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New research reveals the underlying mechanism for a dangerous heart disorder in which low oxygen levels in the heart produce life-threatening arrhythmias.

The discovery, made with human heart muscle cells derived from pluripotent stem cells, offers new targets for therapies aimed at preventing sudden death from heart attack.

Our research shows that within seconds, at low levels of oxygen (hypoxia), a protein called small ubiquitin-like modifier (SUMO) is linked to the inside of the sodium channels which are responsible for starting each heartbeat, says Steve A. N. Goldstein, vice chancellor for health affairs at the University of California, Irvine and professor in the School of Medicine departments of pediatrics and physiology and biophysics.

And, while SUMOylated channels open as they should to start the heartbeat, they re-open when they should be closed. The result is abnormal sodium currents that predispose to dangerous cardiac rhythms.

Every heartbeat begins when sodium channels open and ions to rush into heart cellsthis starts the action potential that causes the heart muscle to contract. When functioning normally, the sodium channels close quickly after opening and stay closed. After that, potassium channels open, ions leave the heart cells, and the action potential ends in a timely fashion, so the muscle can relax in preparation for the next beat.

If sodium channels re-open and produce late sodium currents, as observed in this study with low oxygen levels, the action potential is prolonged and new electrical activity can begin before the heart has recovered risking dangerous, disorganized rhythms.

Fifteen years ago, the Goldstein group reported SUMO regulation of ion channels at the surface of cells. It was an unexpected finding because the SUMO pathway had been thought to operate solely to control gene expression in the nucleus.

This new research shows how rapid SUMOylation of cell surface cardiac sodium channels causes late sodium current in response to hypoxia, a challenge that confronts many people with heart disease, says Goldstein. Previously, the danger of late sodium current was recognized in patients with rare, inherited mutations of sodium channels that cause cardiac Long QT syndrome, and to result from a common polymorphism in the channel we identified in a subset of babies with sudden infant death syndrome (SIDS).

The information gained through the current study offers new targets for therapeutics to prevent late current and arrhythmia associated with heart attacks, chronic heart failure, and other life-threatening low oxygen cardiac conditions.

The National Institutes of Health funded the study, which appears in Cell Reports.

Source: UC Irvine

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How low oxygen levels in the heart can cause arrhythmias - Futurity: Research News

Cardiac Stem Cells Comments Off on How low oxygen levels in the heart can cause arrhythmias – Futurity: Research News | February 20th, 2020

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Global Autologous Stem Cell and Non-Stem Cell Based Therapies Market Latest Research By Business Expansion Plans, Industry Demand Status &...

Cardiac Stem Cells Comments Off on Global Autologous Stem Cell and Non-Stem Cell Based Therapies Market Latest Research By Business Expansion Plans, Industry Demand Status &… | February 20th, 2020

Neuroplast is a company based in Maastricht (the Netherlands) developing autologous stem cell therapies for patients suffering from neurodegenerative diseases such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS) and traumatic brain injury.

Recently, the company has raised 4 million from Dutch-based Brightlands Venture Partners and LIOF and from an existing shareholder and informal investor Lumana Invest BV.

CEO Johannes de Munter said:

The financing and support of the investors will enable us to perform multicenter clinical trials in the Netherlands, Denmark, Germany, and Spain and bring the product to market.

This Dutch startup will use the fund to perform a phase II/III clinical trial with the aim of obtaining conditional market approval for the treatment of patients suffering from Spinal Cord Injury.

Founded by physician Hans de Munter and neurologist Erik Wolters in 2014, Neuroplast has expanded with Juliette van den Dolder, who was appointed as COO and management team member.

In the case of SCI, isolating, manufacturing, and reinserting patients own cells, very promising preclinical outcomes have resulted in an Orphan Drug Designation from European regulatory authorities, allowing a fast-track procedure for the clinical trials. These trials are expected to start in March 2020.

Marcel Kloosterman Director at Brightlands Venture Partners:

Neuroplast combines breakthrough science with a solid management team. In a sizable market characterised by major unmet need, successful treatment of (accident caused) paralysed patients would make life so much easier for them and their families while lowering the burden and costs for the society.

Yearly, 24,500 people in Europe and the USA are diagnosed with Spinal Cord Injury, usually caused by accident. Its worth mentioning that for Europe and the US, the medical cost associated with Spinal Cord Injury is over 13 bn per year.

CEO Johannes de Munter adds:

Neuroplast is becoming an ATMP player in the region and wants to contribute to our beautiful eco-system.

Main image credits:Neuroplast

Stay tuned toSilicon Canalsfor more European technology news

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Dutch startup Neuroplast raises 4M for its stem cell-based technology to treat patients with Spinal Cord Injury - Silicon Canals

Spinal Cord Stem Cells Comments Off on Dutch startup Neuroplast raises 4M for its stem cell-based technology to treat patients with Spinal Cord Injury – Silicon Canals | February 20th, 2020

U.S. Department of Defense Researchers to Study Ability of siFi2 to Drive Axon Regeneration and Functional Recovery following Spinal Cord Injury

NEW YORK, Feb. 19, 2020 (GLOBE NEWSWIRE) -- MicroCures, a biopharmaceutical company developing novel therapeutics that harness the bodys innate regenerative mechanisms to accelerate tissue repair, today announced that it has entered into a material transfer agreement (MTA) with the Henry M. Jackson Foundation (HJF) for the Advancement of Military Medicine. Under terms of the agreement, United States Department of Defense researchers will conduct a preclinical study of siFi2, MicroCures lead product candidate, in animal models of spinal cord injury. siFi2, a small interfering RNA (siRNA) therapeutic that can be applied topically, is designed to enhance recovery after trauma.

Researchers, led by Kimberly Byrnes, Ph.D. of Uniformed Services University of the Health Sciences, will evaluate the potential of siFi2 treatment to drive axon regeneration and functional recovery in a rat model of spinal cord injury. As part of this study, multiple siFi2 formulations will be evaluated in order to assist in the identification of a lead formulation to be advanced into clinical development.

MicroCures technology is based on foundational scientific research at Albert Einstein College of Medicine regarding the fundamental role that cell movement plays as a driver of the bodys innate capacity to repair tissue, nerves, and organs. The company has shown that complex and dynamic networks of microtubules within cells crucially control cell migration, and that this cell movement can be reliably modulated to achieve a range of therapeutic benefits. Based on these findings, the company has established a first-of-its-kind proprietary platform to create siRNA-based therapeutics capable of precisely controlling the speed and direction of cell movement by selectively silencing microtubule regulatory proteins (MRPs).

The company has developed a broad pipeline of therapeutic programs with an initial focus in the area of tissue, nerve and organ repair. Unlike regenerative medicine approaches that rely upon engineered materials or systemic growth factor/stem cell therapeutics, MicroCures technology directs and enhances the bodys inherent healing processes through local, temporary modulation of cell motility. siFi2 is a topical siRNA-based treatment designed to silence the activity of Fidgetin-Like 2 (FL2), a fundamental MRP, within an area of wounded tissue or nerve. In doing so, the therapy temporarily triggers accelerated movement of cells essential for repair into an injury area. Importantly, based on its topical administration, siFi2 can be applied early in the treatment process as a supplement to current standard of care.

The U.S. Department of Defense continues to be a valued and trusted partner for MicroCures as we work to advance research of siFi2 with the goal of ultimately delivering transformative treatments to patients with significant unmet medical needs, said David Sharp, Ph.D., co-founder and chief science officer of MicroCures. With a focus in the area of spinal cord injury, this MTA further demonstrates the broad applicability of our technology platform to a range of therapeutic indications. We look forward to collaborating with Dr. Byrnes and her team at Uniformed Services University of the Health Sciences to continue the advancement of this promising program.

Previously conducted research in a rat model of spinal cord injury has demonstrated that treatment with siFi2 allowed axon growth to occur through the inhibitory barriers that typically appear and prevent healing at the site of injury. Conversely, study results failed to demonstrate similar axon growth through these inhibitory barriers for animals administered a siRNA control treatment. Additional preclinical findings have demonstrated functional improvement in rats with spinal cord injury following treatment with siFi2. This was evidenced by significantly improved hind limb locomotor function in siFi2-treated animals as compared to control subjects at Day 5 (p < 0.05) and Day 7 (p < 0.01).

About MicroCures

Story continues

MicroCures develops biopharmaceuticals that harness innate cellular mechanisms within the body to precisely control the rate and direction of cell migration, offering the potential to deliver powerful therapeutic benefits for a variety of large and underserved medical applications.

MicroCures has developed a broad pipeline of novel therapeutic programs with an initial focus in the area of tissue, nerve and organ repair. The companys lead therapeutic candidate, siFi2, targets excisional wound healing, a multi-billion dollar market inadequately served by current treatments. Additional applications for the companys cell migration accelerator technology include dermal burn repair, corneal burn repair, cavernous nerve repair/regeneration, spinal cord repair/regeneration, and cardiac tissue repair. Cell migration decelerator applications include combatting cancer metastases and fibrosis. The company protects its unique platform and proprietary therapeutic programs with a robust intellectual property portfolio including eight issued or allowed patents, as well as eight pending patent applications.

For more information please visit: http://www.microcures.com

Contact:

Vida Strategic Partners (On behalf of MicroCures)

Stephanie Diaz (investors)415-675-7401sdiaz@vidasp.com

Tim Brons (media)415-675-7402tbrons@vidasp.com

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MicroCures Announces Material Transfer Agreement with Henry M. Jackson Foundation for the Advancement of Military Medicine to Support Preclinical...

Spinal Cord Stem Cells Comments Off on MicroCures Announces Material Transfer Agreement with Henry M. Jackson Foundation for the Advancement of Military Medicine to Support Preclinical… | February 20th, 2020

Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs, announced today that updated results from a Phase I/IIa study of its lead product candidate, OpRegen, a retinal pigment epithelium (RPE) cell transplant therapy currently in development for the treatment of dry age-related macular degeneration (dry AMD), have been accepted for presentation at the 2020 Association for Research in Vision and Ophthalmology (ARVO) Meeting, which will be held May 3rd through May 7th, 2020 at the Baltimore Convention Center in Baltimore, MD. The abstract presentation, entitled, "Phase I/IIa Clinical Trial of Human Embryonic Stem Cell (hESC)-Derived Retinal Pigmented Epithelium (RPE, OpRegen) Transplantation in Advanced Dry Form Age-Related Macular Degeneration (AMD): Interim Results", will be presented as part of the Gene Therapy and Stem cells Session on May 3rd, 2020 from 3:00PM to 4:45PM EDT by Christopher D. Riemann, M.D., Vitreoretinal Surgeon and Fellowship Director, Cincinnati Eye Institute and University of Cincinnati School of Medicine; Clinical Governance Board, Cincinnati Eye Institute (presentation number 865). The presentation will provide updated data from patient cohorts 1 through 4 of the clinical study and will include data on the first patients dosed with both a new subretinal delivery system as well as with a new Thaw-and-Inject (TAI) formulation of OpRegen.

"We continue to be encouraged by positive data with OpRegen for the treatment of dry AMD," stated Brian M. Culley, CEO of Lineage. "The five patients treated as part of cohort 4, which more closely match our intended patient population, have all demonstrated an increase in the number of letters they can read on an Early Treatment Diabetic Retinopathy Scale (ETDRS), having gained between 10 25 letters. Importantly, the first patient treated using both a new subretinal delivery system and our TAI formulation of OpRegen demonstrated notable improvements in vision, having gained 25 readable letters (or 5 lines) 6 months following administration of OpRegen RPE cells, as assessed by the ETDRS. This represents an improvement in visual acuity from a baseline of 20/250 to 20/100 in the treated eye. These visual acuity measurements are meaningful and can translate into quality of life enhancements to things like reading, driving, or avoiding accidents. With the opening of two leading ophthalmology research centers as clinical sites for our study, we are focused on rapid enrollment so that our clinical update at ARVO can be as mature and informative as possible. Our objective is to combine the best cells, the best production process and the best delivery system, which we believe will position us as the front-runner in the race to address the unmet opportunity in the potential billion-dollar dry AMD market."

In addition, Lineage will present new preclinical results from its Vision Restoration Program, a proprietary program based on the ability to generate 3-dimensional human retinal tissue derived from pluripotent cells. Lineages 3-dimensional retinal tissue technology may address the unmet need of implementing a retinal tissue restoration strategy to address a wide range of severe retinal degenerative conditions including retinitis pigmentosa and advanced forms of AMD. In 2017 and 2019, the Small Business Innovation Research program of the National Institutes of Health awarded Lineage grants of close to $2.3 million to further develop this innovative, next generation vision restoration program.

- The poster presentation, entitled, "Transplantation of organoid-derived human retinal tissue in to the subretinal space of CrxRdy/+ cats)," will be presented as part of the Animal models for visual disease and restoration Session on May 4th, 2020 4:00PM to 5:45PM EDT in Session Number 291 by Igor Nasonkin, Ph.D., Principal Investigator, Director of Research & Development at Lineage (Poster board Number: 2253 - B0162).

- The poster presentation, entitled, " Intraocular biocompatibility of Hystem hydrogel for delivery of pharmaceutical agents and cells," will be presented as part of the Stem cells and organoids: Technical advances Session on May 5th, 2020 between 8:45AM to 10:30AM EDT in Session Number 332 by our collaborator Randolph D. Glickman, Ph.D., Professor of Ophthalmology, UT Health San Antonio (Poster board Number: # A0247).

Story continues

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally-differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed either to replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase I/IIa development for the treatment of dry age-related macular degeneration, a leading cause of blindness in the developed world; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase I/IIa development for the treatment of acute spinal cord injuries; and (iii) VAC2, an allogeneic cancer immunotherapy of antigen-presenting dendritic cells currently in Phase I development for the treatment of non-small cell lung cancer. Lineage is also evaluating potential partnership opportunities for Renevia, a facial aesthetics product that was recently granted a Conformit Europenne (CE) Mark. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as "believe," "may," "will," "estimate," "continue," "anticipate," "design," "intend," "expect," "could," "plan," "potential," "predict," "seek," "should," "would," "contemplate," project," "target," "tend to," or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the potential applications in Lineages Vision Restoration Program. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including risks and uncertainties inherent in Lineages business and other risks in Lineages filings with the Securities and Exchange Commission (the SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading "Risk Factors" in Lineages periodic reports with the SEC, including Lineages Annual Report on Form 10-K filed with the SEC on March 14, 2019 and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200218005395/en/

Contacts

Lineage Cell Therapeutics, Inc. IR Ioana C. Hone(ir@lineagecell.com) (510) 871-4188

Solebury Trout IR Gitanjali Jain Ogawa(Gogawa@troutgroup.com)(646) 378-2949

Original post:
Lineage Cell Therapeutics to Present New Data From OpRegen and Vision Restoration Programs at the Association for Research in Vision and Ophthalmology...

Spinal Cord Stem Cells Comments Off on Lineage Cell Therapeutics to Present New Data From OpRegen and Vision Restoration Programs at the Association for Research in Vision and Ophthalmology… | February 20th, 2020

The road into Batlow is littered with the dead.

In the smoky, gray haze of the morning, it's hard to make out exactly what Matt Roberts' camera is capturing. Roberts, a photojournalist with the Australian Broadcasting Corporation, keeps his lens focused on the road as he rolls into the fire-ravaged town 55 miles west of Canberra, Australia's capital. At the asphalt's edge, blackened livestock carcasses lie motionless.

The grim scene, widely shared on social media, is emblematic of the impact the 2019-20 bushfire season has had on Australia's animal life. Some estimates suggest "many, many billions" of animals have been killed, populations of endemic insects could be crippled and, as ash washes into riverways, marine life will be severely impacted. The scale of the bushfires is so massive, scientists are unlikely to know the impact on wildlife for many years.

But even before bushfires roared across the country, Australia's unique native animals were in a dire fight for survival. Habitat destruction, invasive species, hunting and climate change have conspired against them. Populations of native fauna are plummeting or disappearing altogether, leaving Australia with an unenviable record: It has the highest rate of mammal extinctions in the world.

A large share of Australia's extinctions have involved marsupials -- the class of mammals that includes the nation's iconic kangaroos, wallabies, koalas and wombats. A century ago, the Tasmanian tiger still padded quietly through Australia's forests. The desert rat-kangaroo hopped across the clay pans of the outback, sheltering from the sun in dug-out nests.

Now they're gone.

Australia's 2019-20 bushfire season has been devastating for wildlife.

In a search for answers to the extinction crisis, researchers are turning to one lesser-known species, small enough to fit in the palm of your hand: the fat-tailed dunnart. The carnivorous mouse-like marsupial, no bigger than a golf ball and about as heavy as a toothbrush, has a tiny snout, dark, bulbous eyes and, unsurprisingly, a fat tail. It's Baby Yoda levels of adorable -- and it may be just as influential.

Mapping the dunnart's genome could help this little animal become the marsupial equivalent of the lab mouse -- a model organism scientists use to better understand biological processes, manipulate genes and test new approaches to treating disease. The ambitious project, driven by marsupial geneticist Andrew Pask and his team at the University of Melbourne over the last two years, will see scientists take advantage of incredible feats of genetic engineering, reprogramming cells at will.

It could even aid the creation of a frozen Noah's Ark of samples: a doomsday vault of marsupial cells, suspended in time, to preserve genetic diversity and help prevent further decline, bringing species back from the brink of extinction.

If that sounds far-fetched, it isn't. In fact, it's already happening.

Creating a reliable marsupial model organism is a long-held dream for Australian geneticists, stretching back to research pioneered by famed statistician Ronald Fisher in the mid-20th century. To understand why the model is so important, we need to look at the lab mouse, a staple of science laboratories for centuries.

"A lot of what we know about how genes work, and how genes work with each other, comes from the mouse," says Jenny Graves, a geneticist at La Trobe University in Victoria, Australia, who has worked with marsupials for five decades.

The mouse is an indispensable model organism that shares many genetic similarities with humans. It has been key in understanding basic human biology, testing new medicines and unraveling the mysteries of how our brains work. Mice form such a critical part of the scientific endeavor because they breed quickly, have large litters, and are cheap to house, feed and maintain.

The lab mouse has been indispensable in understanding physiology, biology and genetics.

In the 1970s, scientists developed a method to insert new genes into mice. After a decade of refinement, these genetically modified mice (known as "transgenic mice") provided novel ways to study how genes function. You could add a gene, turning its expression up to 11, or delete a gene entirely, shutting it off. Scientists had a powerful tool to discover which genes performed the critical work in reproduction, development and maturation.

The same capability does not exist for marsupials. "At the moment, we don't have any way of manipulating genes in a devil or a kangaroo or a possum," says Graves. Without this capability, it's difficult to answer more pointed questions about marsupial genes and how they compare with mammal genes, like those of mice and humans.

So far, two marsupial species -- the Tammar wallaby and the American opossum -- have been front and center of research efforts to create a reliable model organism, but they both pose problems. The wallaby breeds slowly, with only one baby every 18 months, and it requires vast swaths of land to maintain.

The short-tailed opossum might prove an even more complicated case. Pask, the marsupial geneticist, says the small South American marsupial is prone to eating its young, and breeding requires researchers to sift through hours of video footage, looking for who impregnated whom. Pask also makes a patriotic jab ("they're American so we don't like them") and says their differences from Australian marsupials make them less useful for the problems Australian species face.

But the dunnart boasts all the features that make the mouse such an attractive organism for study: It is small and easy to house, breeds well in captivity and has large litters.

"Our little guys are just like having a mouse basically, except they have a pouch," Pask says.

Pask (front) and Frankenberg inspect some of their dunnarts at the University of Melbourne.

A stern warning precedes my first meeting with Pask's colony of fat-tailed dunnarts.

"It smells like shit," he says. "They shit everywhere."

I quickly discover he's right. Upon entering the colony's dwellings on the third floor of the University of Melbourne's utilitarian BioSciences building, you're punched in the face by a musty, fecal smell.

Pask, a laid-back researcher whose face is almost permanently fixed with a smile, and one of his colleagues, researcher Stephen Frankenberg, appear unfazed by the odor. They've adapted to it. Inside the small room that houses the colony, storage-box-cages are stacked three shelves high. They're filled with upturned egg cartons and empty buckets, which work as makeshift nests for the critters to hide in.

Andrew Pask

Frankenberg reaches in without hesitation and plucks one from a cage -- nameless but numbered "29" -- and it hides in his enclosed fist before peeking out of the gap between his thumb and forefinger, snout pulsing. As I watch Frankenberg cradle it, the dunnart seems curious, and Pask warns me it's more than agile enough to manufacture a great escape.

In the wild, fat-tailed dunnarts are just as inquisitive and fleet-footed. Their range extends across most of southern and central Australia, and the most recent assessment of their population numbers shows they aren't suffering population declines in the same way many of Australia's bigger marsupial species are.

Move over, Baby Yoda.

As I watch 29 scamper up Frankenberg's arm, the physical similarities between it and a mouse are obvious. Pask explains that the dunnart's DNA is much more closely related to the Tasmanian devil, an endangered cat-sized carnivore native to Australia, than the mouse. But from a research perspective, Pask notes the similarities between mouse and dunnart run deep -- and that's why it's such an important critter.

"The dunnart is going to be our marsupial workhorse like the mouse is for placental mammals," Pask says.

For that to happen, Pask's team has to perfect an incredible feat of genetic engineering: They have to learn how to reprogram its cells.

To do so, they collect skin cells from the dunnart's ear or footpad and drop them in a flask where scientists can introduce new genes into the skin cell. The introduced genes are able to trick the adult cell, convincing it to become a "younger," specialized cell with almost unlimited potential.

The reprogrammed cells are known as "induced pluripotent stem cells," or iPS cells, and since Japanese scientists unraveled how to perform this incredible feat in 2006, they have proven to be indispensable for researchers because they can become any cell in the body.

"You can grow them in culture and put different sorts of differentiation factors on them and see if they can turn into nerve cells, muscle cells, brain cells, blood vessels," Pask explains. That means these special cells could even be programmed to become a sperm or an egg, in turn allowing embryos to be made.

Implanting the embryo in a surrogate mother could create a whole animal.

It took about 15 minutes to get this dunnart to sit still.

Although such a technological leap has been made in mice, it's still a long way from fruition for marsupials. At present, only the Tasmanian devil has had iPS cells created from skin, and no sperm or egg cells were produced.

Pask's team has been able to dupe the dunnart's cells into reverting to stem cells -- and they've even made some slight genetic tweaks in the lab. But that's just the first step.

He believes there are likely to be small differences between species, but if the methodology remains consistent and reproducible in other marsupials, scientists could begin to create iPS cells from Australia's array of unique fauna. They could even sample skin cells from wild marsupials and reprogram those.

Doing so would be indispensable in the creation of a biobank, where the cells would be frozen down to -196 degrees Celsius (-273F) and stored until they're needed. It would act as a safeguard -- a backup copy of genetic material that could, in some distant future, be used to bring species back from the edge of oblivion, helping repopulate them and restoring their genetic diversity.

Underneath San Diego Zoo's Beckman Center for Conservation Research lies the Frozen Zoo, a repository of test tubes containing the genetic material of over 10,000 species. Stacked in towers and chilled inside giant metal vats, the tubes contain the DNA of threatened species from around the world, suspended in time.

It's the largest wildlife biobank in the world.

"Our goal is to opportunistically collect cells ... on multiple individuals of as many species as we can, to provide a vast genetic resource for research and conservation efforts," explains Marlys Houck, curator at the Frozen Zoo.

The Zoo's efforts to save the northern white rhino from extinction have been well publicized. Other research groups have been able to create a northern white rhino embryo in the lab, combining eggs of the last two remaining females with frozen sperm from departed males. Scientists propose implanting those embryos in a surrogate mother of a closely related species, the southern white rhino, to help drag the species back from the edge of oblivion.

For the better part of a decade, conservationists have been focused on this goal, and now their work is paying off: In the "coming months," the lab-created northern white rhino embryo will be implanted in a surrogate.

Sudan, the last male northern white rhinoceros, was euthanized in 2018.

Marisa Korody, a conservation geneticist at the Frozen Zoo, stresses that this type of intervention was really the last hope for the rhino, a species whose population had already diminished to just eight individuals a decade ago.

"We only turn to these methods when more traditional conservation methods have failed," she says.

In Australia, researchers are telling whoever will listen that traditional conservation methods are failing.

"We've been saying for decades and decades, many of our species are on a slippery slope," says John Rodger, a marsupial conservationist at the University of Newcastle, Australia, and CEO of the Fauna Research Alliance, which has long advocated for the banking of genetic material of species in Australia and New Zealand.

In October, 240 of Australia's top scientists delivered a letter to the government detailing the country's woeful record on protecting species, citing the 1,800 plants and animals in danger of extinction, and the "weak" environmental laws which have been ineffective at keeping Australian fauna alive.

Institutions around Australia, such as Taronga Zoo and Monash University, have been biobanking samples since the '90s, reliant on philanthropic donations to stay online, but researchers say this is not enough. For at least a decade, they've been calling for the establishment of a national biobank to support Australia's threatened species.

John Rodger

"Our real problem in Australia ... is underinvestment," Rodger says. "You've got to accept this is not a short-term investment."

The current government installed a threatened-species commissioner in 2017 and committed $255 million ($171 million in US dollars) in funding to improve the prospects of 20 mammal species by 2020. In the most recent progress report, released in 2019, only eight of those 20 were identified as having an "improved trajectory," meaning populations were either increasing faster or declining slower compared to 2015.

A spokesperson for the commissioner outlined the $50 million investment to support immediate work to protect wildlife following the bushfires, speaking to monitoring programs, establishment of "insurance populations" and feral cat traps. No future strategies regarding biobanking were referenced.

Researchers believe we need to act now to preserve iconic Australian species like the koala.

In the wake of the catastrophic bushfire season and the challenges posed by climate change, Australia's extinction crisis is again in the spotlight. Koalas are plastered over social media with charred noses and bandaged skin. On the front page of newspapers, kangaroos bound in front of towering walls of flame.

Houck notes that San Diego's Frozen Zoo currently stores cell lines "from nearly 30 marsupial species, including koala, Tasmanian devil and kangaroo," but that's only one-tenth of the known marsupial species living in Australia today.

"Nobody in the world is seriously working on marsupials but us," Rodger says. "We've got a huge interest in maintaining these guys for tourism, national icons... you name it."

There's a creeping sense of dread in the researchers I talk to that perhaps we've passed a tipping point, not just in Australia, but across the world. "We are losing species at an alarming rate," says Korody from the Frozen Zoo. "Some species are going extinct before we even know they are there."

With such high stakes, Pask and his dunnarts are in a race against time. Perfecting the techniques to genetically engineer the tiny marsupial's cells will help enable the preservation of all marsupial species for generations to come, future-proofing them against natural disasters, disease, land-clearing and threats we may not even be able to predict right now.

Pask reasons "we owe it" to marsupials to develop these tools and, at the very least, biobank their cells if we can't prevent extinction. "We really should be investing in this stuff now," he says. He's optimistic.

In some distant future, years from now, a bundle of frozen stem cells might just bring the koala or the kangaroo back from the brink of extinction.

And for that, we'll have the dunnart to thank.

Originally published Feb. 18, 5 a.m. PT.

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Building a 'doomsday vault' to save the kangaroo and koala from extinction - CNET

Skin Stem Cells Comments Off on Building a ‘doomsday vault’ to save the kangaroo and koala from extinction – CNET | February 20th, 2020

Understanding the genetic causes of rare diseases supports drug development. Credit: Shutterstock.

Developing drugs to treat rare diseases is fraught with challenges; these range from trying to recruit from tiny patient populations to fill much-need clinical trials to the complex reimbursement landscape for these innovative, and often bespoke, therapies. However, as scientists improve their understanding of the genetic causes of many rare conditions and regulators explore new reimbursement options, pharma companies and smaller biotech firms are increasingly being empowered to address more of these tricky indications.

In this context, could 2020 be a breakthrough year for patients with rare diseases? Here are three case studies of companies on the verge of having treatments for rare diseases approved Rocket and Fanconi anaemia, PTC Therapeutics and aromatic l-amino acid decarboxylase (AADC) deficiency and, finally, Amryt and epidermolysis bullosa.

Fanconi anaemia (FA) is a rare paediatric inherited diseasecharacterised by bone marrow failure and predisposition to cancer, in the words of Rocket Pharmas CEO Gaurav Shah. Caused by a mutation in the FANC genes, patients with Fanconi experience bone marrow failure as they are unable to create new blood cells.

The current standard of care for Fanconi is a stem cell transplant, but Shah explains the risks involved with these pioneering procedures.

While these transplants do prolong patients lives, the procedure is incredibly difficult and is associated with a high potential for graft-versus-host disease, he says. Stem cell transplants can also lead to an even higher risk of head and neck cancer risk for Fanconi patients; almost everyone with FA who undergoes this procedure dies in their 30s.

Rocket wants to change this situation with its lentiviral vector gene therapy, RP-L102. It is specifically for Fanconi-A, which Shah explains is the most common form of the disease. He adds that the therapy contains patient-derived haematopoietic stem cells that have been generally modified to contain a functional copy of FANCA gene, a mutation which causes Fanconi-A.

RP-L102 is currently in a global registrational Phase IIA study, which has been efficacious and safe in patients so far. The data demonstrate that a single dose of RP-L102 leads to both genetic and functional correction as measured by a progressive increase in corrected peripheral blood and bone marrow cells, says Shah. Most importantly, this treatment can be administered without a conditioning regimen [of chemotherapy and radiation]. [This] means we may be able to treat patients as a preventative measure before bone marrow failure occurs, like a vaccine, with a single dose administration early in life.

Based on these promising signals, RP-L102 has received all accelerated regulatory tools from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The company is hoping to complete its biologics license applications and marketing authorisation applications (MAA) to the two regulators within the next few years.

To overcome challenges facing Rocket in the development of RP-L102, Shah explains the company worked to improve upon its own expertise in rare diseases by working with world-class research and development partners, as well immersing itself within patient communities to learn more about their treatment needs.

Slightly further along the drug approval journey is PTC Therapeutics AADC deficiency drug, PTC-AADC, for which the company recently submitted an MAA to the EMA. The company expects full EMA approval towards the end of 2020 and to treat the first patients either in the first or second quarter of 2021.

PTC acquired PTC-AADC, alongside other gene therapy assets, when it bought rare central nervous system-focused Agilis Biotherapeutics in July 2018, PTCs EMEA and Asia Pacific senior vice-president and general manager Adrian Haigh explains.

AADC deficiency is a rare condition caused by a mutation in the DDC gene, which leads to issues with the AADC enzyme and subsequent reductions in the production of dopamine. Children suffering with AADC deficiency fail to reach neurological and development milestones and have a high risk of death early in life. The only current approach to treating the condition is through dopamine agonists, which Haigh notes are largely ineffective.

The particular approach developed by Agilis, [which is] unlike other forms of gene therapy, involves delivering a very small dose of gene therapy directly into the affected, post-mitotic cells, Haigh says. The rationale is that once youve delivered the drug to post-mitotic cells, which are not dividing, it is going to stay there for a long time.

Other advantages include a reduced chance of significant immune reaction and since the dose is smaller, the treatment could overcome some of the manufacturing issues facing other gene therapies. PTC has decided to bring PTC-AADCs manufacturing in house so they are not reliant on third parties schedules and capacities.

PTCs MAA for its AADC deficiency gene therapy is based on two clinical trials of 26 patients in total. Haigh explains the company has mapped motor milestones, and he noted that in advisory boards with payers theyve been incredibly impressed by our videos showing children progressing from lying flat on their backs to walking around.

He notes that in this case, it is certainly not ethical to drill a hole in a patients head and inject a virus containing a placebo and instead PTC has successfully completed a single-arm trial by comparing with patients natural history. Regulators need to be open to novel clinical trial design, particularly in rare diseases where you have ethical problems, Haigh argues.

The company had to abandon a previous drug in development because they could not agree an economic and deliverable clinical trial design with the FDA.

One of the main challenges that faced PTC in the development of PTC-AADC was diagnosis. Haigh explains they found a lot of patients have been misdiagnosed with either cerebral palsy or epilepsy so the company launched a free genetic testing programme. This also allowed them to find patients to recruit into the trial and estimate the number of patients with AADC deficiency who might be able to benefit from this gene therapy.

Epidermolysis bullosa (EB) is a group of rare skin conditions caused by genetic mutations in the genes that encode for the proteins of the skin, particularly in collagen VII.

There are currently no approved treatments for this condition, EB charity DEBRAs UK branch director of research Caroline Collins notes the condition is managed by regular changing of dressings and the lancing of blisters.

EB is characterised by blisters and wounds on the skin; these wounds are extremely painful and can cover huge areas of the patients body, such as their whole back or entire legs. However, Collins explains these are not like the kinds of wounds you get with ulcers or burns, and they move continuously.

As well as making it incredibly challenging for patients to deal with these never-healing wounds, it also makes it difficult for drug developers to find and establish accepted clinical trial endpoints centred on wound healing. DEBRA is therefore advocating for natural history to be considered in clinical trial designs, Collins explains.

Despite these challenges, UK drug company Amryt is hoping to submit authorisation applications to the FDA and EMA by the end of 2021 for its EB drug, AP101. The company has repurposed the topical gel created for burns wounds to treat EB. It is made from a combination of an extract from the bark of the birch tree and pure sunflower oil, the companys chief medical officer Dr Mark Sumeray explains.

AP101 is currently being studied in a Phase III study Amryt claim this is the biggest global EB trial ever undertaken and has been granted rare paediatric disease designation from the FDA.

Although the current results are blinded, Sumeray explains a recent analysis by an independent data monitoring board found that the firm only needed to increase the number of patients slightly, suggesting that at this point in time, the data would have looked encouraging. Too small a patient population makes it hard for efficacy to be statistically significant.

Since Amryts AP101 may be the first drug approved for EB, Collins emphasises it is important that the company has productive conversations with regulators about the specific challenges of EB. This will help to set the ground for others to follow and further transform the lives of EB patients.

It is clear that Amryt is committed to EB because the company in-licensed a second EB candidate, a topical gene therapy called AP103 in 2018.

Sumeray explains: We have invested a lot of time and effort in the development, not only of the lead product, but also of relationships with physicians and scientists working in EB. If we can figure out how to successfully bring products to the market and have them reimbursed, then all of that knowledge can applied again.

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Rare disease outlook 2020: three therapies set to make waves this year - pharmaceutical-technology.com

Skin Stem Cells Comments Off on Rare disease outlook 2020: three therapies set to make waves this year – pharmaceutical-technology.com | February 20th, 2020

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to enfortumab vedotin-ejfv (Padcev; Astellas Pharma and Seattle Genetics) in combination with Mercks (known as MSD outside the United States and Canada) anti-PD-1 therapy pembrolizumab (Keytruda) for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting.

It is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020. [1] Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. [2] Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide. [3]

The recommended first-line treatment for patients with advanced urothelial cancer is cisplatin-based chemotherapy. For patients who are unable to receive cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens. [4]

Conditionally approvedEnfortumab vedotin-ejfv, a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer, was conditionally approved by the FDA in December 2019 based on the Accelerated Approval Program. [5][6]

Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.

With seven approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.

Continued approval for enfortumab vedotin-ejfv in combination with pembrolizumab for the treatment of patients with advanced or metastatic urothelial cancer may be contingent upon verification and description of clinical benefit in confirmatory trials. [5]

The drug is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting.

Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis). [5]

Breakthrough therapyThe Breakthrough Therapy process is designed to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition. The designation is based upon preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints. In the case of enfortumab vedotin, the designation was based on the initial results from Phase Ib/II EV-103 Clinical Trial.

The FDAs Breakthrough Therapy designation reflects the encouraging preliminary evidence for the combination of enfortumab vedotin and pembrolizumab in previously untreated advanced urothelial cancer to benefit patients who are in need of effective treatment options, said Andrew Krivoshik, M.D., Ph.D., Senior Vice President, and Oncology Therapeutic Area Head, Astellas.

We look forward to continuing our work with the FDA as we progress our clinical development program as quickly as possible.

This is an important step in our investigation of enfortumab vedotin in combination with pembrolizumab as first-line therapy for patients with advanced urothelial cancer who are unable to receive cisplatin-based chemotherapy, said Roger Dansey, M.D., Chief Medical Officer, Seattle Genetics.

Based on encouraging early clinical activity, we recently initiated a phase III trial of this platinum-free combination and look forward to potentially addressing an unmet need for patients.

Clinical trialThe Breakthrough Therapy designation was granted based on results from the dose-escalation cohort and expansion cohort A of the Phase Ib/II trial, EV-103 (NCT03288545), evaluating patients with locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy-treated in the first-line setting with enfortumab vedotin-ejfv in combination with pembrolizumab.

The initial results from the trial were presented at the European Society of Medical Oncology (ESMO) 2019 Congress, and updated findings at the 2020 Genitourinary Cancers Symposium.

EV-103 is an ongoing, multi-cohort, open-label, multicenter phase Ib/II trial of PADCEV alone or in combination, evaluating the safety, tolerability, and efficacy in muscle-invasive, locally advanced and first- and second-line metastatic urothelial cancer.

Adverse eventsSerious adverse reactions occurred in 46% of patients treated with enfortumab vedotin-ejfv. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Discontinuing treatmentAdverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Specific recommendations

HyperglycemiaHyperglycemia occurred in patients treated with enfortumab vedotin-ejfv, including death and diabetic ketoacidosis (DKA), in patients with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In one clinical trial, 8% of patients developed Grade 3-4 hyperglycemia. Patients with baseline hemoglobin A1C 8% were excluded.

Physicians are recommended to closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia and, if blood glucose is elevated (>250 mg/dL), withhold the drug.

Peripheral neuropathyPeripheral neuropathy (PN), predominantly sensory, occurred in 49% of the 310 patients treated with enfortumab vedotin-ejf in clinical trials. Two percent (2%) of patients experienced Grade 3 reactions. In one clinical trial, peripheral neuropathy occurred in patients treated with enfortumab vedotin-ejf with or without preexisting peripheral neuropathy.

The median time to onset of Grade 2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement.

Physicians should:

Occular disordersOcular disorders occurred in 46% of the 310 patients treated with enfortumab vedotin-ejf. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes. Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with enfortumab vedotin-ejf.

The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2).

Physicians should monitor patients for ocular disorders and consider:

Skin reactionsSkin reactions occurred in 54% of the 310 patients treated with enfortumab vedotin-ejf in clinical trials. Twenty-six percent (26%) of patients had a maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. In one clinical trial, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3).

Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement.

Physicians should monitor patients for skin reactions, and consider:

Infusion site extravasationSkin and soft tissue reactions secondary to extravasation have been observed after the administration of enfortumab vedotin-ejf. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed.

Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent (1%) of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation.

Physicians should ensure adequate venous access prior to starting enfortumab vedotin-ejf and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicityEnfortumab vedotin-ejf can cause fetal harm when administered to a pregnant woman.

Physicians should advise patients of the potential risk to the fetus and advise female patients of reproductive potential to use effective contraception during enfortumab vedotin-ejf treatment and for 2 months after the last dose. At the same time, they should advise male patients with female partners of reproductive potential to use effective contraception during treatment with enfortumab vedotin-ejf and for 4 months after the last dose.

Clinical trialA Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) NCT03288545

References[1] American Cancer Society. Cancer Facts & Figures 2020. Online. Last accessed on January 23, 2020.[2] American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). Online. Last accessed on January 23, 2020.[3] International Agency for Research on Cancer. Cancer Tomorrow: Bladder. Online. Last accessed on January 23, 2020.[4] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 4; July 10, 2019. Online. Last accessed on January 23, 2020.[5] Enfortumab vedotin-ejfv (Padcev; Astellas Pharma [package insert]. Northbrook, IL)[6] Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.

A version of this article was first published in ADC Review | Journal of Antibody-drug Conjugates.

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Combination Enfortumab Vedotin + Pembrolizumab Granted Breakthrough Therapy in Bladder Cancer - OncoZine

Skin Stem Cells Comments Off on Combination Enfortumab Vedotin + Pembrolizumab Granted Breakthrough Therapy in Bladder Cancer – OncoZine | February 20th, 2020

On August 23, 2019, the FamilieSCN2A Foundation held their biennial SCN2A Professional and Family meeting, in Seattle, Washington. The gathering brought together 37 families of individuals with mutations in the SCN2A gene, 60 investigators, eight clinicians and five industry groups that conduct research and/or clinical work on conditions related to this genetic change. A number of SFARI scientists and staff also attended the event.

The SCN2A family meeting was one of many events that family organizations of rare, neurodevelopmental disorders organized last summer. These meetings help families connect with others similarly affected as well as professionals working to better understand these conditions and develop new therapeutics. SFARI often attends and facilitates research opportunities carried on at these events.

SCN2A is a high-confidence autism risk gene, which encodes a subunit of a sodium channel in the brain called Nav1.2. When the channel malfunctions, conditions like epilepsy and autism follow. As part of its mission to understand the genetics and neurobiological underpinnings of autism, SFARI has awarded about $3 million for research on SCN2A, and some of this research was presented at the meeting. SFARI also supports a genetics first initiative called Simons Searchlight (formerly known as Simons VIP), which enrolls people with a genetic diagnosis showing rare genetic changes associated with autism and related neurodevelopmental conditions, such as SCN2A.

Many stories that may reflect the different ways SCN2A can be disabled were told at the meeting. One child had his first seizure when he was days old, and now spends many of his days irritable and immobilized by dystonia. Another developed normally until his first seizure as a toddler, which seemed to wipe out all of his skills; his milestones are now hard won in the face of continuing seizures and an autism diagnosis. Another had a sudden regression at 1 year of age, and after a misdiagnosis and seizure medication, she goes to a school for children with autism. Still another suffered from relentless seizures, which robbed her of speech; she died last year at the age of 12.

So far, about 300 different variants of the SCN2A gene have beendocumented, and the functional consequences of many are unclear. Some researchers have developed high-throughput experiments to systematically test each of thesevariants, and to screen compounds that could normalize their function2. Another approach may use genetherapy to boostexpression of the remaining good copy of SCN2A. Either way, finding appropriate in vitro testing grounds for these SCN2A variants is essential and may help personalize treatment approaches or identify more homogeneous patient groups for drug trials.

The meeting also underscored the power of family gatherings to push the science ahead. Investigators could see multiple examples of a rare genetic condition and engage new participants in research studies such as The Investigation of Genetic Exome Research (TIGER), a project of the University of Washington that compares phenotypes of single-gene conditions. In turn, families had the opportunity to express their concerns to scientists and infuse the research proceedings with urgency.

My biggest takeaway from this years conference was the mutual inspiration between the scientists and the families, says Leah Schust, meeting organizer and executive director of the FamilieSCN2A Foundation. Her son has a mutation in SCN2A.

Meeting the researchers working on a cure for our kids motivates us to fight on, Schust says. Then the scientists all say that meeting the families inspires them to go back to their labs and work even harder.

Family focus. The family meeting helped researchers reconsider what would be meaningful clinical endpoints for potential treatments. Schust says that most researchers and industry groups had thought seizure control was the most important issue. After listening to us, they realized that quality of life, movement disorders and autonomic dysfunction are higher on our list of where we would like to see improvement, she says.

When SCN2A mutations were first linked to autism, the gene stood out because it encodes a relatively well-understood protein, unlike many of the other identified genes. Nav1.2 is a voltage-gated channel found exclusively on excitatory neurons in the brain, where it controls the flow of sodium ions into the neuron, and thus its propensity for firing action potential. Experiments have revealed detailed pictures of Nav1.2s structure3, and known drugs alter its function4.

SCN2A also stands out because of its high recurrence rate in autism: unlike other autism genes, SCN2A is mutated with somewhat regular frequency5 (Figure 1).

Just as understanding why a car wont start is critical to fixing it, researchers need to understand how these SCN2A mutations alter the Nav1.2 channel. A current model1 posits that some mutations are gain-of-function, rendering the channel too active and the brain hyperexcitable, leading to infantile epilepsy; conversely, loss-of-function mutations reduce excitability and seem associated with autism and/or intellectual disability, as well as childhood-onset (as opposed to neonatal) seizures.

Yet the functional consequences of most SCN2A mutations remain unknown, and some may not fall neatly into a loss-of-function or gain-of-function category. A way of making sense of these mutations may come from looking at the working parts of Nav1.2, said Arthur Campbell of the Broad Institute of MIT and Harvard. For example, missense SCN2A variants linked to epilepsy seem to hit the channel randomly. But when marking their location on a crystal structure model of the channel, the missense variants cluster in several places: on the voltage sensor, on the linker helix responsible for conveying voltage sensor movement to the channel pore, on an area thought to interact with the beta-subunits involved in chaperoning the channel to the right place, and on the inactivation gate, which closes the pore off from sodium ion flow. He suggested that this knowledge, combined with the structural similarities between all sodium channels, may help drug development for SCN2A-related conditions.

High-throughput systems that can assay hundreds of cells at a time are helping researchers systematically explore SCN2A mutation, explained SFARI Investigator Al George of Northwestern University. While conventional electrophysiology would require weeks of work to characterize a single SCN2A variant, Georges group uses an automated patch-clamp system that can characterize multiple variants transfected into non-neuronal cell lines in a day. Using this system, two variants associated with neonatal seizures both exhibited an exceptional willingness to activate and a slowness to inactivate, which are properties consistent with a gain-of-function interpretation.

The high-throughput set up also promises to expedite the hunt for drugs to normalize SCN2A function: George described a 384-well plate design that allows measurement of the effects of two different drugs, at four different concentrations, on the SCN2A variant and control channels simultaneously. A known drug (carbamazepine) and an experimental drug (PRX-330) shifted channel inactivation to more hyperpolarized voltages, which could help quiet channels with gain-of-function mutations.

To narrow in on potentially therapeutic compounds, Jeff Cottrell and colleagues at the Broad Institute of MIT and Harvard have come up with a two-stage screen to find small molecule activators or inhibitors of Nav1.2 channels. First, compounds are initially tested on non-neural cells transfected with Nav1.2 sodium channels and potassium channels, which enables them to spike. The cells in 384-well plates are stimulated in parallel, and voltage-sensitive dyes give a readout of spiking activity; remarkably, Cottrells system allows data collection from up to 96 wells simultaneously. Any compounds that modulate spiking would then be subjected to the second stage, in a high-throughput electrophysiology assay similar to that described by George. Compounds with helpful mechanisms would then be tested for selectivity for Nav1.2 versus other sodium channels. A selective compound would then be tested in neurons, first in vitro then in vivo. This step-wise process has identified an activating compound that makes Nav1.2 more likely to open at rest and has potent effects on action potentials in brain slices and on electroencephalogram (EEG) traces from mice engineered to carry a disabled copy of SCN2A; however, Cottrell said this particular compound is not a therapeutic candidate in part because it broadens the action potential in a way that could promote seizures. A full screen is underway, and so far has identified 378 modulators from a library of 77,000 compounds.

Beyond academia, J.P. Johnson Jr. of Xenon in Burnaby, British Columbia, discussed the companys work to create sodium channel inhibitors for treating epilepsy. To obtain selective compounds, the group targets the voltage-sensing domain because its structure is the most diverse region of sodium channels. Xenon uses a trial-and-error method to optimize sodium channel inhibitor potency and selectivity. The methodical process has yielded some interesting compounds, including both selective Nav1.6 inhibitors and dual Nav1.6 and Nav1.2 inhibitors. Both quashed spiking in mouse excitatory pyramidal neurons, which contain only Nav1.2 and Nav1.6, but they did not alter spiking in Nav1.1-containing inhibitory neurons. A Nav1.6 selective inhibitor, XEN901, is currently undergoing safety trials in humans.

Kathrin Meyer of Nationwide Childrens Hospital in Columbus, Ohio, addressed the possibility of using gene therapy to normalize malfunctioning Nav1.2 channels. Meyer has been involved in several gene-therapy trials for neuromuscular disorders, including a successful one for infant-onset spinal muscular atrophy type6. Gene therapy for brain diseases was spurred by the discovery of adeno-associated virus 9 (AAV9), which can cross the bloodbrain barrier to deliver genetic material to the central nervous system. AAV9 is small, cannot replicate, does not integrate into host DNA and seems not to cause disease in humans. In considering gene therapy for SCN2A-related conditions, Meyer emphasized an approach that adds back a working copy of the gene, thus sidestepping the need for gene editing to make mutation-specific corrections. Such a treatment would only apply to those with loss-of-function mutations.

The large size of the SCN2A gene precludes its delivery by AAV9, however. As a workaround, Meyer suggested that SCN2As mRNA transcript could be targeted in an attempt to replace only the affected area of the mRNA. So far, such strategies have not been very efficient, but there are new ideas that might address some of the difficulties. Because access to tissue samples of patients with neurological disorders is limited, the development and testing of new therapies is complicated. Meyer suggested developing gene therapies in vitro using neurons reprogrammed from skin cells of patients. This might help identify which patients would react best to a certain treatment. There is likely not a one-fit-for-all situation, she said.

SFARI deputy scientific director John Spiro underscored the need for in vitro systems, citing the organizations initiative to bank blood cells to systematically generate induced pluripotent stem cells from individuals with autism. Simons Searchlight is also a resource of many different biospecimens for researchers. So far, 186 families with SCN2A-related changes have registered, and 83 of these have completed consent, lab reports and medical histories with a large number of blood samples as well. (On the sidelines of the meeting, 18 parents, 11 of their children with SCN2A mutations, and three unaffected siblings donated blood toward this initiative.) Spiro also stressed a need to come up with more quantitative methods of phenotyping, such as wearable electronics that can monitor sleep and circadian rhythms. Data that can be collected longitudinally and at home might provide sensitive outcome measures for clinical trials.

A new role for Nav1.2 has been revealed in recent work described by SFARI Investigator Kevin Bender of the University of California, San Francisco: the channels mediate back-propagating action potentials, which travel into the dendritic trees of neurons. Mice engineered to lack one copy of SCN2A a situation that mimics people with truncating SCN2A mutations that render the resulting Nav1.2 channels useless had cortical neurons with slower action potentials, reduced dendritic excitability and immature synapses based on their shape and function7. This role for Nav1.2 was particularly important later in development: when conditional knockout mice lost an SCN2A copy later in life, their cortical neurons exhibited immature synapses, though their density remained normal. Preliminary experiments suggest that adding back a working copy of SCN2A later in life through transgenic methods or by upregulating transcription of the remaining good copy of SCN2A via CRISPR techniques can restore action potential velocity and synaptic maturity.

Bender stressed how interacting with the SCN2A family group helped focus his research on important aspects of their childrens conditions. For example, parents have noted sensory hypersensitivity in their children, leading Bender to collaborate with colleague Evan Feinberg to use an eye-tracking assay in mice to measure their visual responses. He noted that SCN2A haploinsufficient mice were more sensitive to certain visual stimuli than control mice; if the assay is robust, it could help bridge the gap between SCN2A-related phenotypes in humans and behaviors measured in mice.

As meeting attendees sorted through the new findings, therapeutic questions lingered. An important issue for any therapy, whether drug or gene, will be how early in development one will have to intervene to help someone with an SCN2A mutation. Bender noted that synaptic properties could be rescued in his mice when they were 30 days old equivalent to a 10-year-old human but these and other experiments will have to probe the time periods during which therapies will be maximally effective. To find good measures of efficacy also means understanding the full complement of conditions that beset people with SCN2A mutations. For example, though seizures afflict many, Keith Coffman of Childrens Mercy Hospital in Kansas City, Missouri, suggested that, in some cases, these represent a movement disorder rather than epilepsy. Basic descriptive knowledge like this is imperative for guiding future treatment approaches.

Another smaller SCN2A meeting is planned for this year from July 30 to August 2, in Columbus, Ohio. This will be more family focused, says Schust, and there will be opportunities to participate in research.

There is clearly a lot more work to do before all the terrific basic research that was discussed at this meeting produces meaningful results for families, but it is extremely gratifying to see how much progress has been made on so many fronts and how many new good ideas are emerging, Spiro says. And its terrific to witness firsthand the positive cycle of how families drive researchers and vice versa.

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Seeing through a forest of SCN2A gene variation - SFARI News

Skin Stem Cells Comments Off on Seeing through a forest of SCN2A gene variation – SFARI News | February 20th, 2020

FEBRUARY 19, 2020 When Lt. Col. Jason Barnhill traveled to Africa last summer, he took with him not only the normal gear of an Army officer, but also a 3D printer.

Barnhill, who is the life science program director at the U.S. Military Academy, traveled to Africa to study how 3D printers could be used for field medical care. Barnhills printer was not set up to print objects made out of plastics as the printers are frequently known for. Instead, his printer makes bioprinted items that could one day be used to save Soldiers injured in combat.

The 3D bioprinting research has not reached the point where a printed organ or meniscus can be implanted into the body, but Barnhill and a team of cadets are working to advance the research in the field.

Twenty-six firsties are doing bioprinting research across seven different projects as their capstone this year. Two teams are working on biobandages for burn and field care. Two teams are working on how to bioengineer blood vessels to enable other bioprinted items that require a blood source, such as organs, to be viable. One team is working on printing a viable meniscus and the final team is working on printing a liver.

The basic process of printing biomaterial is the same as what is used to print a plastic figurine. A model of what will be printed is created on the computer, it is digitally sliced into layers and then the printer builds it layer by layer. The difference is the ink that is used.

Instead of heating plastic, 3D bioprinting uses a bioink that includes collagen, a major part of human tissue, and cells, typically stem cells.

A lot of this has to do with the bioink that we want to use, exactly what material were using as our printer ink, if you will, Class of 2020 Cadet Allen Gong, a life science major working on the meniscus project, said. Once we have that 3D model where we want it, then its just a matter of being able to stack the ink on top of each other properly.

Cadets are researching how to use that ink to create a meniscus to be implanted into a Soldiers injured knee or print a liver that could be used to test medicine and maybe one day eliminate the shortage of transplantable organs.

The research at West Point is funded by the Uniformed Services University of Health Science and is focused on increasing Soldier survivability in the field and treating wounded warriors.

Right now, cadets on each of the teams are in the beginning stages of their research before starting the actual printing process. The first stage includes reading the research already available in their area of focus and learning how to use the printers. After spring break, they will have their first chance to start printing with cells.

For the biobandage, meniscus and liver teams, the goal is to print a tangible product by the end of the semester, though neither the meniscus or liver will be something that could be implanted and used.

There are definitely some leaps before we can get to that point, Class of 2020 Cadet Thatcher Shepard, a life science major working on the meniscus project, said of actually implanting what they print. (We have to) make sure the body doesnt reject the new bioprinted meniscus and also the emplacement. There can be difficulties with that. Right now, were trying to just make a viable meniscus. Then, well look into further research to be able to work on methods of actually placing it into the body.

The blood vessel teams are further away from printing something concrete because the field has so many unanswered questions. Their initial step will be looking at what has already been done in the field and what questions still need to be answered. They will then decide on the scope and direction of their projects. Their research will be key to allowing other areas of the field to move forward, though. Organs such as livers and pancreases have been printed, so far, they can only be produced at the micro level because they have no blood flow.

Its kind of like putting the cart before the horse, Class of 2020 Cadet Michael Deegan, a life science major working on one of the blood vessel projects, said. Youve printed it, great, but whats the point of printing it if its not going to survive inside your body? Being able to work on that fundamental step thats actually going to make these organs viable is what drew me and my teammates to be able to do this.

While the blood vessel, liver and meniscus projects have the potential to impact long-term care, the work being done by the biobandage teams will potentially have direct uses in the field during combat. The goal is to be able to take cells from an injured Soldier, specifically one who suffers burns, and print a bandage with built in biomaterial on it to jumpstart the healing process.

Medics would potentially be deployed with a 3D printer in their Humvee to enable bandages to be printed on site to meet the needs of the specific Soldier and his or her exact wound. The projects are building on existing research on printing sterile bandages and then adding a bioengineering element. The bandages would be printed with specialized skin and stem cells necessary to the healing process, jumpstarting healing faster.

Were researching how the body actually heals from burns, Class of 2020 Cadet Channah Mills, a life science major working on one of the biobandage projects, said. So, what are some things we can do to speed along that process? Introducing a bandage could kickstart that healing process. The faster you start healing, the less scarring and the more likely youre going to recover.

The meniscus team is starting with MRI images of knees and working to build a 3D model of a meniscus, which they will eventually be able to print. Unlike a liver, the meniscus doesnt need a blood flow. It does still have a complex cellular structure, though, and a large part of the teams research will be figuring out how and when to implant those cells into what theyre printing.

Of the 26 cadets working on bioprinting projects, 17 will be attending medical school following graduation from West Point. The research they are doing gives them hands-on experience in a cutting-edge area of the medical field. It also enabled them to play a role in improving the care for Soldiers in the future, which will be their jobs as Army doctors.

Being on the forefront of it and just seeing the potential in bioengineering, its pretty astounding, Gong said. But it has also been sobering just to see how much more complicated it is to 3D print biomaterials than plastic.

The bioprinting projects will be presented during the academys annual Projects Day April 30.

By Brandon OConnor

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Cadets Research Bioprinting to Improve Soldier Care - MilitarySpot

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DURHAM, N.C., Feb. 18, 2020 (GLOBE NEWSWIRE) -- Chimerix(CMRX), a biopharmaceutical company focused on accelerating the development of medicines to treat cancer and other serious diseases, today announced that it will host a live conference call and audio webcast on Tuesday, February 25, 2020 at 8:30 a.m. ET to report financial results for the fourth quarter and full-year ended December 31, 2019, and to provide a business overview.

To access the live conference call, please dial (877) 354-4056 (domestic) or (678) 809-1043 (international) at least five minutes prior to the start time, and refer to conference ID 1397800. A live audio webcast of the call will also be available on the Investors section of the Company's website, http://www.chimerix.com. An archived webcast will be available on the Chimerix website approximately two hours after the event.

AboutChimerix

Chimerix is a development-stage biopharmaceutical company dedicated to accelerating the advancement of innovative medicines that make a meaningful impact in the lives of patients living with cancer and other serious diseases. The two clinical-stage development programs are dociparstat sodium (DSTAT) and brincidofovir (BCV).

Dociparstat sodium is a potential first-in-class glycosaminoglycan compound derived from porcine heparin that has low anticoagulant activity but retains the ability to inhibit activities of several key proteins implicated in the retention and viability of AML blasts and leukemic stem cells in the bone marrow during chemotherapy (e.g., CXCL12, selectins, HMGB1, elastase). Mobilization of AML blasts and leukemic stem cells from the bone marrow has been associated with enhanced chemosensitivity and may be a primary mechanism accounting for the observed increases in EFS and OS in Phase 2 with DSTAT versus placebo. Randomized Phase 2 data suggest that DSTAT may also accelerate platelet recovery post-chemotherapy via inhibition of platelet factor 4, a negative regulator of platelet production that impairs platelet recovery following chemotherapy. BCV is an antiviral drug candidate in development as a medical countermeasure for smallpox. For further information, please visit the Chimerix website, http://www.chimerix.com.

Forward Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks and uncertainties that could cause actual results to differ materially from those projected. Forward-looking statements include those relating to, among other things, Chimerixs ability to develop BCV as a medical countermeasure for smallpox; Chimerixs ability to submit and/or obtain regulatory approvals for BCV; and Chimerixs ability to enter into a procurement contract for BCV as a medical countermeasure. Among the factors and risks that could cause actual results to differ materially from those indicated in the forward-looking statements are risks that BCV may not obtain regulatory approval from theFDAor such approval may be delayed or conditioned; risks that development activities related to BCV may not be completed on time or at all; Chimerixs reliance on a sole source third-party manufacturer for drug supply; risks that ongoing or future trials may not be successful or replicate previous trial results, or may not be predictive of real-world results or of results in subsequent trials; risks and uncertainties relating to competitive products and technological changes that may limit demand for our drugs; risks that our drugs may be precluded from commercialization by the proprietary rights of third parties; risks related to procurement of brincidofovir for the treatment of smallpox and additional risks set forth in the Company's filings with theSecurities and Exchange Commission. These forward-looking statements represent the Company's judgment as of the date of this release. The Company disclaims, however, any intent or obligation to update these forward-looking statements.

CONTACT:Investor Relations: Michelle LaSpaluto919 972-7115ir@chimerix.com

Will OConnorStern Investor Relationswill@sternir.com 212-362-1200

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Chimerix to Report Fourth Quarter and Year End 2019 Financial Results and Provide an Operational Update on February 25, 2020 - Yahoo Finance

Bone Marrow Stem Cells Comments Off on Chimerix to Report Fourth Quarter and Year End 2019 Financial Results and Provide an Operational Update on February 25, 2020 – Yahoo Finance | February 18th, 2020

SIOUX CITY (KTIV) - For five years now, the Ruehle family has held a teddy bear drive in memory of Mike Ruehle, who passed from cancer in 2014.

The teddy bears are given to adults and children with a cancer connection, in Mike's memory.

Family and friends knew Mike as "Bear."

The family asks people to consider donating a teddy bear in memory of a loved one, or in honor of healthy family members.

If you'd like to donate, every bear must be new with the tag still attached. The donations will stay in Siouxland.

There are five different locations where you can drop off the bears:

Ruehle's family says the teddy bear drive has donated more than 3,000 stuffed animals to several Siouxland agencies.

But who is the man who inspired the teddy bear drive?

"Very thoughtful person, very giving, he always took the time to listen to other people, just a really compassionate, kindhearted person," said Kerry Ruehle, Mike's Widow.

Mike Ruehle, or as his family called him, Bear, passed away six years ago, after a 12 year battle with cancer.

The family said he was very active in the community and was often coaching numerous sports teams.

They said he had a big heart, and always did what he could to make others feel better, even while he himself had cancer.

"If there were any patients his doctor had, who were having a difficult time with the news or with the adjustment. He would reach out to my dad, and see if my dad would sit down with them and talk about what was going on with them," said Rhett, Mike's son.

Part of the reason the teddy bear drive was started was because of Bear's compassion towards children who were also dealing with cancer.

"He would see a young child going through similar things that he was going through. He would always go out of his way to talk to that little kid and brighten their day a little bit," said Rhett.

Mike had had three different kinds of cancers, and due to the chemotherapy, eventually was diagnosed with MDS, which is a bone marrow failure disorder.

Doctors determined that the best treatment would be a stem cell transplant. The transplant surgery went well, but months later his body began rejecting his brother's stem cells, and within five weeks he had passed away.

"It was a shock because he had been ahead of schedule and everything else. And he had come through things beautifully, so it was quite a shock. But it was god's plan I guess," said Kerry.

But Mike's family wanted a way to keep Mike's memory alive, and that's what also helped start the teddy bear drive.

"My oldest granddaughter is five, she never met her grandpa. But in some ways, she feels as though she did, because of talking about him and she helps me with the bear drive," said Kerry

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Family honors the memory of loved one by collecting teddy bears for families dealing with cancer - KTIV

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NEW YORK, Feb. 18, 2020 (GLOBE NEWSWIRE) -- BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of adult stem cell technologies for neurodegenerative diseases, today announces financial results for fiscal year ended December 31, 2019.

2019 was a tremendous year for BrainStorm, with significant progress and achievements across all clinical and operational fronts, stated Chaim Lebovits, President and Chief Executive Officer of BrainStorm. Most importantly, we fully enrolled our pivotal, double blind, placebo-controlled Phase 3 trial of NurOwn for the treatment of ALS. We announced the trial conducted at six major U.S. medical centers of excellence for ALS, was fully enrolled on October 11, 2019, and on October 28, 2019 the Data and Safety Monitoring Board (DSMB), completed the second planned interim safety analysis for the first 106 patients who received repeat dosing of NurOwn in the Phase 3 trial. The DSMB concluded the trial should continue as planned without any clinical protocol changes. He added, In addition, one of the most prestigious peer-reviewed journals, Neurology, published NurOwn Phase 2 Randomized Clinical Trial in ALS: Safety, Clinical and BioMarker Results, bringing news of our investigational therapy to the global scientific community. And, just last week, we were happy to announce that the Company recently held a high level meeting with the U.S. Food and Drug Administration (FDA) to discuss potential NurOwn regulatory pathways for approval in ALS.

Ralph Kern, MD, MHSc, Chief Operating Officer and Chief Medical Officer of BrainStorm added, 2019 was also a very significant year for those who suffer from progressive Multiple Sclerosis (MS). In February 2019, we announced Cleveland Clinic would serve as our first contracted site for a Phase 2 open-label, multicenter study of repeated intrathecal administration of NurOwn (autologous MSC-NTF cells) in participants with progressive MS (NCT03799718). We enrolled our first patient in March. We contracted with The Stanford University School of Medicine, The Keck School of Medicine of the University of Southern California, and the Mount Sinai Medical Center to further enroll patients. Dr. Kern added, The importance of our research in progressive MS was acknowledged by a $495,000 grant award from the National Multiple Sclerosis Society through its Fast Forward Program, and mid-December, the Data Safety Monitoring Board completed the first, pre-specified interim analysis, of safety outcomes for 9 participants and after careful review of all available clinical trial data, the DSMB unanimously concluded that the study should continue as planned without any protocol modification. As of December 31, 2019 we have enrolled 10 patients in the study (50% enrollment completed).

Fourth Quarter Corporate Highlights:

Financial Results for the Year Ended December 31, 2019 and Recent Updates

For further details on BrainStorms financials, including financial results for the year ended December 31, 2019, refer to the Form 10-K filed with the SEC today.

Conference Call on Tuesday, February 18th @ 8:00 am Eastern Time

The investment community may participate in the conference call by dialing the following numbers:

Those interested in listening to the conference call live via the internet may do so by visiting the Investors & Media page of BrainStorms website at http://www.ir.brainstorm-cell.com and clicking on the conference call link.

A webcast replay of the conference call will be available for 30 days on the Investors & Media page of BrainStorms website:

About NurOwnNurOwn (autologous MSC-NTF cells) represent a promising investigational approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors. Autologous MSC-NTF cells can effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression. NurOwn is currently being evaluated in a Phase 3 ALS randomized placebo-controlled trial and in a Phase 2 open-label multicenter trial in Progressive MS.

About BrainStorm Cell Therapeutics Inc.BrainStorm Cell Therapeutics Inc.is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwnCellular Therapeutic Technology Platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement as well as through its own patents, patent applications and proprietary know-how. Autologous MSC-NTF cells have received Orphan Drug status designation from theU.S. Food and Drug Administration(U.S.FDA) and theEuropean Medicines Agency(EMA) in ALS. Brainstorm has fully enrolled the Phase 3 pivotal trial in ALS (NCT03280056), investigating repeat-administration of autologous MSC-NTF cells at six sites in the U.S., supported by a grant from theCalifornia Institute for Regenerative Medicine(CIRM CLIN2-0989). The pivotal study is intended to support a BLA filing for U.S.FDAapproval of autologous MSC-NTF cells in ALS. Brainstorm received U.S.FDAclearance to initiate a Phase 2 open-label multi-center trial of repeat intrathecal dosing of MSC-NTF cells in Progressive Multiple Sclerosis (NCT03799718) inDecember 2018and has been enrolling clinical trial participants sinceMarch 2019. For more information, visit the company'swebsite.

Safe-Harbor StatementStatements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could causeBrainStorm Cell Therapeutics Inc.'sactual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may", "should", "would", "could", "will", "expect", "likely", "believe", "plan", "estimate", "predict", "potential", and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorms need to raise additional capital, BrainStorms ability to continue as a going concern, regulatory approval of BrainStorms NurOwn treatment candidate, the success of BrainStorms product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorms NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorms ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorms ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation,; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

CONTACTS

Corporate:Uri YablonkaChief Business OfficerBrainStorm Cell Therapeutics Inc.Phone: 646-666-3188uri@brainstorm-cell.com

Investor Relations:Preetam Shah, MBA, PhDChief Financial OfficerBrainStorm Cell Therapeutics Inc.Phone: 862-397-8160pshah@brainstorm-cell.com

Media:Sean LeousWestwicke/ICR PRPhone: +1.646.677.1839sean.leous@icrinc.com

BRAINSTORM CELL THERAPEUTICS INC.

CONSOLIDATED BALANCE SHEETSU.S. dollars in thousands(Except share data)

BRAINSTORM CELL THERAPEUTICS INC.

CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSSU.S. dollars in thousands(Except share data)

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BrainStorm Announces Operational Highlights and Financial Results for the Year Ended December 31, 2019 Conference Call and Webcast @ 8:00 am Eastern...

Bone Marrow Stem Cells Comments Off on BrainStorm Announces Operational Highlights and Financial Results for the Year Ended December 31, 2019 Conference Call and Webcast @ 8:00 am Eastern… | February 18th, 2020

The latest market report published by Credence Research, Inc.GlobalBone Marrow Transplantation Market Growth, Future Prospects, Competitive Analysis, 2018 2026,

Access Free Sample Copy of Research Report @ https://www.credenceresearch.com/sample-request/59660

Market Insights:

Blood cancer is characterized by overproduction of an irregular type of blood cells, resulting in the overproduction of normal cells in the bone marrow preventing normal cells from performing important functions. According to the study references issued by Bristol-Myers Squibb Company by 2040 nearly 1,100,000 people will die from blood cancer, which will account for 7 percent cancer deaths.

Allogeneic bone marrow transplant are reigning the market. The inherent features associated with allogeneic procedures are the graft is free from contaminated tumor cells. Immune graft versus malignancy effect is produced by the immunocompetent cells derived from healthy donor. Low risk of disease recurrence and significant rise in the number of healthy donors drive the allogeneic bone marrow transplantation market growth. Autologous procedure will grow at a rapid pace in the near future due to rise in number of stem cell banks, which store healthy cells from patients and after conditioning treatment are introduced in them to produce healthy blood cells.

Lymphoma is dominating the indication segment for bone marrow transplantation market. There are 2 types Hodgkin lymphoma and Non-Hodgkin lymphoma. The primary factors responsible for its supremacy are significant rise in the patients newly diagnosed with Hodgkin lymphoma and excellent survival rate in patients post bone marrow transplantation procedure. Leukemia is the abnormal high production of white blood cells by the bone marrow. Technological advancement in the bone marrow transplantation technique will reduce the disease recurrence in leukemia patients receiving stem cell therapy.

Access Free Sample Copy of Research Report @ https://www.credenceresearch.com/sample-request/59660

North America is presently the leading regional segment for bone marrow transplantation market with a market share of 38%. The major factors responsible for its significant growth are rising prevalence of chronic lymphocytic leukemia and presence of sophisticated healthcare infrastructure. Europe with a market share of 32% is at second position owing to significant rise in the number of myeloma patients and domicile of major players such as PromoCell GmbH, Merck Millipore Corporation and Lonza Group Ltd. Asia Pacific with a market share of 20% will grow at a faster pace in the near future on account of technological advancement in bone marrow transplantation technique and proactive government policies to curb the mortality rate associated with blood cancer.

Biotechnology firms actively engaged in bone marrow transplantation procedures are AllCells LLC., Conversant Bio., Cellular Dynamics International, Gamida Cell Ltd., Hemacare Corporation, Lonza Group Ltd., Merck Millipore Corporation, Mesoblast Ltd., PromoCell GmbH and STEMCELL Technologies.

Key Market Movements:

Browse the full reportBone Marrow Transplantation Market athttps://www.credenceresearch.com/report/bone-marrow-transplantation-market

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Credence Researchis aworldwide market research and counseling firm that serves drivingorganizations, governments, non-legislative associations, and not-for-benefits.We offer our customers some assistance with making enduring enhancements totheir execution and understand their most imperative objectives. Over almost acentury, weve manufactured a firm extraordinarily prepared to this task.

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Bone Marrow Transplantation Market: Lower risk of disease recurrence and significant rise in the number of healthy donors drive the market growth -...

Bone Marrow Stem Cells Comments Off on Bone Marrow Transplantation Market: Lower risk of disease recurrence and significant rise in the number of healthy donors drive the market growth -… | February 18th, 2020

(MENAFN - GetNews) Age Stop Switzerland luxury line of ground-breaking anti-aging solutions provides women the opportunity to regain their youthful appearance again.

Age Stop Switzerland is a premier skincare solutions company, globally reputed for their exceptional anti-aging products that are backed by scientific results. The Swiss-based beauty products developer and manufacturer have incorporated a powerful combination of innovative ingredients known to stimulate and prolong the skin's youthful appearance.

'At Age Stop Switzerland, our core philosophy is to provide our customers exceptionally advanced skincare formulations that can repair and reverse the visible signs of aging on their facial skin, says the spokesperson for Age Stop Switzerland. 'We are proud to offer you our bouquet of luxury anti-aging treatments that can make skin appear visibly renewed, softer and younger. We strive to take age-defying skin care to a new level with our exceptionally effective formulations.

The Age Stop Switzerland product line contains a high concentration of anti-aging elements in well-researched and tested combinations. Some of the innovative ingredients used in these products include bio-mimetic peptides, Swiss Snow Algae, Alpine Flower Stem Cells, hyaluronic acid, oxygen fusion, vitamins, and bio-available precious stone extracts.

The refreshingly unique and exceptionally effective snow algae powder is sourced from algae found on the snowfields of high mountains. The valuable molecules found in the algae helps protect and maintain the skin's youthful appearance.

Hyaluronic Acid is another powerful anti-aging ingredient used in many Age Stop Switzerland skincare products. Hyaluronic acid has the ability to keep skin hydrated for an extended period of time because of its unique ability to hold 1,000 times its weight in moisture.

Edelweiss plant stem cells extracted from its apical meristem is used as one of the key ingredients in their premium range of products. It works by stimulating the skin stem cells and has an inherent protection mechanism to shield human skin against harsh climatic conditions.

Age Stop Switzerland offers a complete range of anti-aging daily creams and lotions, powered by a dynamic and deeply researched mix of potent ingredients that have been proved by science to deliver real and visible results within just days of use.

The luxury anti-aging line strictly avoids the use of parabens, mineral oil, sulfates, and even any kind of synthetic color and fragrance. The products are never tested on animals.

The scientifically advanced products have been carefully formulated to trigger positive cellular changes and visible creates a rejuvenated and youthful appearance. The skin's natural beauty is enhanced by gradual reduction and elimination of wrinkles, fine lines, dark spots, and other blemishes.

For more information, visit http://www.Age-Stop.EU

About Age Stop Switzerland:

Age Stop Switzerland is a premium Swiss skin care brand committed to advancing the science of staying young. The company offers a wide range of luxury anti-aging skincare products that redefines skin protection. The products from Age Stop Switzerland are created to deliver the latest in globally proven, award-winning anti-aging science based on the revolutionary discovery of ingredients such as Swiss Snow Algae Powder and the pioneering Plant Stem Cell research.

Media Contact Company Name: Age Stop Switzerland Contact Person: Customer Support Email: Send Email Phone: +447432691133 City: Kettering State: Northamptonshire Country: United Kingdom Website: http://age-stop.eu

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Age Stop Switzerland Creates an Exceptional Range of Skincare Products That Can Repair and Rejuvenate Aging Skin - MENAFN.COM

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New therapeutic approaches for chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis are needed because current treatments are often suboptimal in terms of both efficacy and the risks of serious adverse events. Inhibitor of apoptosis proteins (IAPs) are E3 ubiquitin ligases that inhibit cell death pathways and are themselves inhibited by second mitochondria-derived activator of caspases (SMAC). SMAC mimetics (SMs), small-molecule antagonists of IAPs, are being evaluated as cancer therapies in clinical trials. IAPs are also crucial regulators of inflammatory pathways because they influence both the activation of inflammatory genes and the induction of cell death through the receptor-interacting serine-threonine protein kinases (RIPKs), nuclear factor B (NF-B)inducing kinase, and mitogen-activated protein kinases (MAPKs). Furthermore, there is an increasing interest in specifically targeting the substrates of IAP-mediated ubiquitylation, especially RIPK1, RIPK2, and RIPK3, as druggable nodes in inflammation control. Several studies have revealed an anti-inflammatory potential of RIPK inhibitors that either block inflammatory signaling or block the form of inflammatory cell death known as necroptosis. Expanding research on innate immune signaling through pattern recognition receptors that stimulate proinflammatory NF-B and MAPK signaling may further contribute to uncovering the complex molecular roles used by IAPs and downstream RIPKs in inflammatory signaling. This may benefit and guide the development of SMs or selective RIPK inhibitors as anti-inflammatory therapeutics for various chronic inflammatory conditions.

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SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases - Science

Skin Stem Cells Comments Off on SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases – Science | February 18th, 2020

Going gray is a natural part of getting older. It typically starts with a small streak of white in the hair or beard, a sign that a man has reached a certain level of maturity and is now on that steady, inevitable decline to the grave. Hell, it is even conceivable (and highly likely) that some of you might even pluck one of those pale bastards out of your pube patch one night while trying to determine if the source of a vicious case of crotch itch is the crabs or just dry skin. Listen, all were saying is dont be surprised if, within the next few years, you find yourself staring down at your junk, thinking about how that lustrous man bush of yours is starting to resemble Colonel Sanders with a skinless chicken leg dangling out of his mouth. It happens to the best of us.

But hey, getting old isnt always indicative of a silver coiffure. I knew a guy back in high school who had more gray hair on his head than my 73-year-old father does now. So, it seems that age alone isnt always the culprit. In fact, it has been long since believed that stress also plays a critical role in making some men look distinguished beyond their years. Well, come to find out, the concept of stressful events turning us into gray beasts before we are officially deemed DILFs is probably real. Only science says it really comes down to how our fight or flight response is triggered throughout the years that determine when our manes will be deprived of color.

Researchers at Harvards Stem Cell Institute believe they have found a direct correlation between stress and going gray. They recently published a study in the journal Nature, which shows that three kinds of extreme stress mild, short-term pain, psychological stress, and restricted movement has a way of bringing around the gray quicker than what would happen under natural circumstances. At least that is the conclusion reached by lead researcher Dr. Ya-Chieh Hsu and team after putting a legion of mice through the wringer and watching for their response.

The graying process happens as pigment cells called melanocytes start to fade from our hair follicles. Its just that over time, these cells become less prevalent and we begin brandishing that salt and pepper look popularized by legendary screen stars like Brad Pitt and George Clooney.

Eventually, however, all of those cells fade into extinction and our hair just goes completely white, we start receiving AARP benefits and eating apple sauce with every meal. Yet, researchers say that stress can cause these cells to fade out quicker than theyre supposed to long before we start collecting social security and yelling at the neighborhood kids to get off our lawn.

Without getting overly scientific about it, researchers found that high stress seems to produce elevated levels of a chemical in the brain known as noradrenaline. Its one of the kick-ass substances manufactured by the adrenal gland when a persons fight or flight response starts firing on all cylinders. Thats the real culprit to early aging, researchers concluded. They say that once mice were injected with this chemical, they began losing melanocytes and going gray. And the transformation didnt take long either. It turns out that stress can zap our hair color in a matter of days.

When we started to study this, I expected that stress was bad for the body but the detrimental impact of stress that we discovered was beyond what I imagined, Hsu said in a statement. After just a few days, all of the melanocyte stem cells were lost. Once theyre gone, you cant regenerate pigments anymore. The damage is permanent.

While it might be challenging to manage stress in a way that keeps us looking young forever, there is a silver-lining here, boys. Women, presumably the root of all of that premature grayness in the first place, are especially hot for this look. Seriously, a recent survey from Match.com finds that 72 percent of the women on the dating scene find men with gray hair more attractive than those with darker dos. Other studies on the subject have turned out similar results. The only caveat is that women are really only turned on by the gray as long as it doesnt make the man look old. This has something to do with them wanting to feel like a guy can provide some safety and security without having to worry about changing his diapers down the road.

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(Image from Trinity College Dublin)

Researchers in Ireland have developed a prototype patch that they say does the same job as crucial aspects of heart tissue.

The patch was designed to withstand the mechanical demands of heart tissue and mimic the electrical signaling properties that allow the heart to pump blood throughout the body. The researchers believe it brings medtech one step closer to a functional design that could mend a broken heart.

Cardiac patches lined with heart cells can be applied surgically to restore heart tissue in patients who have had damaged tissue removed after a heart attack and to repair congenital heart defects in infants and children. Ultimately, though, the goal is to create cell-free patches that can restore the synchronous beating of the heart cells, without impairing the heart muscle movement. The bioengineers report their work in the journal Advanced Functional Materials.

Researchers are continuously looking to develop new treatments which can include stem cell treatments, biomaterial gel injections and assistive devices, said senior author Michael Monaghan, an assistant professor at Trinity College Dublin, in a news release. Ours is one of few studies that looks at a traditional material, and through effective design allows us to mimic the direction-dependent mechanical movement of the heart, which can be sustained repeatably. This was achieved through a novel method called melt electrowriting and through close collaboration with the suppliers located nationally we were able to customize the process to fit our design needs.

This work was performed in the Trinity Centre for Biomedical Engineering, based in the Trinity Biomedical Sciences Institute in collaboration with Spraybase, a subsidiary of Avectas Ltd.

The mechanical demands of heart muscle cannot be met using polyester-based thermoplastic polymers, which are predominantly the approved options for biomedical applications, according to the researchers. However, the functionality of thermoplastic polymers could be leveraged by its structural geometry. They made a patch that could control the expansion of a material in multiple directions and tune this using an engineering design approach.

The patches were manufactured via melt electrowriting, a core technology of Spraybase, which the company says is reproducible, accurate and scalable. The patches were also coated with the polymer polypyrrole to provide electrical conductivity while maintaining cell compatibility. The patch withstood repeated stretching, which is a dominant concern for cardiac biomaterials, and showed good elasticity, to accurately mimic that key property of heart muscle.

Essentially, our material addresses a lot of requirements, Monaghan said. The bulk material is currently approved for medical device use, the design accommodates the movement of the pumping heart, and has been functionalized to accommodate signaling between isolated contractile tissues. This study currently reports the development of our method and design, but we are now looking forward to furthering the next generation of designs and materials with the eventual aim of applying this patch as a therapy for a heart attack.

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Could this patch help mend a broken heart? - Medical Design & Outsourcing

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Whenever Harry Wuest has a doctors appointment in northern Atlantas hospital cluster dubbed Pill Hill, he makes sure to stop by the office of Dr. Douglas Doug Murphy for a quick chat.

And Murphy, unless hes tied up in the operating room, always takes a few minutes to say hello to his former patient. Remember when . . . ? is how the conversation typically starts, and its always tinged with laughter, often joyful, sometimes bittersweet.

Its a reunion of two men who shaped a piece of Georgias medical history.

Almost 35 years ago, Murphy opened the chest of Wuest and sewed in a new heart, giving him a second shot at life. Wuest was the third heart transplant patient at Emory University Hospital.

Tall, lanky, with short curly hair and a quiet demeanor, Wuest is the longest-surviving heart transplant recipient in Georgia and one of the longest-surviving in the world. The 75-year-old accountant still plays golf twice a week and only recently went from working full-time to part-time.

My heart is doing just fine, he says.

Murphy is now the chief of cardiothoracic surgery at Emory Saint Josephs Hospital and still in the operating room almost every day. He has moved on to become the worlds leading expert in robotically assisted heart surgery.

***

Harry Wuest is originally from Long Island, N.Y. After a stint in the U.S. Air Force, he moved to Florida to work and go to school. He wanted to become a physical education teacher. Then, in 1973, he fell ill. It started with some pain on his left side. He didnt think much of it, but when he got increasingly winded and fatigued, he went to see a doctor.

Several months and numerous specialists later, he received the diagnosis: Cardiomyopathy, a disease of the heart muscle that can make the heart become enlarged, thick and rigid, preventing it from pumping enough blood through the body.

They didnt know how I got it, says Wuest, sitting back in a brown leather armchair in the dark, wood-paneled living room of his Stone Mountain home. Maybe it was a virus. And back then, there wasnt much they could do to treat it, except bed rest.

For the next 12 years, Wuest lived life as best as he could. He got a degree in accounting from the University of Central Florida and worked for a real estate developer. There were good days, but there were more bad days. He was often too weak to do anything, and his heart was getting bigger and bigger.

***

The first successful human-to-human heart transplant was performed in Cape Town, South Africa, in 1967 a medical breakthrough that catapulted the surgeon, Dr. Christiaan Barnard, onto the cover of Life magazine and to overnight celebrity status.

This highly publicized event was followed by a brief surge in the procedure around the world, but overall, heart transplants had a rocky start. Most patients died shortly after the surgery, mainly due to organ rejection. Back then, immunosuppressive drugs, which can counteract rejection, were still in their infancy. Many hospitals stopped doing heart transplants in the 1970s.

That changed with the discovery of a highly effective immunosuppressive agent. Cyclosporine got FDA approval in 1983 and altered the world of organ transplants.

It was shortly thereafter when Emory University Hospital decided to launch a heart transplant program, but none of the senior surgeons wanted to do it. Even with the new drug, it was a risky surgery, and mortality was still high.

Its an all-or-nothing operation, Murphy says, as he sits down in his small office overlooking the greyish hospital compound. Hes wearing light blue scrubs from an early morning surgery. At 70, he still has boyish looks, with a lean build and an air of laid-back confidence. If you have a number of bad outcomes initially, it can be detrimental to your career as a surgeon, he says.

But Murphy didnt really have a choice. He remembers that during a meeting of Emorys cardiac surgeons in 1984, he was paged to check on a patient. When he returned, the physicians congratulated him on being appointed the head of the new heart transplant program. He was the youngest in the group and had been recruited from Harvards Massachusetts General Hospital just three years before.

Yeah, thats how I became Emorys first transplant surgeon, says Murphy.

He flew to California to shadow his colleagues at Stanford University Hospital, where most heart transplants were performed at the time. Back home at Emory, he put together a team and rigorously rehearsed the operation. The first transplant patient arrived in April 1985. The surgery was successful, as was the second operation less than a month later.

Around the same time, Harry Wuest wound up in a hospital in Orlando. He needed a transplant, but none of the medical centers in Florida offered the procedure. One of his doctors recommended Emory, and Wuest agreed. I knew I was dying. I could feel it. He was flown to Atlanta by air ambulance and spent several weeks in Emorys cardiac care unit until the evening of May 23, when Murphy walked into his room and said, Weve got a heart.

***

The heart, as the patient later learned, came from a 19-year-old sophomore at Georgia Tech who had been killed in a car crash.

Organ transplants are a meticulously choreographed endeavor, where timing, coordination and logistics are key. While Murphy and his eight-member team were preparing for the surgery, Wuest was getting ready to say farewell to his family his wife and three teenage sons and to thank the staff in the cardiac ward.

I was afraid, he recalls, especially of the anesthesia. It scared the heck out of me. He pauses during the reminiscence, choking briefly. I didnt know if I was going to wake up again.

The surgery took six hours. Transplants usually happen at night because the procurement team, the surgeons who retrieve different organs from the donor, only start working when regularly scheduled patients are out of the operating room.

Despite the cultural mystique surrounding the heart as the seat of life, Murphy says that during a transplant surgery, its not like the big spirit comes down to the operating room. Its very technical. As the team follows a precise routine, emotions are kept outside the door. We dont have time for that. Emotions come later.

After waking up from the anesthesia, Wuests first coherent memory was of Murphy entering the room and saying to a nurse, Lets turn on the TV, so Harry can watch some sports.

Wuest spent the next nine days in the ICU and three more weeks in the hospital ward. In the beginning, he could barely stand up or walk, because he had been bedridden weeks before the surgery and had lost a lot of muscle. But his strength came back quickly. I could finally breathe again, he says. Before the surgery, he felt like he was sucking in air through a tiny straw. I cannot tell you what an amazing feeling that was to suddenly breathe so easily.

Joane Goodroe was the head nurse at Emorys cardiovascular post-op floor back then. When she first met Wuest before the surgery, she recalls him lying in bed and being very, very sick. When she and the other nurses finally saw him stand up and move around, he was a whole different person.

In the early days of Emorys heart transplant program, physicians, nurses and patients were a particularly close-knit group, remembers Goodroe, whos been a nurse for 42 years and now runs a health care consulting firm. There were a lot of firsts for all of us, and we all learned from each other, she said.

Wuest developed friendships with four other early transplant patients at Emory, and he has outlived them all.

When he left the hospital, equipped with a new heart and a fresh hunger for life, Wuest made some radical changes. He decided not to return to Florida but stay in Atlanta. Thats where he felt he got the best care, and where he had found a personal support network. And he got a divorce. Four months after the operation, he went back to working full-time: first in temporary jobs and eventually for a property management company.

After having been sick for 12 years, I was just so excited to be able to work for eight hours a day, he recalls. That was a big, big deal for me.

At 50, he went back to school to get his CPA license. He also found new love.

Martha was a head nurse in the open-heart unit and later ran the cardiac registry at Saint Josephs Hospital. Thats where Wuest received his follow-up care and where they met in 1987. Wuest says for him it was love at first sight, but it took another five years until she finally agreed to go out with him. Six months later, they were married.

Having worked in the transplant office, I saw the good and the bad, Martha Wuest says. A petite woman with short, perfectly groomed silver hair, she sits up very straight on the couch, her small hands folded in her lap.Not every transplant patient did as well as Harry. And I had a lot of fear in the beginning. Now he may well outlive her, she says with a smile and a wink.

Wuests surgeon, meanwhile, went on to fight his own battles. Two and a half years into the program, Murphy was still the only transplant surgeon at Emory and on call to operate whenever a heart became available. Frustrated and exhausted, he quit his position at Emory and signed up with Saint Josephs (which at the time was not part of the Emory system) and started a heart transplant program there.

At St. Joes, Murphy continued transplanting hearts until 2005. In total, he did more than 200 such surgeries.

Being a heart transplant surgeon is a grueling profession, he says, and very much a younger surgeons subspecialty.

He then shifted his focus and became a pioneer in robotically assisted heart surgery.He has done more than 3,000 operations with the robot, mostly mitral valve repairs and replacements more than any other cardiac surgeon in the world.

***

Since Murphy sewed a new heart into Wuest, 35 years ago, there has been major progress in the field of heart transplants,but it has been uneven.

Medications to suppress the immune system have improved, says Dr. Jeffrey Miller, a transplant surgeon and heart failure specialist at Emory. As a result, we are seeing fewer cases of rejections of the donor heart.

Also, there are new methods of preserving and transporting donor hearts.

Yet patients requiring late-stage heart failure therapy, including transplantation, still exceed the number of donor hearts available. In 2019, 3,551 hearts were transplanted in the United States, according to the national Organ Procurement and Transplantation Network. But 700,000 people suffer from advanced heart failure, says the American Heart Association.

New technologies and continued research are providing hope to many of these patients. There has been significant progress in the development of partial artificial hearts, known as Left Ventricular Assist Devices, or LVADs, says Miller.

These are implantable mechanical pumps that assist the failing heart. Patients are back out in society living normal lives while theyre waiting for their donor hearts, he explains.

LVADs are used not only as bridge devices but as destination therapy as well, maintaining certain patients for the remainder of their lives.

Also, total artificial hearts have come a long way since the first artificial pump was implanted in a patient in 1969.

Long-term research continues into xenotransplantation, which involves transplanting animal cells, tissues and organs into human recipients.

Regenerative stem cell therapy is an experimental concept where stem cell injections stimulate the heart to replace the rigid scar tissue with tissue that resumes contraction, allowing for the damaged heart to heal itself after a heart attack or other cardiac disease.

Certain stem cell therapies have shown toreverse the damage to the heart by 30 to 50 percent, says Dr. Joshua Hare, a heart transplant surgeon and the director of the Interdisciplinary Stem Cell Institute at the University of Miamis Miller School of Medicine.

All of these ideas have potential, says Miller. But they have a lot of work before were ready to use them as alternatives to heart transplantation. I dont think were talking about the next few years.

Besides Emory, other health care systems in Georgia that currently have a heart transplant program are Piedmont Healthcare, Childrens Healthcare of Atlanta and Augusta University Health.

Organ rejection remains a major issue, and long-term survival rates have not improved dramatically over the past 35 years. The 10-year survival is currently around 55 percent of patients, which makes long-term-survivors like Harry Wuest rare in the world of heart transplants.

The United Network of Organ Sharing, or UNOS, which allocates donor hearts in the United States, doesnt have comprehensive data prior to 1987. An informal survey of the 20 highest-volume hospitals for heart transplants in the 1980s found only a scattering of long-term survivors.

***

Being one of the longest-living heart transplant recipients is something that Wuest sees as a responsibility to other transplant patients, but also to the donors family, which hes never met. If you as a transplant recipient reject that heart, thats like a second loss for that family.

Part of this responsibility is living a full and active life. Both he and Martha have three children from their previous marriages, and combined they have 15 grandchildren. Most of their families live in Florida, so they travel back and forth frequently. Wuest still works as a CPA during tax season, and he does advocacy for the Georgia Transplant Foundation. In addition to golf, he enjoys lifting weights and riding his bike.

Hes had some health scares over the years. In 2013, he was diagnosed with stage 1 kidney cancer, which is in remission. Also, he crossed paths with his former surgeon, and not just socially. In 2014, Murphy replaced a damaged tricuspid valve in Wuests new heart. That operation went well, too.

Murphy says there are several reasons why Wuest has survived so long. Obviously, his new heart was a very good match. But a patient can have the best heart and the best care and the best medicines and still die a few months or years after the transplantation, the surgeon says. Attitude plays a key role.

Wuest was psychologically stable and never suffered from depression or anxiety, Murphy says. Hes a numbers guy. He knew the transplant was his only chance, and he was set to pursue it.

Wuest attributes his longevity to a good strong heart from his donor; good genetics; great doctors and nurses; and a life that he loves. Im just happy to be here, he says.

Quoting his former surgeon and friend, he adds: Doug always said, Having a transplant is like running a marathon. And Im in for the long haul.

Katja Ridderbusch is an Atlanta-based journalist who reports for news organizations in the U.S. and her native Germany. Her stories have appeared in Kaiser Health News, U.S. News & World Report and several NPR affiliates.

This is a slightly modified version of the article 34 Years with a New Heart, published by Georgia Health News on February 18, 2020.

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- First conditional approval of ZYNTEGLOTM (autologous CD34+ cells encoding A-T87Q-globin gene) gene therapy for patients 12 years and older with transfusion-dependent -thalassemia who do not have 0/0 genotype in Europe achieved in 2019; Germany launch underway

- Announced positive top-line data from pivotal Phase 2 KarMMa study of ide-cel in relapsed and refractory multiple myeloma

- Presented clinical data across studies of LentiGlobin gene therapy for -thalassemia (betibeglogene autotemcel) and LentiGlobin gene therapy for sickle cell disease (SCD) and bb21217 in multiple myeloma at American Society of Hematology (ASH) Annual Meeting

- Ended quarter with $1.24 billion in cash, cash equivalents and marketable securities

bluebird bio, Inc. (NASDAQ: BLUE) today reported financial results and business highlights for the fourth quarter and full year ended December 31, 2019.

"2019 was truly a transformative year for bluebird, with our first commercial product now launched in Europe and exciting progress across our first four clinical programs and pipeline," said Nick Leschly, chief bluebird. "Notably, our data in SCD continues to build, and at the ASH annual meeting in December we presented data that showed a 99% reduction in the annualized rate of vaso-occlusive crises (VOC) and acute chest syndrome (ACS) in HGB-206 Group C patients with history of VOCs and ACS who had at least six months follow-up. In -thalassemia, the consistency with which patients who do not have a 0/0 genotype in our Northstar-2 (HGB-207) study are achieving transfusion independence is very encouraging and were starting to see indications that we may be able to see similar outcomes with many patients with 0/0 genotypes as well in our Northstar-3 (HGB-212 study). These data put us in a strong position as we progress our European launch, currently underway in Germany. At the end of 2019, we also announced positive top-line data from the pivotal KarMMa study of ide-cel. We and our partners at BMS look forward to submitting these data to the FDA in the first half of this year. Amidst all of our progress in 2019, our birds demonstrated time and again their dedication to patients and ability to meet and learn from the many challenges we have faced along the way. I look forward to facing the challenges of 2020 with this amazing flock."

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Recent Highlights:

TRANSFUSION-DEPENDENT -THALASSEMIA

LAUNCH IN GERMANY In January 2020, bluebird bio announced the launch of ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene), a 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 in Germany. The company signed its first agreements with statutory health insurances utilizing bluebirds innovative value-based payment model and providing coverage for ZYNTEGLO for up to 50% of patients in Germany, and the first qualified treatment center was established at University Hospital of Heidelberg to provide ZYNTEGLO to patients. The company anticipates treating the first commercial patient in the first half of 2020.

UPDATED LENTIGLOBIN FOR -THALASSEMIA DATA At the American Society of Hematology (ASH) meeting in December 2019, bluebird bio presented new data from its studies of LentiGlobin gene therapy for -thalassemia (betibeglogene autotemcel) in patients with TDT: long-term data from the completed Phase 1/2 Northstar study (HGB-204), updated data from the Phase 3 Northstar-2 study (HGB-207) in patients with non-0/0 genotypes, and updated data from the Phase 3 Northstar-3 study (HGB-212) in patients with 0/0 genotypes or an IVS-I-110 mutation.

BIOLOGICS LICENSE APPLICATION (BLA) SUBMISSION bluebird bio has initiated its rolling BLA submission of LentiGlobin for -thalassemia for approval in the U.S. and is engaged with the FDA in discussions regarding the requirements and timing of certain information to be provided in the BLA, including information regarding various release assays for LentiGlobin for -thalassemia. Subject to these ongoing discussions, the company is currently planning to complete the BLA submission in the second half of 2020.

SICKLE CELL DISEASE (SCD)

HGB-211 bluebird bio is announcing today plans to launch HGB-211, the companys second Phase 3 study of LentiGlobin for sickle cell disease (SCD). This study is expected to enroll approximately 18 patients ages 2-14 years with SCD and elevated stroke risk, stroke being one of the most severe complications during childhood and adolescence. The primary endpoint of the study will be transcranial doppler response without transfusion. HGB-211 is in addition to the companys previously announced Phase 3 study (HGB-210) and is intended to support potential approval of LentiGlobin for SCD in pediatric patients at elevated stroke risk. HGB-211 is expected to begin enrolling patients in 2020.

UPDATED LENTIGLOBIN FOR SCD DATA At the ASH meeting in December 2019, bluebird bio presented new data from patients in Groups A, B and C in the Phase 1/2 HGB-206 study in patients with SCD. Group C patients are being treated under a study protocol utilizing hematopoietic stem cell (HSC) mobilization and apheresis with plerixafor, and a refined manufacturing process to increase vector copy number and engraftment potential of gene-modified HSCs. The company also disclosed that the target enrollment in HGB-206 has been achieved.

MULTIPLE MYELOMA

KARMMA TOPLINE In December 2019, Bristol-Myers Squibb and bluebird bio announced positive top-line results from the pivotal Phase 2 KarMMa study of ide-cel in relapsed and refractory multiple myeloma. The study met its primary endpoint and key secondary endpoint, demonstrating deep and durable responses in a heavily pre-treated multiple myeloma patient population. Safety results are consistent with the data presented in CRB-401 study.

BB21217 DATA At the ASH meeting in December 2019, bluebird bio and Bristol-Myers Squibb presented updated data from ongoing CRB-402 Phase 1 study of BCMA-targeted CAR T cell therapy bb21217 in relapsed and refractory multiple myeloma. The dose escalation part of CRB-402 is complete, and the dose expansion part of the study is ongoing.

COMPANY

FORTY SEVEN COLLABORATION In November 2019, bluebird bio and Forty Seven announced that they have entered into a research collaboration to pursue clinical proof-of-concept for Forty Sevens novel antibody-based conditioning regimen, FSI-174 (anti-cKIT antibody) plus magrolimab (anti-CD47 antibody), with bluebirds ex vivo lentiviral vector hematopoietic stem cell (LVV HSC) gene therapy platform. Under the terms of the agreement, bluebird bio will provide its ex vivo LVV HSC gene therapy platform and Forty Seven will contribute its innovative antibody-based conditioning regimen for the collaboration.

Upcoming Anticipated Milestones:

Regulatory

Submission of a BLA to the U.S. FDA for ide-cel in patients with relapsed and refractory multiple myeloma in the first half of 2020, in partnership with Bristol-Myers Squibb.

Submission of a BLA to the U.S. FDA and a Marketing Authorization Application to the European Medicines Agency for Lenti-D in patients with cerebral adrenoleukodystrophy by the end of 2020.

Clinical

Submission for presentation of ide-cel clinical data from the KarMMa study in the first half of 2020, in partnership with Bristol-Myers Squibb.

Submission for presentation of ide-cel clinical data from the CRB-401 study in 2020, in partnership with Bristol-Myers Squibb.

Initiation of the Phase 3 HGB-210 study of LentiGlobin for SCD in patients with a history of vaso-occlusive crises in the first half of 2020.

Initiation of the Phase 3 HGB-211 study of LentiGlobin for SCD in patients at risk of stroke in 2020.

Updated data presentation from ALD-102 in patients with CALD by the end of 2020.

Updated data presentation from the Northstar-2 (HGB-207) clinical study in patients with transfusion-dependent -thalassemia (TDT) and non-0/0 genotypes by the end of 2020.

Updated data presentation from the Northstar-3 (HGB-212) clinical study in patients with TDT and a 0/0 genotype or an IVS-I-110 mutation by the end of 2020.

Updated data presentation from HGB-206 clinical study in patients with SCD by the end of 2020.

Commercial and Foundation Building

ZYNTEGLO first commercial patients treated in the first half of 2020.

ZYNTEGLO access and reimbursement in additional EU countries established by the end of 2020.

Fourth Quarter and Full Year 2019 Financial Results

Cash Position: Cash, cash equivalents and marketable securities as of December 31, 2019 and December 31, 2018 were $1.24 billion and $1.89 billion, respectively. The decrease in cash, cash equivalents and marketable securities is primarily related to cash used in support of ordinary course operating and commercial-readiness activities.

Revenues: Collaboration and license and royalty revenues were $10.0 million for the three months ended December 31, 2019 compared to $19.2 million for the three months ended December 31, 2018. Collaboration and license and royalty revenues were $44.7 million for the year ended December 31, 2019 compared to $54.6 million for the year ended December 31, 2018. The decrease in both periods was primarily attributable to a decrease in collaboration revenue under our arrangement with Bristol-Myers Squibb, partially offset by an increase in license and royalty revenue.

R&D Expenses: Research and development expenses were $161.8 million for the three months ended December 31, 2019 compared to $119.7 million for the three months ended December 31, 2018. Research and development expenses were $582.4 million for the year ended December 31, 2019 compared to $448.6 million for the year ended December 31, 2018. The increase in both periods was primarily driven by costs incurred to advance and expand the companys pipeline.

SG&A Expenses: Selling, general and administrative expenses were $76.2 million for the three months ended December 31, 2019 compared to $53.5 million for the three months ended December 31, 2018. Selling, general and administrative expenses were $271.4 million for the year ended December 31, 2019 compared to $174.1 million for the year ended December 31, 2018. The increase in both periods was largely attributable to costs incurred to support the companys ongoing operations and growth of its pipeline as well as commercial-readiness activities.

Net Loss: Net loss was $223.3 million for the three months ended December 31, 2019 compared to $149.0 million for the three months ended December 31, 2018. Net loss was $789.6 million for the year ended December 31, 2019 compared to $555.6 million for the year ended December 31, 2018.

LentiGlobin for -thalassemia Safety

Non-serious adverse events (AEs) observed during the HGB-204, HGB-207 and HGB-212 clinical studies that were attributed to LentiGlobin for -thalassemia were hot flush, dyspnoea, abdominal pain, pain in extremities, thrombocytopenia, leukopenia, neutropenia and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to LentiGlobin for -thalassemia for TDT.

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.

With more than five years of follow-up to date, there have been no new unexpected safety events, no deaths, no graft failure and no cases of vector-mediated replication competent lentivirus or clonal dominance. In addition, there have been no new reports of veno-occlusive liver disease (VOD) as of the data cutoff presented at ASH.

About LentiGlobin for -Thalassemia (betibeglogene autotemcel)

The European Commission granted conditional marketing authorization for LentiGlobin for -thalassemia, to be marketed as ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene) gene therapy, for patients 12 years and older with 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.

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.

LentiGlobin for -thalassemia 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.

The conditional marketing authorization for ZYNTEGLO is only valid in the 28 member states of the EU as well as Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration granted LentiGlobin for -thalassemia Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT.

bluebird bio has initiated its rolling BLA submission of LentiGlobin for -thalassemia for approval in the U.S. and is engaged with the FDA in discussions regarding the requirements and timing of certain information to be provided in the BLA, including information regarding various release assays for LentiGlobin for -thalassemia. Subject to these ongoing discussions, the company is currently planning to complete the BLA submission in the second half of 2020.

LentiGlobin for -thalassemia 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), 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 LentiGlobin for -thalassemia. 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.

The full common name for ZYNTEGLO: A genetically modified autologous CD34+ cell enriched population that contains hematopoietic stem cells transduced with lentiviral vector encoding the A-T87Q-globin gene.

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 financial condition, results of operations, as well as statements regarding the plans for regulatory submissions and commercialization for ZYNTEGLO and the companys product candidates, including anticipated regulatory milestones, the execution of the companys commercial launch plans, planned clinical studies, as well as the companys intentions regarding the timing for providing further updates on the development and commercialization of ZYNTEGLO and the companys product candidates. 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 risks that the preliminary positive efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in our ongoing or future clinical trials; the risk of cessation or delay of any of the ongoing or planned clinical studies and/or our development of our product candidates; the risk that the current or planned clinical trials of our product candidates will 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 candidates, resulting in delay to our anticipated timelines for regulatory submissions, including our applications for marketing approval; the risk that we will encounter challenges in the commercial launch of ZYNTEGLO in the European Union, including in managing our complex supply chain for the delivery of drug product, in the adoption of value-based payment models, or in obtaining sufficient coverage or reimbursement for our products; the risk that our collaborations, including the collaborations with Bristol-Myers Squibb and Forty Seven, will not continue or will not be successful; and the risk that any one or more of our product candidates, will not be successfully developed, approved or commercialized. 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-K, 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.

bluebird bio, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss(in thousands, except per share data)(unaudited)

For the three months endedDecember 31,

For the year endedDecember 31,

2019

2018

2019

2018

Revenue:

Collaboration revenue

$ 7,159

$ 18,382

$ 36,469

$ 52,353

License and royalty revenue

2,838

861

8,205

2,226

Total revenues

9,997

19,243

44,674

54,579

Operating expenses:

Research and development

161,821

119,722

582,413

448,589

Selling, general and administrative

76,202

53,508

271,362

174,129

Cost of license and royalty revenue

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bluebird bio Reports Fourth Quarter and Full Year 2019 Financial Results and Highlights Operational Progress - Yahoo Finance

Cardiac Stem Cells Comments Off on bluebird bio Reports Fourth Quarter and Full Year 2019 Financial Results and Highlights Operational Progress – Yahoo Finance | February 18th, 2020