the Russell 3000 Index. The annual reconstitution of the Russell indexes is done to capture the 4,000 largest U.S. stocks by market capitalization.

On June 15, 2020, BrainStorm announced that the company has been granted Small and Medium-Sized Enterprise (SME) status by the European Medicines Agency (EMA). SME status allows the company to participate in a number of financial incentives including a 90-100% reduction in the EMA fee for scientific advice, clinical study protocol design, endpoints and statistical considerations, quality inspections of facilities, and fee waivers for selective EMA pre- and post-authorization regulatory filings, including Orphan Drug and PRIME designations.

Conclusion

Were excited about the potential for NurOwn in AD and we look forward to the initiation of the Phase 2a trial later in 2020. We have recently made a few changes to our model, including the inclusion of NurOwn in AD and lowering of the discount rate from 20% to 15% for all indications. We model for the company to file for approval of NurOwn in AD in 2026 and to be granted approval in 2027. We currently estimate peak sales of over $2 billion for NurOwn in AD in both the U.S. and E.U. Using a 25% probability of approval leads to an NPV of $113 million. Combined with the NPV for NurOwn in ALS ($700 million) and MS ($41 million) along with the companys current cash position and potential cash from warrants leads to a valuation for the company of a bit less than $900 million. Dividing by the companys current fully diluted share count of 35.7 million leads to a valuation of $25 per share.

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BCLI: KOL Event Gives Overview of the use of NurOwn in Alzheimer's Disease; Raising Valuation to $25/Share - Zacks Small Cap Research

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Original post:
Research and therapy with induced pluripotent stem cells ...

NEW YORK, July 06, 2020 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB) today announced that an expanded access protocol (EAP) has been initiated in the United States for compassionate use of its allogeneic mesenchymal stem cell (MSC) product candidate remestemcel-L in the treatment of COVID-19 infected children with cardiovascular and other complications of multisystem inflammatory syndrome (MIS-C). Patients aged between two months and 17 years may receive one or two doses of remestemcel-L within five days of referral under the EAP.

The protocol was filed with the United States Food and Drug Administration (FDA) and provides physicians with access to remestemcel-L for an intermediate-size patient population1 under Mesoblasts existing Investigational New Drug (IND) application. According to the FDA, expanded access is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.

MIS-C is a life-threatening complication of COVID-19 in otherwise healthy children and adolescents that includes massive simultaneous inflammation of multiple critical organs and their vasculature. In approximately 50% of cases this inflammation is associated with significant cardiovascular complications that directly involve heart muscle and may result in decreased cardiac function. In addition, the virus can result in dilation of coronary arteries with unknown future consequences. Recent articles from Europe and the United States have described this disease in detail.2-5

Mesoblast Chief Medical Officer Dr Fred Grossman said: The extensive body of safety and efficacy data generated to date using remestemcel-L in children with graft versus host disease suggest that our cellular therapy could provide a clinically important therapeutic benefit in MIS-C patients, especially if the heart is involved as a target organ for inflammation. Use of remestemcel-L in children with COVID-19 builds on and extends the potential application of this cell therapy in COVID-19 cytokine storm beyond the most severe adults with acute respiratory distress syndrome.

Remestemcel-L Remestemcel-L is an investigational therapy comprising culture-expanded mesenchymal stem cells derived from the bone marrow of an unrelated donor and is administered in a series of intravenous infusions. Remestemcel-L is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in several diseases by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues.

1.www.clinicaltrials.gov; NCT044564392.Lancet2020; May 7. DOI: https://doi.org/10.1016/S0140-6736(20)31094-13.Lancet. 2020; (May 13) https://doi.org/10.1016/S0140-6736(20)31103-X4.https://www.nejm.org/doi/full/10.1056/NEJMoa20217565.https://www.nejm.org/doi/full/10.1056/NEJMoa2021680

About MesoblastMesoblast Limited (Nasdaq:MESO; ASX:MSB) is a world leader in developing allogeneic (off-the-shelf) cellular medicines. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of commercial products and late-stage product candidates. Mesoblast has a strong and extensive global intellectual property (IP) portfolio with protection extending through to at least 2040 in all major markets. The Companys proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblasts Biologics License Application to seek approval of its product candidate RYONCIL (remestemcel-L) for pediatric steroid-refractory acute graft versus host disease (acute GVHD) has been accepted for priority review by the United States Food and Drug Administration (FDA), and if approved, product launch in the United States is expected in 2020. Remestemcel-L is also being developed for other inflammatory diseases in children and adults including moderate to severe acute respiratory distress syndrome. Mesoblast is completing Phase 3 trials for its product candidates for advanced heart failure and chronic low back pain. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

Forward-Looking StatementsThis announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward- looking statements include, but are not limited to, statements about: the timing, progress and results of Mesoblasts preclinical and clinical studies; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies; the timing or likelihood of regulatory filings and approvals; and the pricing and reimbursement of Mesoblasts product candidates, if approved; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

Release authorized by the Chief Executive.

For further information, please contact:

Here is the original post:
Expanded Access Protocol Initiated for Compassionate Use of Remestemcel-L in Children With Multisystem Inflammatory Syndrome Associated With COVID-19...

New York, July 1 (IANS) A team of US scientists, led by an Indian-origin researcher revealed that SARS-CoV-2 (coronavirus), the virus behind Covid-19, can infect heart cells in a lab dish.

This suggests it may be possible for heart cells in Covid-19 patients to be directly infected by the virus.

The discovery, published today in the journal Cell Reports Medicine, was made using heart muscle cells that were produced by stem cell technology.

"We not only uncovered that these stem cell-derived heart cells are susceptible to infection by a novel coronavirus, but that the virus can also quickly divide within the heart muscle cells," said study researcher Arun Sharma from the Cedars-Sinai Board of Governors Regenerative Medicine Institute in the US.

"Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection," Sharma added.Although many COVID-19 patients experience heart problems, the reasons remain unclear. Pre-existing cardiac conditions or inflammation and oxygen deprivation resulting from the infection have all been implicated.

But there has until now been only limited evidence the SARS-CoV-2 virus directly infects the individual muscle cells of the heart.The study also demonstrated human stem cell-derived heart cells infected by SARS-CoV-2 change their gene expression profile.This offers further confirmation the cells can be actively infected by the virus and activate innate cellular 'defence mechanisms' in an effort to help clear-out the virus.

"This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmia, heart failure and viral myocarditis," said study co-author Clive Svendsen.

"While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in Covid-19," Svendsen added.

Researchers also found that treatment with an ACE2 antibody was able to blunt viral replication on stem cell-derived heart cells, suggesting that the ACE2 receptor could be used by SARS-CoV-2 to enter human heart muscle cells.

"By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell," said Sharma. "This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection," he explained.

The study used human induced pluripotent stem cells (iPSCs), a type of stem cell that is created in the lab from a person's blood or skin cells. IPSCs can make any cell type found in the body, each one carrying the DNA of the individual. "This work illustrates the power of being able to study human tissue in a dish," the authors wrote.

--IANS

bu/pgh

The rest is here:
Coronavirus may infect heart cells of Covid-19 patients: Study - Sify News

Los Angeles: Researchers, including those of Indian-origin, have shown that the novel coronavirus can infect lab-grown cardiac muscle cells, indicating it may be possible for the virus to directly cause heart infection in COVID-19 patients.The study, published in the journal Cell Reports Medicine, was based on experiments conducted in lab-grown heart muscle cells which were produced from unspecialised human stem cells.We not only uncovered that these stem cell-derived heart cells are susceptible to infection by novel coronavirus, but that the virus can also quickly divide within the heart muscle cells, said study co-author Arun Sharma from the Cedars-Sinai Board of Governors Regenerative Medicine Institute in the US.Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection, Sharma said.Although many COVID-19 patients experience heart problems, the scientists said the reasons for these symptoms are not entirely clear. They said pre-existing cardiac conditions, or inflammation and oxygen deprivation that result from the infection have all been implicated.According to the scientists, there is only limited evidence available that the novel coronavirus, SARS-CoV-2, directly infects individual muscle cells of the heart. The current study showed that SARS-CoV-2 can infect heart cells derived from human stem-cells and change how the genes in these cells helped make proteins.Based on this observation, the scientists confirmed that human heart cells can be actively infected by the virus, activating innate cellular defense mechanisms in an effort to help clear out the virus. Citing the limitations of the study, they said these findings are not a perfect replicate of what is happening in the human body since the research was carried out in lab-grown heart cells. However, this knowledge may help investigators use stem cell-derived heart cells as a screening platform to identify new antiviral compounds that could alleviate viral infection of the heart, believes study co-author Clive Svendsen.This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmias, heart failure and viral myocarditis, said Svendsen, director of the Regenerative Medicine Institute.While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in COVID-19, Svendsen said. The scientists also found that treatment with an antibody protein could lock onto the human cell surface receptor ACE2 a known SARS-CoV-2 gateway into cells.According to the researchers, the antibody treatment was able to blunt viral replication on the lab-grown heart cells, suggesting that the ACE2 receptor could be used by the virus to enter human heart muscle cells. By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell, Sharma said.This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection, he added.In the study, the researchers also used human induced pluripotent stem cells, or iPSCs, which are a type of undifferentiated cells grown in the lab from a persons blood or skin cells. They said iPSCs can make any cell type found in the body, each one carrying the genetic material of the individual. According to the scientists, tissue-specific cells created in this way are used for research, and for creating and testing potential disease treatments.It is plausible that direct infection of cardiac muscle cells may contribute to COVID-related heart disease, said Eduardo Marban, executive director of the Smidt Heart Institute in the US, and study co-author. This key experimental system could be useful to understand the differences in disease processes of related coronaviral pathogens, SARS and MERS, said Vaithilingaraja Arumugaswami, another co-author of the study from the University of California Los Angeles in the US.PTI

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Coronavirus may infect heart cells of COVID-19 patients, scientists say - Kashmir Reader

New York, July 1 : A team of US scientists, led by an Indian-origin researcher revealed that SARS-CoV-2 (coronavirus), the virus behind Covid-19, can infect heart cells in a lab dish.

This suggests it may be possible for heart cells in Covid-19 patients to be directly infected by the virus.

The discovery, published today in the journal Cell Reports Medicine, was made using heart muscle cells that were produced by stem cell technology.

We not only uncovered that these stem cell-derived heart cells are susceptible to infection by a novel coronavirus, but that the virus can also quickly divide within the heart muscle cells, said study researcher Arun Sharma from the Cedars-Sinai Board of Governors Regenerative Medicine Institute in the US.

Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection, Sharma added.Although many COVID-19 patients experience heart problems, the reasons remain unclear. Pre-existing cardiac conditions or inflammation and oxygen deprivation resulting from the infection have all been implicated.

But there has until now been only limited evidence the SARS-CoV-2 virus directly infects the individual muscle cells of the heart.The study also demonstrated human stem cell-derived heart cells infected by SARS-CoV-2 change their gene expression profile.This offers further confirmation the cells can be actively infected by the virus and activate innate cellular defence mechanisms in an effort to help clear-out the virus.

This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmia, heart failure and viral myocarditis, said study co-author Clive Svendsen.

While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in Covid-19, Svendsen added.

Researchers also found that treatment with an ACE2 antibody was able to blunt viral replication on stem cell-derived heart cells, suggesting that the ACE2 receptor could be used by SARS-CoV-2 to enter human heart muscle cells.

By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell, said Sharma. This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection, he explained.

The study used human induced pluripotent stem cells (iPSCs), a type of stem cell that is created in the lab from a persons blood or skin cells. IPSCs can make any cell type found in the body, each one carrying the DNA of the individual. This work illustrates the power of being able to study human tissue in a dish, the authors wrote.

Continue reading here:
Rahul Gandhi to interact with nurses on July 1 - WeForNews

New York, July 1 : A team of US scientists, led by an Indian-origin researcher revealed that SARS-CoV-2 (coronavirus), the virus behind Covid-19, can infect heart cells in a lab dish.

This suggests it may be possible for heart cells in Covid-19 patients to be directly infected by the virus.

The discovery, published today in the journal Cell Reports Medicine, was made using heart muscle cells that were produced by stem cell technology.

We not only uncovered that these stem cell-derived heart cells are susceptible to infection by a novel coronavirus, but that the virus can also quickly divide within the heart muscle cells, said study researcher Arun Sharma from the Cedars-Sinai Board of Governors Regenerative Medicine Institute in the US.

Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection, Sharma added.Although many COVID-19 patients experience heart problems, the reasons remain unclear. Pre-existing cardiac conditions or inflammation and oxygen deprivation resulting from the infection have all been implicated.

But there has until now been only limited evidence the SARS-CoV-2 virus directly infects the individual muscle cells of the heart.The study also demonstrated human stem cell-derived heart cells infected by SARS-CoV-2 change their gene expression profile.This offers further confirmation the cells can be actively infected by the virus and activate innate cellular defence mechanisms in an effort to help clear-out the virus.

This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmia, heart failure and viral myocarditis, said study co-author Clive Svendsen.

While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in Covid-19, Svendsen added.

Researchers also found that treatment with an ACE2 antibody was able to blunt viral replication on stem cell-derived heart cells, suggesting that the ACE2 receptor could be used by SARS-CoV-2 to enter human heart muscle cells.

By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell, said Sharma. This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection, he explained.

The study used human induced pluripotent stem cells (iPSCs), a type of stem cell that is created in the lab from a persons blood or skin cells. IPSCs can make any cell type found in the body, each one carrying the DNA of the individual. This work illustrates the power of being able to study human tissue in a dish, the authors wrote.

Read the original here:
Coronavirus: WHO warns the worst is yet to come - WeForNews

Los Angeles, Jul 1 (PTI) Researchers, including those of Indian-origin, have shown that the novel coronavirus can infect lab-grown cardiac muscle cells, indicating it may be possible for the virus to directly cause heart infection in COVID-19 patients.

The study, published in the journal Cell Reports Medicine, was based on experiments conducted in lab-grown heart muscle cells which were produced from unspecialised human stem cells.

"We not only uncovered that these stem cell-derived heart cells are susceptible to infection by novel coronavirus, but that the virus can also quickly divide within the heart muscle cells," said study co-author Arun Sharma from the Cedars-Sinai Board of Governors Regenerative Medicine Institute in the US.

"Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection," Sharma said.

Although many COVID-19 patients experience heart problems, the scientists said the reasons for these symptoms are not entirely clear.

They said pre-existing cardiac conditions, or inflammation and oxygen deprivation that result from the infection have all been implicated.

According to the scientists, there is only limited evidence available that the novel coronavirus, SARS-CoV-2, directly infects individual muscle cells of the heart.

The current study showed that SARS-CoV-2 can infect heart cells derived from human stem-cells and change how the genes in these cells helped make proteins.

Based on this observation, the scientists confirmed that human heart cells can be actively infected by the virus, activating innate cellular "defense mechanisms" in an effort to help clear out the virus.

Citing the limitations of the study, they said these findings are not a perfect replicate of what is happening in the human body since the research was carried out in lab-grown heart cells.

However, this knowledge may help investigators use stem cell-derived heart cells as a screening platform to identify new antiviral compounds that could alleviate viral infection of the heart, believes study co-author Clive Svendsen.

"This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmias, heart failure and viral myocarditis," said Svendsen, director of the Regenerative Medicine Institute.

"While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in COVID-19," Svendsen said.

The scientists also found that treatment with an antibody protein could lock onto the human cell surface receptor ACE2 -- a known SARS-CoV-2 ''gateway'' into cells.

According to the researchers, the antibody treatment was able to blunt viral replication on the lab-grown heart cells, suggesting that the ACE2 receptor could be used by the virus to enter human heart muscle cells.

"By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell," Sharma said.

"This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection," he added.

In the study, the researchers also used human induced pluripotent stem cells, or iPSCs, which are a type of undifferentiated cells grown in the lab from a person''s blood or skin cells.

They said iPSCs can make any cell type found in the body, each one carrying the genetic material of the individual.

According to the scientists, tissue-specific cells created in this way are used for research, and for creating and testing potential disease treatments.

"It is plausible that direct infection of cardiac muscle cells may contribute to COVID-related heart disease," said Eduardo Marban, executive director of the Smidt Heart Institute in the US, and study co-author.

"This key experimental system could be useful to understand the differences in disease processes of related coronaviral pathogens, SARS and MERS," said Vaithilingaraja Arumugaswami, another co-author of the study from the University of California Los Angeles in the US. PTI VISVIS

Disclaimer :- This story has not been edited by Outlook staff and is auto-generated from news agency feeds. Source: PTI

See more here:
Coronavirus may infect heart cells of COVID-19 patients, scientists say - Outlook India

Cardiosphere-Derived Cells

The formation of cardiospheres from human and murine heart tissue was first described in 2004 by Messina and coworkers [16]. It was demonstrated that, when placed in adherent plates, heart explants generated a layer of fibroblast-like cells over which small, phase-bright cells migrated. These phase-bright cells were collected and transferred to nonadherent plates where they originated three-dimensional structures named cardiospheres. Cardiospheres were clonogenic and when co-cultured with rat neonatal cardiomyocytes expressed troponin I and connexin 43. Additionally, there was visual evidence that cardiospheres showed synchronous contractions with cardiomyocytes. When transplanted into infarcted hearts, these cells started to express myosin heavy chain as well as -smooth muscle actin and platelet endothelial cell adhesion molecule, which resulted in functional improvement. Curiously, when the expression of surface molecules was analyzed by flow cytometry, cardiospheres showed a 25% expression of c-kit. Thus, it is possible that c-kit+ cells contribute to the characteristics observed in cardiospheres, explaining the similar findings between these two cardiac progenitor/stem cell types.

However, it was only in 2007 that Marbns group described cardiosphere-derived cells (CDCs) [19]. They slightly changed Messinas protocol by placing cardiospheres in adherent plates where cells were grown in monolayers instead of three-dimensional structures. The advantage of this step was that cell expansion in monolayers was easier and faster, which would facilitate future clinical use. Flow cytometry showed that c-kit expression was still present in similar levels to those described by Messina and coworkers. Additionally, high expression levels of CD105 and CD90 were found, indicating a mesenchymal phenotype. When co-cultured with rat neonatal cardiomyocytes, CDCs presented spontaneous intracellular calcium transients and action potentials, as well as INa, IK1 and ICa,L currents. In vivo, injection of CDCs in acute myocardial infarctions (MI) prevented further ejection fraction deterioration 3 weeks after MI when compared to placebo and fibroblast injected mice. In 2009, Marbns group also reported functional benefit and reduction of infarct size in a porcine animal model after CDC injection [37], a preclinical model that prompted a phase I clinical trial (CADUCEUS, ClinicalTrials.gov, Identifier NCT00893360).

Nonetheless, the usage of cardiospheres as a source of cardiac stem cells has been refuted. Andersen and coworkers showed that even though cardiospheres can be produced from heart specimens, they do not hold cardiomyogenic potential and simply represent aggregated fibroblasts [38]. This group also found cells that expressed cardiac contractile proteins, such as myosin heavy chain and troponin T, in cardiospheres. However, the findings were attributed to the presence of contaminating heart tissue fragments in the explant-derived cell suspension. By adding a filtration step in which explant-derived cells were passed through cell strainers prior to cardiosphere formation, the presence of cells expressing cardiac contractile proteins was eliminated. In addition, this group showed that phase-bright cells were of hematopoietic origin and did not organize into spheric structures, a characteristic attributed to the fibroblast-like cells.

In response to Andersens findings, Marbns group published a revalidation of the CDC isolation method [39]. Using a strategy identical to the one described by Hsieh and colleagues [8], cardiomyocytes were irreversibly labeled with GFP after a tamoxifen pulse (see Fig. 8.1). Isolation of CDCs from these transgenic mouse hearts did not reveal the presence of GFP+ cells, refuting the possibility that cardiac differentiation of CDCs was due to the presence of contaminating myocardial tissue fragments. Additionally, they reported that cardiospheres were consistently negative for CD45, indicating that CDCs do not contain cells of hematopoietic origin. The authors also emphasized that Andersen and coworkers used different isolation protocols, which could justify the discrepancies found in results.

Even though they demonstrated that CDCs expressed myosin heavy chain after transplantation into myocardial infarctions in mice [17], indicating that cardiomyogenic differentiation was possible in vivo, an additional mechanism was proposed to explain the improvement in cardiac function. Chimenti and colleagues studied the relative roles of direct regeneration versus paracrine effects promoted by human CDCs in a mouse infarction model [40]. The paracrine hypothesis has been used frequently to explain the beneficial effects observed with several types of adult stem cells or bone marrowderived cells used in cell therapy experiments. According to this hypothesis, stem cells could act secreting signaling molecules, which may influence cardiomyocyte survival and angiogenesis and could also recruit endogenous cardiac stem cells. Chimenti and coworkers demonstrated that CDCs secrete high levels of insulin growth factor-1 (IGF-1), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). Moreover, using in vivo bioluminescence assays, the authors showed that no cells could be found in the heart 1 week after injection, even though functional improvement persisted until 3 weeks post-MI. Therefore, it seems that cell persistence is not important for functional improvement, strengthening the paracrine hypothesis. To address this issue, the authors quantified capillary density and viable myocardium analyzing the contributions of human (injected) and mouse (endogenous) cells to each of these variables 1-week post-MI [40]. They found that, for both variables, the contribution of endogenous cells was more prominent than that of injected cells. Hence, the release of factors seems to be more important than direct regeneration in the improvement of cardiac function after cell therapy with CDCs.

Recently, results of a phase I clinical trial using CDCs were published [41]. The safety of autologous intracoronary delivery of CDCs to patients 1.5 to 3 months after MI was evaluated. Cells were obtained from endomyocardial biopsies and cultured according to the protocols previously established by Eduardo Marbns group. Patients with a recent MI (less than 4 weeks) and left ventricular ejection fraction ranging from 25% to 45% were eligible for inclusion. Twelve months after cell therapy, patients treated with CDCs had a 12.3% decrease in scar size, whereas the control group had a 2.2% reduction, as measured by late enhancement after gadolinium MRI. However, no differences were detected in ejection fraction between cell-treated and control groups. It is important to note that this was a safety study; therefore, phase II double-blinded placebo-controlled clinical trials still need to be performed to access efficacy of therapy with CDCs in humans. Additionally, a more thorough cell biologic characterization of CDCs is required to understand provenience, molecular identity, and mechanism of action of these cells as potential cardioprotective agents.

Link:
Cardiac Stem Cell - an overview | ScienceDirect Topics

Febrero 2013

James T. Willerson, MD

James T. Willerson, MD,Texas Heart Institute

Heart and vascular disease (or cardiovascular disease, CVD) are the leading causes of death and disability in the world, despite a large proportion of it being preventable.

In the US alone, 82.6 million Americans have some form of CVD. Someone dies from CVD every 33 seconds. More than 40,000 children are born each year with a congenital heart defect.

One of the most promising new avenues for CVD treatment is the use of adult stem cells, to help heal and regenerate damaged hearts.

How can stem cells help the heart?

Stem cells are actually part of our natural circulating rescue system. They travel out of the bone marrow and patrol the circulation system looking for areas of injury to repair. We also have resident stem cells in every organ of the body.

Our first-in-the-world stem cell research at the the Stem Cell Center of the Texas Heart Institute, and subsequent clinical trials in humans, have shown that a patient's own stem cells, harvested from their bone marrow, can help generate new heart muscle tissues and blood vessels in hearts damaged by heart attacks or severe heart failure.

Advances in Stem Cells

After years of study, we have found that when people reach their early 60s, and they begin to have health issues with their bodies, their stem cells also lose their restorative powers. Subsequent research has shown, however, that certain specific cells can be taken from the body fat or bone marrow of healthy young individuals and may be used therapeutically in older patients without adverse immunological reaction. Clinical trials are ongoing and we are constantly learning more about this.

As a result of this work, the National Heart Lung and Blood Institute has established a nationwide consortium of leading medical and research institutions, the Cardiovascular Cell Therapy Research Network (CCTRN), to carry cardiac cell therapy research forward. We are very optimistic about the future of this type of stem cell therapy.

Building New Organs and Reversing Disease

Another area of great promise is the emerging field of regenerative medicine. Dr. Doris Taylor recently joined the Texas Heart Institute as Director of Regenerative Medicine Research. Through her pioneering work, we now have the capability to deplete animal and human hearts of all of their cellular structure and regenerate the "decellularized" scaffolds into healthy organs by the infusion of stem cells. These methods also work on other organs in the body. Many believe that these "bioartificial" organs are the early steps toward our ability to grow new organs for people using their own adult stem cells. We are optimistic that the technology will allow us to begin safe clinical trials in humans within only a few years.

In sum, many advances in stem cells, genetics, and regenerative medicine hold great promise and these fields are advancing rapidly. The next decade or more will undoubtedly be a golden age for progress. We are determined to push the field forward until heart and vascular disease are a thing of the past and our children have a more heart-healthy future ahead of them.

James T. Willerson, MD, is a living legend in cardiovascular medicine. He is the President and Medical Director of the Texas Heart Institute, and the immediate past President of the University of Texas Health Science Center in Houston. Dr. Willerson is a native Texan; he attend UT Austin, Baylor College of Medicine, Harvard Medical School, and trained at Massachusetts General Hospital in Boston. Dr. Willerson has received numerous honors and awards, including the Gold Heart Award, the highest award from the American Heart Association. He has been elected a Fellow in the Royal Society of Medicine of the UK, and made an Honorary Member of the Societies of Cardiology in Peru, Spain, Greece, Venezuela, and Chile. Dr. Willerson is currently President of the International Academy of Cardiovascular Sciences. There is also a swimming scholarship named for him at UT Austin.

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Stem Cells for Cardiac Patients

Regenerative Medicine Market: Snapshot

Regenerative medicine is a part of translational research in the fields of molecular biology and tissue engineering. This type of medicine involves replacing and regenerating human cells, organs, and tissues with the help of specific processes. Doing this may involve a partial or complete reengineering of human cells so that they start to function normally.

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Regenerative medicine also involves the attempts to grow tissues and organs in a laboratory environment, wherein they can be put in a body that cannot heal a particular part. Such implants are mainly preferred to be derived from the patients own tissues and cells, particularly stem cells. Looking at the promising nature of stem cells to heal and regenerative various parts of the body, this field is certainly expected to see a bright future. Doing this can help avoid opting for organ donation, thus saving costs. Some healthcare centers might showcase a shortage of organ donations, and this is where tissues regenerated using patients own cells are highly helpful.

There are several source materials from which regeneration can be facilitated. Extracellular matrix materials are commonly used source substances all over the globe. They are mainly used for reconstructive surgery, chronic wound healing, and orthopedic surgeries. In recent times, these materials have also been used in heart surgeries, specifically aimed at repairing damaged portions.

Cells derived from the umbilical cord also have the potential to be used as source material for bringing about regeneration in a patient. A vast research has also been conducted in this context. Treatment of diabetes, organ failure, and other chronic diseases is highly possible by using cord blood cells. Apart from these cells, Whartons jelly and cord lining have also been shortlisted as possible sources for mesenchymal stem cells. Extensive research has conducted to study how these cells can be used to treat lung diseases, lung injury, leukemia, liver diseases, diabetes, and immunity-based disorders, among others.

Global Regenerative Medicine Market: Overview

The global market for regenerative medicine market is expected to grow at a significant pace throughout the forecast period. The rising preference of patients for personalized medicines and the advancements in technology are estimated to accelerate the growth of the global regenerative medicine market in the next few years. As a result, this market is likely to witness a healthy growth and attract a large number of players in the next few years. The development of novel regenerative medicine is estimated to benefit the key players and supplement the markets growth in the near future.

Global Regenerative Medicine Market: Key Trends

The rising prevalence of chronic diseases and the rising focus on cell therapy products are the key factors that are estimated to fuel the growth of the global regenerative medicine market in the next few years. In addition, the increasing funding by government bodies and development of new and innovative products are anticipated to supplement the growth of the overall market in the next few years.

On the flip side, the ethical challenges in the stem cell research are likely to restrict the growth of the global regenerative medicine market throughout the forecast period. In addition, the stringent regulatory rules and regulations are predicted to impact the approvals of new products, thus hampering the growth of the overall market in the near future.

Global Regenerative Medicine Market: Market Potential

The growing demand for organ transplantation across the globe is anticipated to boost the demand for regenerative medicines in the next few years. In addition, the rapid growth in the geriatric population and the significant rise in the global healthcare expenditure is predicted to encourage the growth of the market. The presence of a strong pipeline is likely to contribute towards the markets growth in the near future.

Global Regenerative Medicine Market: Regional Outlook

In the past few years, North America led the global regenerative medicine market and is likely to remain in the topmost position throughout the forecast period. This region is expected to account for a massive share of the global market, owing to the rising prevalence of cancer, cardiac diseases, and autoimmunity. In addition, the rising demand for regenerative medicines from the U.S. and the rising government funding are some of the other key aspects that are likely to fuel the growth of the North America market in the near future.

Furthermore, Asia Pacific is expected to register a substantial growth rate in the next few years. The high growth of this region can be attributed to the availability of funding for research and the development of research centers. In addition, the increasing contribution from India, China, and Japan is likely to supplement the growth of the market in the near future.

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Global Regenerative Medicine Market: Competitive Analysis

The global market for regenerative medicines is extremely fragmented and competitive in nature, thanks to the presence of a large number of players operating in it. In order to gain a competitive edge in the global market, the key players in the market are focusing on technological developments and research and development activities. In addition, the rising number of mergers and acquisitions and collaborations is likely to benefit the prominent players in the market and encourage the overall growth in the next few years.

Some of the key players operating in the regenerative medicine market across the globe areVericel Corporation, Japan Tissue Engineering Co., Ltd., Stryker Corporation, Acelity L.P. Inc. (KCI Licensing), Organogenesis Inc., Medtronic PLC, Cook Biotech Incorporated, Osiris Therapeutics, Inc., Integra Lifesciences Corporation, and Nuvasive, Inc.A large number of players are anticipated to enter the global market throughout the forecast period.

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Regenerative Medicine Market Analysis Growth Demand, Key Players, Share Size, and Forecast To 2025 - 3rd Watch News

On February 67, 2020, the Simons Foundation Autism Research Initiative (SFARI) convened a two-day workshop to explore the possibility of gene therapies for autism spectrum disorder (ASD), a neurodevelopmental condition associated with changes in over 100 genes. Inspired by the recent, stunning successes of gene therapy for the fatal neuromuscular disorder spinal muscular atrophy (SMA)1, and by the accumulation of genes confidently associated with ASD2, SFARI welcomed a diverse collection of researchers to begin to think about whether a similar approach could be taken for ASD. Because gene therapy attempts to fix what is broken at the level of a causative gene, it would offer a more direct and imminent strategy than mitigation of the many and as yet mostly unclear downstream effects of a damaged gene.

The workshop was organized in 20 talks and several discussion panels, which tackled many outstanding issues, including how to choose candidate target genes and predict outcomes; how to optimize vectors for gene delivery; how to decide when to intervene; which animal models to develop; how to find appropriate endpoints for clinical trials and understand the available regulatory pathways. SFARI also raised the question of how its funding might best propel gene therapy efforts amid the emerging, complex ecosystem of academic laboratories, biotech companies, and pharmaceutical industries.

Even the opportunity to have this discussion is very rewarding, said SFARI Investigator Matthew State of the University of California, San Francisco (UCSF), one of the investigators who directed teams of geneticists to analyze the Simons Simplex Collection (SSC).

These efforts have offered up multiple potentially feasible therapeutic targets. Though rare, de novo disruptive mutations in the highest confidence ASD genes often result in severe impairment characterized not only by social difficulties, but also by intellectual disability and seizures. The combination of a single gene mutation of large effect coupled with particularly severe outcomes that include ASD are likely to offer the most immediate targets for gene therapy. For now, this leaves out a large number of individuals with autism for whom genetic causes are not yet known and are likely the result of a combination of many small effect alleles across a large number of genes.

Highlights from talks and discussion panel, chaired by Rick Lifton of Rockefeller University

In the first talk of the workshop, State brought the group up to speed on ASD genomics. The most recent tally from exome-sequencing in simplex cases of ASD highlighted 102 genes in which rare mutations confer individually large risks2. In contrast, the task of identifying common variants carrying very small risks remains quite challenging, with less than a half dozen alleles so far identified with confidence3. The rare, disruptive mutations that result in loss of function of one gene copy are an attractive focus for gene therapy because of the tractability of targeting a single spot in the genome per individual and because, in the vast majority of cases, there remains a single unchanged allele. This points to ways to boost gene and/or protein expression back toward the normal state by leveraging the unaffected copy. But both the limited number of cases known so far combined with the possibility that different mutations to the same gene may have different effects complicate thinking about how to prioritize targets for gene therapy.

State made several points that were continually touched on throughout the workshop. Many ASD genes are highly expressed during midfetal development in the cortex, and additional experiments will need to determine whether and how long a window of opportunity may be present for successful gene therapy postnatally. Given the relatively small number of people with these conditions, new clinical trial designs are needed that dont rely on comparisons between large control and intervention groups (see also Bryan Kings talk below).

Beyond the gene-crippling mutations found in the exome, disruptions to transcription may also dramatically raise risk for autism and may be corrected with a type of gene therapy using ASOs. SFARI Investigator Stephan Sanders of UCSF focused on the role of splicing, the process by which an initial transcript is turned into messenger RNA by removal of introns and joining together of exons. Splicing is disrupted in at least 1.5 percent of individuals with ASD4, and possibly many more, as suggested by transcript irregularities found in postmortem autism brain5. Sanders described Illuminas Splice AI project in which machine-learning helps predict noncoding variants that can alter splicing, including those beyond typical splice sites found near a gene6. As a result of incorporating sequence information around and between splice sites, this computational tool detected more mutations with predicted splice-altering consequences in people with ASD and intellectual disability than in those without the condition.

An ASO designed to bind specific portions of RNA could conceivably correct errors in transcription. ASOs have already been approved for use in other disorders in order to skip exons, retain exons or to degrade mRNA. Unlike other forms of gene therapy, ASOs do not permanently alter the genome, making it a kind of gene therapy lite. This reversibility has both disadvantages (having to re-infuse the ASO every few months) and advantages (multiple opportunities to optimize the dose and target; serious adverse effects are not permanent).

Jonathan Weissman of UCSF discussed the available toolbox for controlling gene expression developed by many different laboratories. To turn genes on or off, he has developed a method to combine CRISPR with an enzymatically inactive (dead) Cas9, which can then be coupled with a transcriptional activator (CRISPRa) or repressor (CRISPRi)7 (Figure 2). In the case of loss-of-function mutations, Weissman outlined strategies to make the remaining good allele work harder: increase transcription via CRISPRa, decrease mRNA turnover, increase translation of a good transcript via modification of upstream open reading frames (uORFs) or increase a proteins stability, possibly through small molecules acting on the ubiquitin system8. That said, the effects on a cell may be complicated. Using Perturb-Seq screens, Weissman described genetic interaction manifolds that show nonlinear mapping between genotype and single cell transcriptional phenotypes9. Additionally, Weissman summarized recent work from his laboratory that has identified large numbers of uORFs that result in polypeptides, some of which affect cellular function.

SFARI Investigator Michael Wigler of Cold Spring Harbor Laboratories echoed the idea of a gene-therapy strategy that increases expression of the remaining good copy of a gene, especially given that in his estimate, 45 percent of simplex cases of autism carried a de novo, likely disrupting variant. He also called attention to the uterine environment, especially the challenge posed by expression of paternally derived antigens in the fetus and the impact of a potential maternal immune response, and the need to understand how it interacts with de novo genetic events.

Highlights from talks and discussion panel, chaired by Arnon Rosenthal of Alector

The discussion turned to finding ways of getting genes into the central nervous system. The AAV is the darling of gene therapy, given that it does not replicate and is not known to cause disease in humans. A version that can cross the blood-brain barrier (AAV9) was used to deliver a gene replacement to children with SMA intravenously; though this effectively delivered the genetic cargo to ailing motor neurons in the spinal cord, it does not work that well at delivering genes throughout the brain.

Ben Deverman of the Stanley Center at the Broad Institute of MIT and Harvard detailed his efforts to optimize AAV for efficient transduction of brain cells through a targeted evolution process: his team engineers millions of variants in the capsid of the virus, then screens them for entry into the nervous system and transduction of neurons and glia. This has yielded versions (called AAV-PHP.B and AAV-PHP.eB) that more efficiently enter the brain10,11. One successfully delivered the MECP2 gene to the brain of a Rett syndrome mouse model, resulting in ameliorated symptoms and an extended lifespan12. Unfortunately, these viruses dont work in human cells or in all mouse strains. A quick mouse genome-wide association study (GWAS) revealed that the Ly6a gene mediates efficient blood-brain barrier crossing of AAV-PHP.B and AAV-PHP.eB13. Now his group has identified Ly6a-independent capsids that may translate better to humans. He also noted that the PHP.B vectors have tissue specificity for brain and liver.

With an estimated 87 percent of autism-associated genes raising risk through haploinsufficiency (having only one functional gene copy out of the two), SFARI Investigator Nadav Ahituv of UCSF made the case for approaches that boost expression of the remaining good copy of a gene through endogenous mechanisms a strategy he called cis-regulation therapy. This method also provides a way to work around the small four kb payload of AAV, which strains to contain cDNA of many autism genes. A recent study by his group used CRISPRa targeted at an enhancer or promoter of SIM1 and promoter of MC4R, both obesity genes, in mice. Using one AAV vector for a dCas9 joined to a transcription activator, and another AAV vector having a guide RNA targeting either a promoter or an enhancer, and a guide RNA targeting a promoter, the researchers injected the vectors together into the hypothalamus, which resulted in increased SIM1 or MC4R transcription and reversed the obesity phenotype brought on by loss of these genes14. Targeting regulatory elements had the added benefit of tissue specificity, and there seemed to be a ceiling effect for SIM1 expression, which suggested an endogenous safeguard against overexpression at work. He is now collaborating with SFARI Investigator Kevin Bender, also at UCSF, to apply this approach to the autism gene SCN2A.

Botond Roska of the Institute of Molecular and Clinical Ophthalmology in Basel, Switzerland pointed out that getting genes to the cells where they are needed is crucial when treating eye diseases. Off-target effects there can induce degeneration of healthy cells. For this reason, Roska and his group have created AAVs that target specific cell types in the retina by developing synthetic promoters that efficiently promote expression of the viruss cargo15. The promoters they designed were educated guesses based on four approaches: likely regulatory elements close to genes expressed with cell-type specificity in the retina, conserved elements close to cell typespecific genes, binding sites for cell typespecific transcription factors and open chromatin close to cell typespecific genes. Screening a library of these in mouse, macaque and human retina revealed some with high cell-type specificity (Figure 3). Importantly, macaque data predicted success in human retina much better than did mouse data. In preliminary experiments, and more relevant to gene therapy for ASD, these cell-specific vectors also had some success in mouse cortex, for example lighting up parvalbumin neurons or an apparently new type of astrocyte.

Roska also described new methods for delivery, in which nanoparticles are coated with AAV, then drawn into the brain using magnets16. This magnetophoresis technique allows a library of experimental AAVs to be tested at the same time in one monkey. Steering nanoparticles with magnets gives more control of vector placement and gene delivery. He argued that these in the future could access even deep structures of the brain.

Highlights from talks and discussion panel, chaired by Steven Hyman of the Broad Institute at MIT and Harvard

Kathy High of Spark Therapeutics reviewed the story of gene therapy for spinal muscular atrophy (SMA) type 1. Though she was not directly involved in that research, she is well aware of the regulatory atmosphere surrounding gene therapy, given that Spark Therapeutics developed the first approved AAV-delivered gene for a form of retinal dystrophy. The SMA story is a useful case study in that an ASO-based therapy (nusinersen, marketed as Spinraza), approved in 2016, set the stage for a gene-replacement therapy, marketed as Zolgensma (onasemnogene abeparvovec). Ultimately, the amount of data supporting Zolgensmas approval was modest: a Phase one dose study of 15 infants1, and an ongoing Phase three trial of 21 infants and safety data from 44 individuals. Yet the approval was helped by the dramatic results and clear endpoints: those receiving a single intravenous infusion of an AAV9 vector containing a replacement gene all remained alive at 20 months of age, whereas only 8 percent survived to that age in the natural history data, which compiles the diseases untreated course. High mentioned that maintaining product quality for gene therapeutics may prove trickier than for typical medications.

The attractive, highly customizable nature of gene therapy might have a regulatory downside in that different vector payloads, even when designed to do the same thing, could invite separate approval processes. Though not knowing how regulatory agencies would view this, High said that their perspectives are bound to evolve as more gene therapy trials are completed.

Getting to ASD-related syndromes, Bender talked about SCN2A, which encodes the sodium channel Nav1.2. SCN2A mutations in humans can be gain of function or loss of function; gain-of-function mutations are associated with early onset epilepsy, and loss-of-function mutations with intellectual disability and ASD. In a mouse model missing one copy of SCN2A, Bender and his group have discovered a role for SCN2A in action potential generation in the first week after birth, and in synaptic function and maturation afterward through regulation of dendritic excitability18 (Figure 4). Using AAV containing CRISPRa constructs developed with the Ahituv lab, the researchers successfully increased SCN2A expression, and recovered synapse function and maturity, even when done several weeks postnatally. Getting the appropriate dosage is critical since gain-of-function mutations are linked to epilepsy. However, Bender reported even when SCN2A expression increased to double normal levels, no hints of hyperexcitability appeared. We might be able to overdrive this channel as much as we want and actually may not have risk of producing an epileptic insult, he said. Next steps are to figure out the developmental windows for intervention, evaluate changes in seizure sensitivity and extend this kind of cis-regulatory approach to other ASD genes.

Angelman syndrome is another condition that attracts interest for gene therapy, in part because neurons already harbor an appropriate replacement gene. Angelman syndrome stems from mutations to the maternally inherited UBE3A gene, which is particularly damaging to neurons because they only express the maternal allele, while the paternal allele is silenced by an antisense transcript. SFARI Investigator Mark Zylka of the University of North Carolina and colleagues showed in 2011 that this paternal allele could be unsilenced with a cancer drug in a mouse model of Angelman syndrome19. Since then, three companies have built ASOs to do the same thing, and these are going into clinical trials. To get a more permanent therapeutic, Zylka has been developing CRISPR/Cas9 systems to reactivate paternal UBE3A, and preliminary experiments show that injecting this construct into the brains of embryonic mice, and then again at birth, results in brain-wide expression of paternal UBE3A and is long-lasting (at least 17 months). Zylka is now making human versions of these constructs. He later noted rare cases of mosaicism for the Angelman syndrome mutation people with 10 percent normal cells in blood have a milder phenotype20, which suggests that even inefficient transduction of a gene vector could help.

Zylka also made a case for prenatal interventions in Angelman syndrome: studies of mouse models indicate that early reinstatement of UBE3A expression in mouse embryos rescues multiple Angelman syndrome-related phenotypes, whereas later postnatal interventions rescue fewer of these21; for humans, a diagnostic, cell-based, noninvasive prenatal test will be available soon22; ultrasound-guided injections into fetal brain of nonhuman primates have been developed23; prenatal surgeries are now standard of care for spinal bifida; and intervening prenatally decreases the risk of an immunogenic response to an AAV vector or its cargo. During the discussion, it was noted that another benefit of acting early was that less AAV would be needed to transduce a much smaller brain; however, a drawback is the lack of data on Angelman syndrome development from birth to one year of age. This natural history would be necessary for understanding whether a prenatal therapy is more effective than treatment of neonates.

SFARI Investigator Guoping Feng of the Massachusetts Institute of Technology has been investigating SHANK3, a high-confidence autism risk gene linked to a severe neurodevelopmental condition called Phelan-McDermid syndrome, which is marked by intellectual disability, speech impairments, as well as ASD. SHANK3 is a scaffold protein important for organizing post-synaptic machinery in neurons. Mouse studies by Feng have shown that SHANK3 re-expression in adult mice that have developed without it can remedy some, but not all, of their phenotypes, including dendritic spine densities, neural function in the striatum and social interaction24. Furthermore, early postnatal re-expression rescued most phenotypes. This makes SHANK3 a potential candidate for gene therapy; however, it is a very large gene 5.2kb as a cDNA that is difficult to fit into a viral vector. To get around this, Fengs group has designed a smaller SHANK3 mini-gene as a substitute for the full-sized version. Preliminary experiments show that AAV delivery of the mini-gene can rescue phenotypes like anxiety, social behavior and corticostriatal synapse function in SHANK3 knockout mice. Feng also discussed his success in editing the genome in marmosets and macaques using CRISPR/Cas9 technology and showed data from a macaque model of SHANK3 dysfunction25. These models may help test gene therapy approaches and identify biomarkers of brain development closely related to the human disorder.

For people with rare conditions brought on by even rarer mutations, individualized gene therapies can provide a pathway for treatment. SFARI Investigator Timothy Yu of Boston Childrens Hospital/Harvard described his N-of-1 study in treating a girl with Batten disease, a recessive disorder in which a child progressively loses vision, speech and motor control while developing seizures. In a little over a year, an ASO that targeted her unusual splice-site mutation in the CLN7 gene was designed, developed and given intrathecally to the girl26. The lift was in negotiating with the FDA and working with private organizations, not just in the science, Yu said. After a year of treatment with the ASO (dubbed milasen after the girl, Mila), there were no serious adverse events; seizure frequency and duration had decreased (Figure 5); and possibly her decline had slowed. Though she remains blind, without intelligible speech and unable to walk on her own, she was still attentive and could respond happily to her familys voices. The highly personalized framework for this drugs approval is completely different from how medications meant for populations are approved, and it opens a regulatory can of worms, Yu said, though he added that the regulators were willing to countenance drug approval for an individuals clinical benefit.

Rett syndrome is a neurodevelopmental condition caused by mutations to the MECP2 gene that has a substantial research base in mouse models. Over 10 years ago, mouse models highlighted the possibility for therapeutics in this condition when Rett-associated phenotypes were rescued by adding back MECP2, even in adulthood27. This reversibility has spurred interest in gene therapy for Rett syndrome, but getting the MECP2 dose right is critical, said Stuart Cobb of the University of Edinburgh and Neurogene: just as too little MECP2 leads to Rett syndrome, too much also results in severe phenotypes. For this reason, it would be nice to package a replacement MECP2 gene with other regulatory elements to control its expression, but this results in constructs that do not fit into viral vectors. To make more room, Cobb and his colleagues have been able to chop away two-thirds of the MECP2, reserving two domains that interact to make a complex on DNA (Figure 6). Mice with this mini-gene are viable and have near normal phenotypes; likewise, injecting this mini-gene into MECP2-deficient mice extended their survival28. Doubling the dose, however, substantially lowered survival. Putting in safety valves to prevent overexpression is going to be quite important, he said. One idea is to add back a construct containing only the last two exons of MECP2, which is where most Rett mutations land. These would then be spliced into native transcripts (called trans-splicing), and thus their expression controlled by endogenous regulatory elements.

Underscoring the double-edged sword of MECP2 dosage, Yingyao Shao from Huda Zoghbis lab at Baylor described an MECP2 duplication syndrome (MDS) in humans, which features hypotonia, intellectual disability, epilepsy and autism. Experiments in an MDS mouse model, which carries one mouse version and one human version of MECP2, recapitulates some of the phenotypes of the human condition and can be rescued by an ASO targeting the human allele29. Shao described work to optimize the ASO for translation into humans, which involved developing a more humanized MDS model that carries two human MECP2 alleles. An acute injection of the ASO was able to knock down MECP2 expression in a dose-dependent manner in these mice, and RNA levels dropped a week after injection, with protein levels falling a week later. MECP2 target genes also normalized their expression level, and one maintained this for at least 16 weeks post-injection. The ASO also rescued behavioral phenotypes of motor coordination and fear conditioning, but not of anxiety; these corrections followed the molecular effects, and these timelines would be important to keep in mind while designing clinical trials. Shao also noted that overtreatment with the ASO resulted in Rett-associated phenotypes, but that this was reversible, which suggests that some fine-tuning of dosing in humans might be possible.

To avoid overtreatment and toxicity of any MDS-directed therapy, Mirjana Maletic-Savatic, also at Baylor, is leaving no stone unturned in a hunt for MDS biomarkers that can predict, in each individual, the safety of a particular dose and regimen. Such biomarkers would also help monitor individuals during treatment, give information about target engagement and identify candidates for a particular treatment. Anything found to be sensitive to expression levels of MECP2 could also be useful for Rett, though she noted that MECP2 levels measured in blood do not track linearly with gene copy number. Thus, because of interindividual variability, her approach is to collect a kitchen sink of data deriving composite biomarkers that accurately reflect the stage and severity of disease in a given case. She and her colleagues are collecting clinical, genetic, neurocircuitry (such as EEG and sleep waves), immunology and molecular data detected in blood, urine and CSF. These measures are also being explored in induced neurons derived from skin samples of people with MDS. She highlighted two interrelated potential biomarkers in the blood of those with this condition; both measures are downstream targets of MECP2 and are responsive to ASO treatment.

Highlights from Early detection and clinical trial issues talks and panel discussion, chaired by Paul Wang of SFARI

Coming up with objective measures of a persons status either their eligibility for a treatment, or whether the treatment has engaged with its target or even whether the treatment is effective is a real necessity in autism-related conditions, which comprise multiple interrelated behaviors. Eye-tracking methodology may provide such a marker, argued SFARI Investigator Ami Klin of Emory University. Focusing on the core social challenges of autism, Klin, Warren Jones and colleagues have been studying children as they view naturalistic social scenes to quantify their social attention patterns. This has revealed how remarkably early in development social visual learning begins and that this process is disrupted in infants later diagnosed with ASD prior to features associated with the condition appearing. By missing social cues, autism in many ways creates itself, moment by moment, Klin said. In considering gene therapy, it may be useful to know that eye looking (how much a subject looks at a persons eyes, an index of social visual engagement) in particular and social visual engagement in general are under genetic control30; that eye-tracking differences emerge as early as 26 months of age; and that homologies in social visual engagement exist between human babies and nonhuman infant primates.

In getting to a point to test gene therapies, identifying those who need them is essential. Wendy Chung of Columbia University and the Simons Foundation illustrated how diagnosis is yoked closely to therapy. To illustrate this, she described her pilot study of newborn blood spots to screen for SMA; at the start, no treatment was available, but the screen identified newborns for a clinical trial of nusinersin. Notably, the screen only cost an additional 11 cents per baby. In the three years since her pilot screen began, the FDA approved two gene therapies for SMA and the SMA screen was adopted for nationwide newborn screening. Currently she is piloting a screen for Duchenne muscular dystrophy and plans to develop a platform that will allow researchers to add other conditions. In prioritizing genetic conditions for gene therapy, she outlined some ideas for focus, such as genes resulting in phenotypes that would not be identified early without screening, those that are relatively frequent, those that are lethal or neurodegenerative, those with a treatment in clinical trials or with FDA-approved medications, and those conditions that are reversible.

In the meantime, Chung also outlined SFARIs involvement in establishing well-characterized cohorts of individuals with autism, which can help lay a groundwork for gene therapy. People with an ASD diagnosis can join SPARK (Simons Foundation Powering Autism Research for Knowledge), which collects medical, behavioral and genetic information (through analysis of DNA from saliva, at no cost to the participant). If a de novo genetic variant is found in one of ~150 genes, that person is referred to Simons Searchlight, which fosters rare conditions communities and which is also compiling natural history data on people with these mutations.

Bryan King of UCSF discussed how current trial designs for ASD were inadequate for gene therapy trials. As ASD prevalence has grown, parallel design trials with one group receiving an experimental medicine and the other a placebo are the standard, but these wont be possible for the rare conditions that are candidates for gene therapy. Also, change is hard to capture, given the malleable nature of ASD: with no intervention, diagnosis can shift between ASD and pervasive developmental disorder-not otherwise specified (PDD-NOS) in 1284 months (as defined by the DSM-IV). Current scales are subjective and may miss specific items of clinical significance. (Last year, SFARI funded four efforts to develop more sensitive outcome measures.) King outlined other pitfalls in ASD clinical trials, including significant placebo responses, inadequate sample sizes and not being specific enough when asking about adverse effects. King also mentioned improvements that may arise from just enrolling in a study, which could prompt previously housebound families to venture out with their child, which could kick off a cascade of positive effects. He reiterated how, for gene therapy, a natural history comparison group may be more appropriate, combined with solid outcome measures.

SFARI Investigator James McPartland of Yale University then underlined the need for objective biomarkers for clinical trials, for which there are currently none that are FDA qualified for ASD. As the director of the Autism Biomarkers Consortium for Clinical Trials (ABC-CT), he works with other scientists to develop reliable biomarkers that can be scaled for use in large samples across different sites. McPartland noted a biomarker studied in the ABC-CT: an event-related potential (N170) to human faces, which is on average slower in ASD than in typically developing children. He is working on ways to make it easier for people with ASD and intellectual disabilities to participate in biomarker studies and to make them more socially naturalistic. In discussion, he mentioned he thought it would be possible to look for these kinds of biomarkers in younger children.

SFARI Investigator Shafali Jeste of the University of California, Los Angeles recounted her experience in working with children with genetic syndromes associated with neurodevelopmental conditions. Though she is asked to participate in clinical trials for these conditions, she senses the field has some work to do to be ready for these trials, particularly in those with additional challenges such as epilepsy and intellectual disability. Meaningful and measurable clinical endpoints are still insufficient, and there needs to be more ways to improve accessibility of these trials for these rare conditions. This means developing new measures, such as gait-mat technology that senses walking coordination, or EEG measures in waking and sleep, which have been applied to people with chromosome 15q11.2-13.1 duplication (dup15q) syndrome, who have severe intellectual disability and motor impairments. Jeste also emphasized that increasing remote access to some measures can make a big difference for a trial; for example, a trial of a behavioral intervention for tuberous sclerosis complex that required weekly lab visits was disappointingly under-enrolled until researchers revamped it so most of the intervention could be done remotely31.

By grappling with the challenges to gene therapy for ASD, the workshop marked out a faint road map of a way forward. As the scientific questions are answered, the regulatory and clinical trial infrastructure will need to develop apace, and coordination between private, academic and advocacy sectors will be essential. But as gene therapy for diverse human conditions continues to be explored and gene discovery in ASD continues, there is reason to believe that some forms of ASD can eventually benefit from this strategy.This workshop provided a terrific discussion about the challenges in developing targeted gene interventions and their potentially transformative effects as therapies, said John Spiro, Deputy Scientific Director of SFARI. We are grateful to all theparticipants, and SFARI looks forward to translating these discussions into focused funding decisions in the near future.

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SFARI | SFARI workshop explores challenges and opportunities of gene therapies for autism spectrum disorder - SFARI News

Stem Cell Assay Market: Snapshot

Stem cell assay refers to the procedure of measuring the potency of antineoplastic drugs, on the basis of their capability of retarding the growth of human tumor cells. The assay consists of qualitative or quantitative analysis or testing of affected tissues andtumors, wherein their toxicity, impurity, and other aspects are studied.

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With the growing number of successfulstem cell therapytreatment cases, the global market for stem cell assays will gain substantial momentum. A number of research and development projects are lending a hand to the growth of the market. For instance, the University of Washingtons Institute for Stem Cell and Regenerative Medicine (ISCRM) has attempted to manipulate stem cells to heal eye, kidney, and heart injuries. A number of diseases such as Alzheimers, spinal cord injury, Parkinsons, diabetes, stroke, retinal disease, cancer, rheumatoid arthritis, and neurological diseases can be successfully treated via stem cell therapy. Therefore, stem cell assays will exhibit growing demand.

Another key development in the stem cell assay market is the development of innovative stem cell therapies. In April 2017, for instance, the first participant in an innovative clinical trial at the University of Wisconsin School of Medicine and Public Health was successfully treated with stem cell therapy. CardiAMP, the investigational therapy, has been designed to direct a large dose of the patients own bone-marrow cells to the point of cardiac injury, stimulating the natural healing response of the body.

Newer areas of application in medicine are being explored constantly. Consequently, stem cell assays are likely to play a key role in the formulation of treatments of a number of diseases.

Global Stem Cell Assay Market: Overview

The increasing investment in research and development of novel therapeutics owing to the rising incidence of chronic diseases has led to immense growth in the global stem cell assay market. In the next couple of years, the market is expected to spawn into a multi-billion dollar industry as healthcare sector and governments around the world increase their research spending.

The report analyzes the prevalent opportunities for the markets growth and those that companies should capitalize in the near future to strengthen their position in the market. It presents insights into the growth drivers and lists down the major restraints. Additionally, the report gauges the effect of Porters five forces on the overall stem cell assay market.

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Global Stem Cell Assay Market: Key Market Segments

For the purpose of the study, the report segments the global stem cell assay market based on various parameters. For instance, in terms of assay type, the market can be segmented into isolation and purification, viability, cell identification, differentiation, proliferation, apoptosis, and function. By kit, the market can be bifurcated into human embryonic stem cell kits and adult stem cell kits. Based on instruments, flow cytometer, cell imaging systems, automated cell counter, and micro electrode arrays could be the key market segments.

In terms of application, the market can be segmented into drug discovery and development, clinical research, and regenerative medicine and therapy. The growth witnessed across the aforementioned application segments will be influenced by the increasing incidence of chronic ailments which will translate into the rising demand for regenerative medicines. Finally, based on end users, research institutes and industry research constitute the key market segments.

The report includes a detailed assessment of the various factors influencing the markets expansion across its key segments. The ones holding the most lucrative prospects are analyzed, and the factors restraining its trajectory across key segments are also discussed at length.

Global Stem Cell Assay Market: Regional Analysis

Regionally, the market is expected to witness heightened demand in the developed countries across Europe and North America. The increasing incidence of chronic ailments and the subsequently expanding patient population are the chief drivers of the stem cell assay market in North America. Besides this, the market is also expected to witness lucrative opportunities in Asia Pacific and Rest of the World.

Global Stem Cell Assay Market: Vendor Landscape

A major inclusion in the report is the detailed assessment of the markets vendor landscape. For the purpose of the study the report therefore profiles some of the leading players having influence on the overall market dynamics. It also conducts SWOT analysis to study the strengths and weaknesses of the companies profiled and identify threats and opportunities that these enterprises are forecast to witness over the course of the reports forecast period.

Some of the most prominent enterprises operating in the global stem cell assay market are Bio-Rad Laboratories, Inc (U.S.), Thermo Fisher Scientific Inc. (U.S.), GE Healthcare (U.K.), Hemogenix Inc. (U.S.), Promega Corporation (U.S.), Bio-Techne Corporation (U.S.), Merck KGaA (Germany), STEMCELL Technologies Inc. (CA), Cell Biolabs, Inc. (U.S.), and Cellular Dynamics International, Inc. (U.S.).

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Stem Cell Assay Market In-Depth Analysis and Forecast 2017-2025 - Daily Veterans

Houston has played a significant role in boosting the nations biotech industry. While Houston is still a hotspot for energy and oil, the city is steadily becoming a burgeoning life sciences hub. In fact, the city boasted the third fastest-growing biotech community in the nation between 2014 and 2017, according to a CBRE report. Houstons biotech industry is gaining momentum due to an increase in funding as well. According to the Greater Houston Partnership, nearly $180 million in VC funding was allocated to the citys ecosystem of life sciences-related companies in 2019 alone.

Like many startups and tech companies across Houston, the citys life sciences leaders have been tackling some of the worlds most pressing issues. Whether theyre developing oncology drug candidates or advancing genomic medicine through the creation of sequencing technologies, the citys biotech organizations are pulling on decades of research and determination to transform the medical landscape on a global scale. Heres a look at 15 biotech companies in Houston making a major impact on medical research and discovery.

Founded: 2015

Focus: Canine Cancer Treatment

What they do:CAVU Biotherapiesprovides immune-based solutions to treat cancer and autoimmune diseases in dogs. The company offers an immune health monitoring service, which describes a dogs immune system through the use of a blood sample, as well as an autologous prescription product that retrains and expands a dogs T cells to recognize and fight cancer. CAVU Biotherapies ultimate aim is to use its immune-guided medicine to treat horses, cats, andeventually, humans.

Founded: 2006

Focus: Stem Cell Banking + Therapy

What they do: Founded by David Eller and Dr. Stanley Jones, Celltex Therapeutics focuses on developing stem cell therapies for a variety of conditions. The companys stem cell processing and banking methods are designed to ensure the genetic integrity and uniformity of an individuals cells in quantities necessary for therapeutic applications. Using proprietary technology, Celltex Therapeutics enables stem cells to be used for regenerative therapy for conditions like vascular, autoimmune and degenerative diseases.

Founded: 2006

Focus: Cell Therapy

What they do: InGeneron is a clinical stage cell therapy company that specializes in novel, evidence-based regenerative medicine therapies. The companys therapy is designed to repair injured tissue, improve the quality of life for patients and modify the progression of their disease. InGeneron focuses mainly on musculoskeletal indications such as pain management.

Founded: 2006

Focus: Cancer Treatment

What they do: Moleculin Biotech is a pharmaceutical company dedicated to the treatment of highly resistant cancers and viruses. The company develops oncology drug candidates for highly resistant tumors as well as as prodrug to exploit the potential uses of inhibitors of glycolysis. Guided by the aim to provide new hope to cancer patients, Moleculin Biotech focuses on discovering new treatments for acute myeloid leukemia, skin cancer, pancreatic cancer and brain tumors.

Founded: 2001

Focus: Nanomedicine

What they do: Nanospectra Biosciences is spearheading a patient-centric use of nanomedicine for the removal of cancerous tissues. The companys ultra-focal nanoshell technology is designed to thermally destroy solid tumors without damaging adjacent healthy tissue. Nanospectra Biosciences aims to maximize treatment efficacy while minimizing side effects associated with surgery, radiation and traditional focal therapies.

Founded: 2018

Focus: Cell Therapy

What they do: Marker Therapeutics is an immuno-oncology company that focuses on the development of next-generation T cell-based immunotherapies. With the aim of treating hematological malignancies and solid tumor indications, the company uses its own MultiTAA T cell technology, which is based on the selective expansion of non-engineered, tumor-specific T cells. Marker Therapeutics is also working on developing proprietary DNA expression technology that is intended to improve the cellular immune systems ability to recognize and destroy diseased cells.

Founded: 2008

Focus: 3D Cell Culture

What they do: Nano3D Biosciences is dedicated to the development of 3D cell culture solutions. The companys core technology allows them to levitate or bioprint cells, which results in the formation of cultures that are more easily assembled and handled. Nano3D Biosciences products and services are intended for biomedical research, drug discovery, precision medicine, toxicology and regenerative medicine.

Founded: 2017

Focus: Small Molecule Inhibitors

What they do: Tvardi Therapeutics is a clinical-stage biotech company working on a new class of medicines for cancer, chronic inflammation and fibrosis. The company is focusing on the creation of orally delivered, small molecule inhibitors of STAT3, which is a key regulatory protein positioned at the intersection of many disease pathways. Tvardi Therapeutics is dedicated to delivering safe and effective solutions for use in the treatment of numerous diseases.

Founded: 2011

Focus: Targeted Cancer Therapies

What they do: Salarius Pharmaceuticals focuses on developing targeted therapies to treat various types of cancers. The companys lead candidate, Seclidemstat, is intended to treat Ewing sarcoma, a pediatric and young adult bone cancer that currently lacks targeted therapies. Salarius Pharmaceuticals performs clinical trials for the treatment of other advanced solid tumors including prostate, breast and ovarian cancers.

Founded: 2013

Focus: Genomic Medicine

What they do: Founded by Michael Metzker, RedVault Biosciences develops technologies with the aim of advancing genomic medicine. The company is currently working on a variety of projects including the development of sequencing technologies to determine haplotypes and structural variation in complex genomes. RedVault Biosciences is dedicated to identifying technology needs, creating and testing ideas, and transferring deliverables to production and distribution.

Founded: 2010

Focus: DNA Sequencing

What they do: Avance Biosciences focuses on assay development, assay validation and sample testing using next-generation DNA sequencing and other biological methods. The company offers biologics testing, diagnostic assay validation, GMO genomic testing, gene / cell therapy testing, digital and real-time PCR, microbial testing and more. Avance Biosciences aim is to assist its clients in advancing drug development and genomic research.

Founded: 2008

Focus: Bioremediation

What they do: Bionex Technology develops cost-effective, natural solutions for cleaning oil-polluted soil. The companys Super Microbe spill solution is naturally derived from microbes that digest and convert harmful contaminants on the ground and in soil, therefore lowering flammability, suppressing harmful vapors and creating a safer environment for spill responders. Bionex Technology offers a variety of other bioremediation products such as a customizable degreaser and detergent used for cleaning industrial tools.

Founded: 2016

Focus: Stem Cell Research

What they do: Located in nearby Sugar Land, Hope Biosciences is dedicated to developing stem cell-based therapies that are safe, effective and secure. The companys proprietary technology enables patients to make virtually unlimited and identical stem cells from their own tissue. Hope Biosciences offers stem cell banking solutions for both adults and newborns.

Founded: 2013

Focus: Interventional Cardiology

What they do: Saranas has created technology that enables the early detection and monitoring of bleeding complications associated with vascular access procedures. The companys monitoring system checks changes in the blood vessels electrical resistance before monitoring if bleeding has occurred from an unintentionally injured blood vessel. Saranas aims to allow physicians to mitigate downstream consequences by addressing bleeds before they become complications.

Founded: 1984

Focus: Microbiology

What they do: Microbiology Specialists Inc. specializes in microbiology testing, playing a role in microbial investigations and studies. The company also focuses on infectious disease diagnosis, forensic bacteriology and mycology, medical device testing and infection prevention. Microbiology Specialists Inc. is committed to delivering reliable, accurate and cost-effective microbiological results.

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15 Biotech Companies In Houston To Know - Built In

With a full devotion and dedication this superior GLOBAL HUMAN EMBRYONIC STEM CELL MARKET report is presented to the clients that extend their reach to success. Market parameters covered in this advertising report can be listed as market definition, currency and pricing, market segmentation, market overview, premium insights, key insights and company profile of the key market players. Each parameter included in this GLOBAL HUMAN EMBRYONIC STEM CELL MARKET business research report is again explored deeply for the better and actionable market insights. Geographical scope of the products is also carried out comprehensively for the major global areas which helps define strategies for the product distribution in those areas.

TheGlobal Human Embryonic Stem Cell Marketstudy with 100+ market data Tables, Pie Chat, Graphs & Figures is now released by Data Bridge Market Research. The report presents a complete assessment of the Market covering future trend, current growth factors, attentive opinions, facts, and industry validated market data forecast till 2026. Delivering the key insights pertaining to this industry, the report provides an in-depth analysis of the latest trends, present and future business scenario, market size and share ofMajor Players such as Arizona Board of Regents, STEMCELL Technologies Inc, Cellular Engineering Technologies, CellGenix GmbH, PromoCell GmbH, Lonza, Kite Pharma, Takeda Pharmaceutical Company Limited, BrainStorm Cell Limited., CELGENE CORPORATION, Osiris Therapeutics,Inc, U.S. Stem Cell, Inc and amny More

Global human embryonic stem cell market estimated to register a healthy CAGR of 10.5% in the forecast period of 2019 to 2026. The imminent market report contains data for historic year 2017, the base year of calculation is 2018 and the forecast period is 2019 to 2026. The growth of the market can be attributed to the increase in tissue engineering process.

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Market Dynamics:

Set of qualitative information that includes PESTEL Analysis, PORTER Five Forces Model, Value Chain Analysis and Macro Economic factors, Regulatory Framework along with Industry Background and Overview.

Global Human Embryonic Stem Cell Market By Type (Totipotent Stem Cells, Pluripotent Stem Cells, Unipotent Stem Cells), Application (Regenerative Medicine, Stem Cell Biology Research, Tissue Engineering, Toxicology Testing), End User (Research, Clinical Trials, Others), Geography (North America, Europe, Asia-Pacific, South America, Middle East and Africa) Industry Trends and Forecast to 2026

Global Human Embryonic Stem Cell Research Methodology

Data Bridge Market Research presents a detailed picture of the market by way of study, synthesis, and summation of data from multiple sources.The data thus presented is comprehensive, reliable, and the result of extensive research, both primary and secondary. The analysts have presented the various facets of the market with a particular focus on identifying the key industry influencers.

Major Drivers and Restraints of the Human Embryonic Stem Cell Industry

Complete report is available (TOC) @https://www.databridgemarketresearch.com/toc/?dbmr=global-human-embryonic-stem-cell-market

The titled segments and sub-section of the market are illuminated below:

By Type

By Application

By End User

Top Players in the Market are:

Some of the major companies functioning in global human embryonic stem cell market are Arizona Board of Regents, STEMCELL Technologies Inc, Cellular Engineering Technologies, CellGenix GmbH, PromoCell GmbH, Lonza, Kite Pharma, Takeda Pharmaceutical Company Limited, BrainStorm Cell Limited., CELGENE CORPORATION, Osiris Therapeutics,Inc, U.S. Stem Cell, Inc, Waisman Biomanufacturing, Caladrius, Pfizer Inc., Thermo Fisher Scientific, Merck KGaA, Novo Nordisk A/S, Johnson & Johnson Services, Inc and SA Biosciences Corporation among others.

How will the report help new companies to plan their investments in the Human Embryonic Stem Cell market?

The Human Embryonic Stem Cell market research report classifies the competitive spectrum of this industry in elaborate detail. The study claims that the competitive reach spans the companies of.

The report also mentions about the details such as the overall remuneration, product sales figures, pricing trends, gross margins, etc.

Information about the sales & distribution area alongside the details of the company, such as company overview, buyer portfolio, product specifications, etc., are provided in the study.

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Some of the Major Highlights of TOC covers:

Chapter 1: Methodology & Scope

Definition and forecast parameters

Methodology and forecast parameters

Data Sources

Chapter 2: Executive Summary

Business trends

Regional trends

Product trends

End-use trends

Chapter 3: Human Embryonic Stem Cell Industry Insights

Industry segmentation

Industry landscape

Vendor matrix

Technological and innovation landscape

Chapter 4: Human Embryonic Stem Cell Market, By Region

Chapter 5: Company Profile

Business Overview

Financial Data

Product Landscape

Strategic Outlook

SWOT Analysis

Thanks for reading this article, you can also get individual chapter wise section or region wise report version like North America, Europe or Asia.

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An absolute way to forecast what future holds is to comprehend the trend today!Data Bridge set forth itself as an unconventional and neoteric Market research and consulting firm with unparalleled level of resilience and integrated approaches. We are determined to unearth the best market opportunities and foster efficient information for your business to thrive in the market. Data Bridge endeavors to provide appropriate solutions to the complex business challenges and initiates an effortless decision-making process.

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GLOBAL HUMAN EMBRYONIC STEM CELL MARKET Analysis 2020 With COVID 19 Impact Analysis| Leading Players, Industry Updates, Future Growth, Business...

CAMBRIDGE, Mass.--(BUSINESS WIRE)--bluebird bio, Inc. (Nasdaq: BLUE) announced that new data from its ongoing Phase 1/2 HGB-206 study of investigational LentiGlobin gene therapy for adult and adolescent patients with sickle cell disease (SCD) show a near-complete reduction of serious vaso-occlusive crises (VOCs) and acute chest syndrome (ACS). These data are being presented at the Virtual Edition of the 25th European Hematology Association (EHA25) Annual Congress.

Vaso-occlusive crises (VOCs) are the painful, life-threatening episodes that are the primary clinical manifestation of sickle cell disease. The nearly complete elimination of VOCs that we saw in this study is impressive and demonstrates the potential of LentiGlobin for SCD as a treatment for this serious disease, said David Davidson, M.D., chief medical officer, bluebird bio. These results illustrate the type of outcomes we believe are needed to provide truly meaningful improvements for people living with sickle cell disease. In addition, the improvement of laboratory measures of hemolysis and red cell physiology, with nearly pan-cellular distribution of the anti-sickling HbAT87Q, suggest LentiGlobin for SCD may substantially modify the causative pathophysiology of SCD. We are pleased to have reached a general agreement with the FDA on the clinical data required to support a submission for LentiGlobin for SCD and we plan to seek an accelerated approval. We look forward to working with the entire SCD community to bring forward a disease modifying option for patients.

SCD is a serious, progressive and debilitating genetic disease caused by a mutation in the -globin gene that leads to the production of abnormal sickle hemoglobin (HbS). HbS causes red blood cells to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and unpredictable, painful VOCs. For adults and children living with SCD, this means painful crises and other life altering or life-threatening acute complicationssuch as ACS, stroke and infections. If patients survive the acute complications, vasculopathy and end-organ damage, resulting complications can lead to pulmonary hypertension, renal failure and early death; in the U.S. the median age of death for someone with sickle cell disease is 43 - 46 years.

As a physician treating sickle cell for over 10 years, the excruciating pain crises that my patients suffer from is one of the most challenging and frustrating aspects of this disease, said presenting study author Julie Kanter, M.D., University of Alabama at Birmingham. The promising results of this study, which show patients have an almost complete elimination of VOCs and ACS, suggest LentiGlobin for SCD has real potential to provide a significant impact for people living with sickle cell disease.

LentiGlobin for SCD was designed to add functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once patients have the A-T87Q-globin gene, their red blood cells can produce anti-sickling hemoglobin, HbAT87Q, that decreases the proportion of HbS, with the goal of reducing sickled red blood cells, hemolysis and other complications.

As of March 3, 2020, a total of 37 patients have been treated with LentiGlobin for SCD to-date in the HGB-205 (n=3) and HGB-206 (n=34) clinical studies. The HGB-206 total includes: Group A (n=7), B (n=2) and C (n=25).

HGB-206: Group C Updated Efficacy Results

In Group C of HGB-206, 25 patients were treated with LentiGlobin for SCD and have up to 24.8 months of follow-up (median of 12.1; min.-max.: 2.824.8 months). Results from Group C are as of March 3, 2020 and include efficacy data for 16 patients who had at least a Month 6 visit, and safety data for 18 patients, which includes two patients who were at least six months post-treatment but results from a Month 6 visit are not available.

In 16 patients with six or more months of follow-up, median levels of gene therapy-derived anti-sickling hemoglobin, HbAT87Q, were maintained with HbAT87Q contributing at least 40% of total hemoglobin. At last visit reported, total hemoglobin ranged from 9.6 16.2 g/dL and HbAT87Q levels ranged from 2.7 9.4 g/dL. At Month 6 the production of HbAT87Q was associated with a reduction in the proportion of HbS in total hemoglobin. Patients had a median of 60% HbS. All patients in Group C were able to stop regular blood transfusions and remain off transfusions at three months post-treatment.

There was a 99.5% mean reduction in annualized rate of VOC and ACS among the 14 patients who had at least six months of follow-up and a history of VOCs or ACS, defined as four or more VOC or ACS events in the two years prior to treatment. These 14 patients had a median of eight events in the two years prior to treatment (min.-max.: 4 28 events).

There were no reports of serious VOCs or ACS at up to 24 months post-treatment in patients with at least six months of follow-up (n=18). As previously reported, one non-serious Grade 2 VOC was observed in a patient approximately 3.5 months post-treatment with LentiGlobin for SCD.

In sickle cell disease, red blood cells become sickled and fragile, rupturing more easily than healthy red blood cells. The breakdown of red blood cells is hemolysis and this process occurs normally in the body. However, in sickle cell disease hemolysis happens too quickly due to the fragility of the red blood cells, which results in hemolytic anemia.

Patients treated with LentiGlobin for SCD demonstrated improvement in key markers of hemolysis, which are indicators of the health of red blood cells. Lab results assessing these indicators were available for the majority of the 18 patients with 6 months of follow-up. The medians for reticulocyte counts (n=15), lactate dehydrogenase (LDH) levels (n=13) and total bilirubin (n=16) improved compared to screening and stabilized by Month 6. In patients with Month 24 data (n=5) these values approached the upper limit of normal by Month 24. These results suggest treatment with LentiGlobin for SCD is improving biological markers of sickle cell disease.

Assays were developed by bluebird bio to enable the detection of HbAT87Q and HbS protein in individual red blood cells as well as to assess if HbAT87Q was pancellular, present throughout all of a patients red blood cells. Samples from a subset of patients in Group C were assessed. In nine patients who had at least six months of follow-up, the average proportion of red blood cells positive for HbAT87Q was greater than 70%, and on average more than 85% of red blood cells contained HbAT87Q at 18 months post-treatment, suggesting near-complete pancellularity of HbAT87Q distribution.

HGB-206: Group C Safety Results

As of March 3, 2020, the safety data from all patients in HGB-206 are generally reflective of underlying SCD and the known side effects of hematopoietic stem cell collection and myeloablative conditioning. There were no serious adverse events related to LentiGlobin for SCD, and the non-serious, related adverse events (AEs) were mild-to-moderate in intensity and self-limited.

One patient with a history of frequent pre-treatment VOE, pulmonary and systemic hypertension, venous thrombosis, obesity, sleep apnea and asthma had complete resolution of VOEs following treatment, but suffered sudden death 20 months after treatment with LentiGlobin for SCD. The patients autopsy revealed cardiac enlargement and fibrosis, and concluded the cause of death was cardiovascular, with contributions from SCD and asthma. The treating physician and an independent monitoring committee agreed this death was unlikely related to LentiGlobin for SCD gene therapy.

The presentation is now available on demand on the EHA25 website:

About HGB-206

HGB-206 is an ongoing, Phase 1/2 open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for SCD that includes three treatment cohorts: Groups A (n=7), B (n=2) and C (n=25). A refined manufacturing process that was designed to increase vector copy number (VCN) and improve engraftment potential of gene-modified stem cells was used for Group C. Group C patients also received LentiGlobin for SCD made from HSCs collected from peripheral blood after mobilization with plerixafor, rather than via bone marrow harvest, which was used in Groups A and B of HGB-206.

LentiGlobin for Sickle Cell Disease Regulatory Status

bluebird bio reached general agreement with the U.S. Food and Drug Administration (FDA) that the clinical data package required to support a Biologics Licensing Application (BLA) submission for LentiGlobin for SCD will be based on data from a portion of patients in the HGB-206 study Group C that have already been treated. The planned submission will be based on an analysis using complete resolution of severe vaso-occlusive events (VOEs) as the primary endpoint with at least 18 months of follow-up post-treatment with LentiGlobin for SCD. Globin response will be used as a key secondary endpoint.

bluebird bio anticipates additional guidance from the FDA regarding the commercial manufacturing process, including suspension lentiviral vector. bluebird bio announced in a May 11, 2020 press release it plans to seek an accelerated approval and expects to submit the U.S. BLA for SCD in the second half of 2021.

About LentiGlobin for Sickle Cell Disease

LentiGlobin for sickle cell disease is an investigational gene therapy being studied as a potential treatment for SCD. bluebird bios clinical development program for LentiGlobin for SCD includes the ongoing Phase 1/2 HGB-206 study and the ongoing Phase 3 HGB-210 study.

LentiGlobin for SCD received orphan medicinal product designation from the European Commission for the treatment of SCD.

The U.S. FDA granted orphan drug designation, regenerative medicine advanced therapy (RMAT) designation and rare pediatric disease designation for LentiGlobin for SCD.

LentiGlobin for SCD is investigational and has not been approved in any geography.

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of betibeglogene autotemcel for -thalassemia or LentiGlobin for SCD. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

About bluebird bio, Inc.

bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders, including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition; cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash., Durham, N.C., and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

LentiGlobin and bluebird bio are trademarks of bluebird bio, Inc.

bluebird bio Forward-Looking Statements

This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the companys development and regulatory plans for the LentiGlobin for SCD product candidate, and the companys intentions regarding the timing for providing further updates on the development of the product candidate. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the risk that the COVID-19 pandemic and resulting impact on our operations and healthcare systems will affect the execution of our development plans or the conduct of our clinical studies; the risk that even if LentiGlobin for SCD addresses ACS and VOC events, that it may not address progressive organ damage experienced by patients with SCD; the risk that the efficacy and safety results observed in the patients treated in our prior and ongoing clinical trials of LentiGlobin for SCD may not persist or be durable; the risk that the efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in when treating additional patients in our ongoing or planned clinical trials; the risk that the HGB-206 and HGB-210 clinical studies as currently contemplated may be insufficient to support regulatory submissions or marketing approval in the United States and European Union; the risk that regulatory authorities will require additional information regarding our product candidate, resulting in a delay to our anticipated timelines for regulatory submissions, including our application for marketing approval. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

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New Data Show Near Elimination of Sickle Cell Disease-Related Vaso-Occlusive Crises and Acute Chest Syndrome in Phase 1/2 Clinical Study of bluebird...

CAMBRIDGE, Mass.--(BUSINESS WIRE)--bluebird bio, Inc. (Nasdaq: BLUE) today announced that new data from ongoing Phase 3 studies of betibeglogene autotemcel (beti-cel; formerly LentiGlobin for -thalassemia gene therapy) show pediatric, adolescent and adult patients with a range of genotypes of transfusion-dependent -thalassemia (TDT) achieve and maintain transfusion independence with hemoglobin (Hb) levels that are near-normal (10.5 g/dL). These data are being presented at the Virtual Edition of the 25th European Hematology Association (EHA25) Annual Congress.

With more than a decade of clinical experience evaluating gene therapy in patients with transfusion dependent -thalassemia across a wide range of ages and genotypes, we have built the most comprehensive understanding of treatment outcomes in the field, said David Davidson, M.D., chief medical officer, bluebird bio. Seeing patients achieve transfusion independence and maintain that positive clinical benefit over time with robust hemoglobin levels reflects our initial vision of the potential of beti-cel. The accumulating long-term data demonstrating improvements in bone marrow histology, iron balance and red cell biology support the potential of beti-cel to correct the underlying pathophysiology of transfusion-dependent -thalassemia.

A total of 60 pediatric, adolescent and adult patients across genotypes of TDT have been treated with beti-cel in the Phase 1/2 Northstar (HGB-204) and HGB-205 studies, and the Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies as of March 3, 2020. In studies of beti-cel, transfusion independence is defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL.

TDT is a severe genetic disease caused by mutations in the -globin gene that results in significantly reduced or absent adult hemoglobin (HbA). In order to survive, people with TDT maintain Hb levels through lifelong, chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Patients with transfusion-dependent -thalassemia do not make enough healthy red blood cells and cannot live without chronic transfusions; for patients that means a lifetime of necessary visits to a hospital or clinic and reliance on an often unreliable blood supply, which compounds the challenges of managing this disease, said presenting study author Professor John B. Porter, MA, M.D., FRCP, FRCPath, University College London Hospital, London, UK. These results showing patients free from transfusions and maintaining near-normal hemoglobin levels after treatment with beti-cel is a positive outcome for people living with transfusion-dependent -thalassemia. In addition, we now have more data that provide further evidence that most of these patients have a measurable improvement in markers of healthy red blood cell production.

Beti-cel is a one-time gene therapy designed to address the underlying genetic cause of TDT by adding functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). This means there is no need for donor HSCs from another person, as is required for allogeneic HSC transplantation (allo-HSCT). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived Hb, at levels that eliminate or significantly reduce the need for transfusions.

Northstar-2 (HGB-207) Efficacy

As of March 3, 2020, all 23 patients in HGB-207 were treated and have been followed for a median of 19.4 months. These patients ranged in age from four to 34 years, including eight pediatric (<12 years of age) and 15 adolescent/adult (>12 years of age) patients. Only 19 patients were evaluable for transfusion independence; four additional patients do not yet have sufficient follow-up to be assessed for transfusion independence.

Eighty-nine percent of evaluable patients (17/19) achieved transfusion independence, with median weighted average total Hb levels of 11.9 g/dL (min-max: 9.4 12.9 g/dL) over a median of 19.4 months of follow-up to date (min-max: 12.3 31.4 months). These 17 patients previously required a median of 17.5 transfusions per year (min-max: 11.5 37 transfusions per year).

Improved iron levels, as measured by serum ferritin and hepcidin levels (proteins involved in iron storage and homeostasis), were observed and trends toward improved iron management were seen. Over half of patients stopped chelation therapy, which is needed to reduce excess iron caused by chronic blood transfusions. Seven out of 23 patients began using phlebotomy for iron reduction.

Analysis of Healthy Red Blood Cell Production

In exploratory analyses, biomarkers of ineffective erythropoiesis (red blood cell production) were evaluated in patients who achieved transfusion independence in HGB-207.

The myeloid to erythroid (M:E) ratio in bone marrow from patients who achieved transfusion independence increased from a median of 1:3 (n=17) at baseline to 1:1.2 (n=16) at Month 12. Improvement of the M:E ratio, the ratio of white blood cell and red blood cell precursors in the bone marrow, suggests an improvement in mature red blood cell production. Images illustrating the bone marrow cellularity at baseline, Month 12 and Month 24 are available in the EHA25 presentation (abstract #S296): Improvement in erythropoiesis in patients with transfusion-dependent -thalassemia following treatment with betibeglogene autotemcel (LentiGlobin for -thalassemia) in the Phase 3 HGB-207 study.

Additionally, biomarkers of erythropoiesis continue to demonstrate a trend toward normalization in patients who achieved transfusion independence, including improved levels over time of erythropoietin, a hormone involved in red blood cell production; reticulocytes, immature red blood cells; and soluble transferrin receptor, a protein measured to help evaluate iron status. The continued normalization of red blood cell production over time among some patients who achieved transfusion independence supports the disease-modifying potential of beti-cel in patients with TDT.

Northstar-3 (HGB-212) Efficacy

As of March 3, 2020, 15 patients (genotypes: 9 0/0, 3 0/ +IVS1-110, 3 homozygous IVS-1-110 mutation) were treated and had a median follow-up of 14.4 months (min-max: 1.124.0 months). Median age at enrollment was 15 (min-max: 4 33 years).

Six of eight evaluable patients achieved transfusion independence, with median weighted average total Hb levels of 11.5 g/dL (min-max: 9.5 13.5 g/dL), and continued to maintain transfusion independence for a median duration of 13.6 months (min-max: 12.2 21.2 months) as of the data cutoff.

Eighty-five percent of patients (11/13) with at least seven months of follow-up had not received a transfusion in more than seven months at time of data cutoff. These 11 patients previously required a median of 18.5 transfusions per year (min-max: 11.0 39.5 transfusions per year). In these patients, gene therapy-derived HbAT87Q supported total Hb levels ranging from 8.814.0 g/dL at last visit.

Betibeglogene autotemcel Safety

Non-serious adverse events (AEs) observed during the HGB-207 and HGB-212 trials that were considered related or possibly related to beti-cel were tachycardia, abdominal pain, pain in extremities, leukopenia, neutropenia and thrombocytopenia. One serious event of thrombocytopenia was considered possibly related to beti-cel.

In HGB-207, serious events post-infusion in two patients included three events of veno-occlusive liver disease and two events of thrombocytopenia. In HGB-212, serious events post-infusion in two patients included two events of pyrexia.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

In both Phase 3 studies, there have been no deaths, no graft failure, no cases of vector-mediated replication competent lentivirus or clonal dominance, no leukemia and no lymphoma.

The presentations are now available on demand on the EHA25 website:

About betibeglogene autotemcel

The European Commission granted conditional marketing authorization (CMA) for betibeglogene autotemcel (beti-cel; formerly LentiGlobin gene therapy for -thalassemia), marketed as ZYNTEGLO gene therapy, for patients 12 years and older with transfusion-dependent -thalassemia (TDT) who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available. On April 28, 2020, the European Medicines Agency (EMA) renewed the CMA for ZYNTEGLO, supported by data from 32 patients treated with ZYNTEGLO, including three patients with up to five years of follow-up.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT maintain Hb levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Beti-cel adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

Non-serious adverse events (AEs) observed during clinical studies that were attributed to beti-cel included abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnea, pain in extremity and non-cardiac chest pain. Two serious adverse events (SAE) of thrombocytopenia was considered possibly related to beti-cel.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

The CMA for beti-cel is valid in the 27 member states of the EU as well as UK, Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration (FDA) granted beti-cel orphan drug designation and Breakthrough Therapy designation for the treatment of transfusion-dependent -thalassemia. Beti-cel is not approved in the U.S.

Beti-cel continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies. For more information about the ongoing clinical studies, visit http://www.northstarclinicalstudies.com or clinicaltrials.gov and use identifier NCT02906202 for Northstar-2 (HGB-207) and NCT03207009 for Northstar-3 (HGB-212).

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of betibeglogene autotemcel or LentiGlobin for SCD. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

About bluebird bio, Inc.

bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

ZYNTEGLO, LentiGlobin, and bluebird bio are trademarks of bluebird bio, Inc.

bluebird bio Forward-Looking Statements

This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: the risk that the COVID-19 pandemic and resulting impact on our operations and healthcare systems will affect the execution of our development plans or the conduct of our clinical studies; the risk that the efficacy and safety results observed in the patients treated in our prior and ongoing clinical trials of beti-cel may not persist; and the risk that the efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated with additional patients in our ongoing or planned clinical trials or in the commercial context; the risk that the FDA will require additional information regarding beti-cel, resulting in a delay to our anticipated timelines for regulatory submissions, including submission of our BLA. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

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Majority of Evaluable Patients Across Genotypes Achieve Transfusion Independence and Maintain It with Near-Normal Hemoglobin Levels in Phase 3 Studies...

The company said the move was aimed at the development of next generation cellular immunotherapy FLASH-CAR technology

(), a clinical-stage developer of cell-based technologies and therapeutics, announced Thursday that it has struck a three-way material transfer agreement (MTA) with Weill Cornell Medicine in New York City and the companys strategic partner, Arbele Limited.

With this agreement, Avalon GloboCare and Arbele Limited intend to collaborate with Weill Cornell Medicine and co-develop the standardized laboratory steps necessary to generate clinical-grade CAR-T and CAR-natural killer (NK) cells for use in future human clinical trials with Avalons first FLASH-CAR platform candidate, AVA-011.Similar to T-cells, NK cells are a type of white blood cell, also able to attack cancer cells, but utilize different mechanisms.

The company said this process development step will provide the bridge between Avalons benchtop research and the bio-manufacturing processes to potentially deliver the clinical-grade cellular immunotherapy product to patients.

READ:Avalon GloboCare advancing immune cell therapy to treat blood cancers using FLASH-CAR technology

We are excited about this agreement to translate our cellular therapy candidates into standardized, clinical-grade cell products that could be used in future clinical trials, Avalon GloboCare CEO David Jin said in a statement.

This step reflects our dedication to establishing an infrastructure to develop our cellular immunotherapy candidates and to maintain the highest possible standards for generating clinical-grade cells for human cancer trials, he added.

AVA-011 is a next generation cellular immunotherapy candidate using Avalons FLASH-CAR technology that targets both CD19 and CD22 tumor antigens on cancer cells. Avalon has already successfully completed pre-clinical research on AVA-011, including tumor cytotoxicity studies.

Avalon expects to begin a first-in-human clinical trial with AVA-011 for the treatment of relapsed or refractory B-cell lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma in the first quarter of 2021. The goal is to use AVA-011 as a bridge to bone marrow stem cell transplant therapy, currently the only curative approach for patients with these blood cancers.

Avalons next generation immune cell therapy using FLASH-CAR technology is being co-developed with the companys strategic partner Arbele Limited. The adaptable FLASH-CAR platform can be used to create personalized cell therapy from a patients own cells, as well as off-the-shelf cell therapy from a universal donor, expanding the reach of cancer patients that can be treated.

Avalon, based in Freehold, New Jersey, specializes in developing cell-based technologies and is involved in the management of stem-cell banks and clinical laboratories.

Contact the author Uttara Choudhury at [emailprotected]

Follow her on Twitter: @UttaraProactive

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Avalon GloboCare strikes three-way material transfer agreement with Weill Cornell Medicine and Arbele Limited - Proactive Investors USA & Canada