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A powerful "genome editing" technology known as CRISPR has been used by researchers since 2012 to trim, disrupt, replace or add to sequences of an organism's DNA. Now, scientists at Johns Hopkins Medicine have shown that the system also precisely and efficiently alters human stem cells.

In a recent online report on the work in Molecular Therapy, the Johns Hopkins team says the findings could streamline and speed efforts to modify and tailor human-induced pluripotent stem cells (iPSCs) for use as treatments or in the development of model systems to study diseases and test drugs.

"Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren't that far away," says Zhaohui Ye, Ph.D., an instructor of medicine at the Johns Hopkins University School of Medicine. "This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells."

CRISPR originated from a microbial immune system that contains DNA segments known as clustered regularly interspaced short palindromic repeats. The engineered editing system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions far more efficiently than other gene editing techniques, such as TALEN, short for transcription activator-like effector nuclease.

Despite CRISPR's advantages, a recent study suggested that it might also produce a large number of "off-target" effects in human cancer cell lines, specifically modification of genes that researchers didn't mean to change.

To see if this unwanted effect occurred in other human cell types, Ye; Linzhao Cheng, Ph.D., a professor of medicine and oncology in the Johns Hopkins University School of Medicine; and their colleagues pitted CRISPR against TALEN in human iPSCs, adult cells reprogrammed to act like embryonic stem cells. Human iPSCs have already shown enormous promise for treating and studying disease.

The researchers compared the ability of both genome editing systems to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another. As model genes, the researchers used JAK2, a gene that when mutated causes a bone marrow disorder known as polycythemia vera; SERPINA1, a gene that when mutated causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that's been recently discovered to be a "safe harbor" in the human genome for inserting foreign genes.

Their comparison found that when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all three gene systems, inducing up to 100 times more cuts. However, when using these genome editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs, the researchers report.

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'CRISPR' science: Newer genome editing tool shows promise in engineering human stem cells

How does CDI's technology work? A human biological sample, for example blood or skin, is obtained, and the cells within the sample are grown under appropriate cell culture conditions. In the episomal reprogramming method, vectors containing multiple reprogramming genes are introduced into the cells.

While the vectors turn genes in the cell on and off, reprogramming them to a stem cell state, they do not integrate into the genome itself. This method alleviates concerns arising over the potential risks associated with the insertion of foreign DNA to induce reprogramming, which other prior iPS methods use (bottom row in illustration above).

iPS cells are somatic cells (e.g., skin or blood) that have been genetically reprogrammed to a pluripotent stem cell state through forced expression of pluripotency genes.By definition, iPS cells replicate indefinitely and have the potential to differentiate into any cell type in the human body.

Reprogramming factors are the genes introduced into somatic cells that induce a pluripotent stem cell state. Initial reports describing the creation of human iPS cells utilized four reprogramming factors: OCT4, SOX2, KLF4 and MYC (OSKM) (Takahashi, et al. 2007) or OCT4, SOX2, NANOG and LIN28 (OSNL) (Yu, et al. 2007). Subsequent studies revealed that reprogramming using a specific combination of all 6 of these factors combined with SV40LT and a cocktail of small molecules yields iPS cells at much higher efficiency (Yu, et al. 2009; Yu, et al. 2011).

iPS cells are genetically reprogrammed through forced expression of pluripotency genes into somatic cells.The expression of these genes can be accomplished using a variety of different methods.The episomal reprogramming method introduces pluripotency genes into a target cell using circular DNA plasmid vectors (i.e. episomes) that replicate autonomously within the cell cytoplasm and do not integrate into the host cell genome.

Initial methods of iPS cell reprogramming utilized retroviral and lentiviral vectors to introduce pluripotency genes into somatic cells. While these methods generally work well, the viral DNA integrates into the genome of the target cell, and the resulting iPS cells (and cells differentiated from them) will contain foreign DNA, which may result in defects and errors. By contrast, episomal vectors replicate autonomously within the cell cytoplasm and do not integrate into the host genome. In addition, the episomal vectors are released from the target cell at a rate of ~5% per cell cycle resulting in transgene-free or footprint-free iPS cells.These features, combined with recent advancements in episomal reprogramming efficiency, have led to a strong preference for this method to alleviate concerns about genome integrity for drug discovery and cell therapy applications.

Episomal reprogramming has been reported successful from a variety of somatic cells, including fibroblasts, lymphoblastoid cells, and peripheral blood mononuclear cells. Importantly, CDI has optimized its episomal reprogramming method to achieve high efficiency iPS cell generation from small amounts of human peripheral blood. Not only does this enable more streamlined and less invasive collection of donor samples, but ensures increased sterility and lower cost production of iPS cells. In addition, efficient iPS cell production from peripheral blood enables access to large banks of normal and disease-associated clinical samples for disease research and drug screening.

CDIs suite of MyCell Products includes episomal reprogramming of customer-provided donor samples and subsequent genetic engineering and/or differentiation of the iPS cells. In addition, for researchers who would like to generate their own iPS cells, CDIs episomal reprogramming technology is available as a kit from Life Technologies, including Episomal iPSC Reprogramming Vectors, Vitronectin, and Essential 8 Medium. Customer-generated iPS cells using this kit may then be transferred to CDI for genetic engineering and/or differentiation through MyCell Products.

Integration-free iPS cells have been generated using a variety of methods including adenovirus, Sendai virus, piggyBac, minicircle vectors, and direct introduction of protein or synthesized mRNA. The efficiency and success rate of these methods varies depending on the source of somatic cells and experimental conditions, but in general these approaches are limited by impractically low reprogramming efficiency, requirement for higher biosafety containment, and/or labor- and cost-intensive protocols that require repeated transfection/infection.Compared to these methods, episomal reprogramming is virus-free, safe to use, stable, and inexpensive.

A variety of small molecules have been identified that can functionally substitute for one or more reprogramming factors and/or improve the efficiency of iPS cell reprogramming. However, no combination of small molecules has been shown to functionally substitute for all four reprogramming factors. The use of small molecules in iPS cell reprogramming offers some practical advantages including the ability to optimize the chemical structure, fine-tune dose and concentration, and simplify handling and application protocols. However, the use of small molecules presents a number of scientific challenges. Most notably, small molecules may have more than one target, which may or may not be known. In addition, unexpected toxicity and other side effects in vivo may interfere with the clinical application of small molecules.

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CDI | iPS Cells - Cellular Dynamics International

CGI Illustration by Peter Crowther Associates c/o Dbut Art

Andrea Accomazzo: Comet chaser | Suzanne Topalian: Cancer combatant | Radhika Nagpal: Robot-maker | Sheik Humarr Khan: Ebola doctor | David Spergel: Cosmic sceptic | Maryam Mirzakhani: Surface explorer | Pete Frates: Ice-bucket challenger | Koppillil Radhakrishnan: Rocket launcher | Masayo Takahashi: Stem-cell tester | Sjors Scheres: Structure solver | Ones to watch

A former test pilot steered the Rosetta mission to an icy world in deep space. By Elizabeth Gibney

Andreas Reeg/Agentur Focus/Eyevine

Nearly two decades ago, Andrea Accomazzo got into trouble with his girlfriend when she found a scrap of paper on his desk. In his handwriting was scrawled a phone number next to a female name: Rosetta.

She thought it was a girl, says Accomazzo. I had to explain to my jealous Italian girlfriend that Rosetta is an interplanetary mission that is flying to a comet in almost 20 years.

Ever since, Accomazzo has divided his attention. He eventually married his girlfriend and has also spent the past 18 years pursuing the comet 67P/ChuryumovGerasimenko. As flight director for the mission, Accomazzo led the team that steered Rosetta to its August rendezvous with the comet, following a 6.4-billion-kilometre journey from Earth. The pinnacle of the project came in November, when Rosetta successfully set down a lander named Philae, providing scientists with the first data from the surface of a comet and making it one of the most successful missions in the history of the European Space Agency (ESA).

Accomazzo did not act alone: it took a large operations team at ESA to manoeuvre Rosetta with enough precision to drop Philae down just 120 metres from the centre of the landing zone. Given that we'd had a 500-metre error circle, that was not a bad shot, says Fred Jansen, who led the mission. When Philae's anchoring systems failed, the craft bounced into a shady site where it could not charge its solar panels, so the lander lost power after 64 hours. But in that time, it gathered a trove of data that will add to the information collected by Rosetta about the comet's structure and composition. Armed with those insights, scientists hope to better understand the origin and evolution of the Solar System, including whether comets could have brought water and organic molecules to Earth during its infancy.

Accomazzo started off his career focused on a different type of flight. He first trained as a test pilot in the Italian Air Force. But although he loved flying, he found the culture too constraining and after two years he quit to study aerospace engineering. With his quiet, hard-working, sometimes no-nonsense nature, colleagues say that Accomazzo brings a bit of the military with him into mission control.

For Accomazzo, the biggest parallel between flying a fighter jet and Rosetta is the need for split-second judgements. You have to prepare and train a lot to be able to make the right decision, very quickly, he says. Between launch and landing, his team ran 87 full-day simulations.

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365 days: Nature's 10

Major study: Professor Thomas Preiss from ANU JCSMR who has been involved in an international project researching stem cells. Photo: Graham Tidy

Scientists, including some from Canberra, have identified a new type of stem cell which is easier to grow and manipulate as part of a major study detailing the changes cells undergo as they reprogram into stem cells.

Experts from across the globe, including some from the Australian National University John Curtin School of Medical Research, have carried out the most detailed study of how specialised body cells can be reprogrammed to be like cells from the early embryo.

"The ultimate goal with this work is to develop therapies in regenerative medicine which is a therapeutic approach whereby you would ultimately replace cells or tissues or organs that are failing in a patient with replacement parts that are made in a laboratory from the patient's own cells or from genetically highly similar stem cells," Professor Thomas Preiss from ANU's JCSMR said.

Professor Preiss said it was hoped the research could help speed up the development of treatments for many illnesses and conditions.

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"There's a range of diseases where tissues are damaged or cells or lost. It ranges from neurodegenerative disease to spinal cord injuries, stroke, diabetes, blood and kidney diseases and ultimately perhaps even heart disease," he said.

"I'm not saying our publication immediately enables any of these therapies but we're working on the molecular basis of understanding the process of making cells that would be useful for this kind of therapy."

Fifty experts in stem cell biology and genomics technologies have been involved in Project Grandiose which mapped the detailed molecular process involved in the generation of induced pluripotent stem (iPS) cells.

Since the 2012 Nobel Prize winning discovery that body cells can in principle be coaxed to become iPS cells, there has been a surge in research to better understand iPS cell reprogramming.

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Researchers identify stem cells that can be reprogrammed

PUBLIC RELEASE DATE:

26-Nov-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center @sumedicine

Induced pluripotent stem cells made from patients with a form of blistering skin disease can be genetically corrected and used to grow back healthy skin cells in laboratory dishes, researchers at the Stanford University School of Medicine have found. They've termed the new technique "therapeutic reprogramming."

The skin cells formed normal human skin when grafted onto the backs of laboratory mice, they said.

The findings represent a major advance in the battle against the disease, epidermolysis bullosa, in which the top layer of skin, called the epidermis, sloughs off with the slightest friction, leaving open wounds that are difficult to heal. Severely stricken children who survive into their late teens or early 20s often die from invasive squamous cell carcinoma, a skin cancer that can arise during repeated cycles of skin wounding and healing.

"Epidermolysis bullosa is a truly horrible, debilitating skin disease in which the top layer of skin is not properly anchored to the underlying layers," said Anthony Oro, MD, PhD, professor of dermatology. "When they are born, the trauma of birth rips away their skin, and they continue to suffer severe skin wounds that require constant bandaging and medical attention throughout their lives."

Stanford has one of the largest epidermolysis bullosa clinics in the world, with an extremely active and engaged population of patients and their families eager to help researchers. The Stanford Department of Dermatology has been working to find new treatments for the disease for over 20 years. The latest advance, in which researchers replaced the mutated, disease-causing gene in the donor-made induced pluripotent stem cells with a healthy version, was funded by an $11.7 million grant from the California Institute for Regenerative Medicine.

New avenue of treatment

"This treatment approach represents an entirely new paradigm for this disease," Oro said. "Normally, treatment has been confined to surgical approaches to repair damaged skin, or medical approaches to prevent and repair damage. But by replacing the faulty gene with a correct version in stem cells, and then converting those corrected stem cells to keratinocytes, we have the possibility of achieving a permanent fix -- replacing damaged areas with healthy, perfectly matched skin grafts."

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Blistering skin disease may be treatable with 'therapeutic reprogramming,' researchers say

New York, New York (PRWEB) November 17, 2014

Beyond Batten Disease Foundation (BBDF) and the New York Stem Cell Foundation (NYSCF) have been selected as a national innovator by the Milken Institute and will present their breakthrough findings about juvenile Batten disease at the 6th annual Partnering for Cures, November 16-18 in New York City. The presentation will highlight the collaborative efforts of NYSCF, BBDF and Batten Disease Support and Research Association.

Craig and Charlotte Benson established Beyond Batten Disease Foundation in August 2008 after their then five-year-old daughter, Christiane, was diagnosed with juvenile Batten disease. Together with hundreds of families affected by Batten disease, and many more supporters who share their hope and resolve, they are working tirelessly to create a brighter future for Christiane, and all children with Batten disease.

Watch the Benson Family story:

The Benson Family Story

Beyond Batten Disease and the New York Stem Cell Foundation hope to ramp up funding and partnerships to develop stem cell resources to investigate and explore new treatments and ultimately find a cure for juvenile Batten disease, a fatal illness-affecting children as they convene at the FasterCures, conference. The Washington, D.C.-based center of the Milken Institute will bring together nearly 1,000 medical research leaders, investors and decision-makers to forge the collaborations needed to speed and improve outcomes-driven R&D. NYSCF scientists have created the first iPS cells from a neurological disease and the first ever stem cell disease model from any disease. This discovery was named Time Magazine #1 breakthrough in 2008 because it was the first time anyone has made stem cells from a person with a disease and used them to produce the type of cell that degenerated in that patient. Again, in 2012 Time Magazine recognized the Beyond Batten Disease Foundations creation of a rate genetic disease test as a top ten medical breakthrough.

We know the genetic mutations associated with juvenile Batten disease. This partnership will result in stem cell models of juvenile Batten, giving researchers an unprecedented look at how the disease develops, speeding research towards a cure, said Susan L. Solomon, NYSCF Chief Executive Officer.

Working with NYSCF to generate functional neuronal subtypes from patients and families is a stellar example of one of our key strategies in the fight against juvenile Batten disease: creating resource technology with the potential to transform juvenile Batten disease research and accelerate our timeline to a cure, said Danielle M. Kerkovich, PhD, BBDF Principal Scientist.

Juvenile Batten disease begins in early childhood between the ages of five and ten. Initial symptoms typically begin with progressive vision loss, followed by personality changes, behavioral problems, and slowed learning. These symptoms are followed by a progressive loss of motor functions, eventually resulting in wheelchair use and premature death. Seizures and psychiatric symptoms can develop at any point in the disease.

Juvenile Batten disease is one disorder in a group of rare, fatal, inherited disorders known as Batten disease. Over 40 different errors (mutations) in the CLN3 segment of DNA (gene) have been attributed to juvenile Batten disease. The pathological hallmark of juvenile Batten is a buildup of lipopigment in the bodys tissues. It is not known why lipopigment accumulates or why brain and eventually, heart cells are selectively damaged. It is, however, clear that we need disease-specific tools that reflect human disease in order to figure this out and to build therapy.

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Beyond Batten Disease Foundation and the New York Stem Cell Foundation Chosen as a National Innovator by the Milken ...

Published November 07, 2014

A team of stem cell scientists has identified the biological mechanisms of Parkinsons disease and recreated a model of the disease in a dish.

Researchers at The New York Stem Cell Foundation (NYSCF) Research Institute studied a pair of identical twins one with Parkinsons and one without as well as another unrelated Parkinsons patient and four healthy control subjects to observe key characteristics of the disease. After comparing the individuals biological factors, they noticed differences in the patients neurons ability to produce dopamine. Dopamine production is deficient in Parkinsons disease.

"The unique scenario of identical twins, one with this disease and one without, allowed our scientists an unprecedented look into the mechanisms of Parkinson's disease," Susan L. Solomon, NYSCF chief executive officer, said in a news release. "Advanced stem cell research techniques allow us to push the boundaries of science and see what actually goes wrong at the cellular level, step by step during the disease process."

Parkinsons disease affects an estimated 500,000 people in the United States, according to the National Institutes of Health (NIH). The average age of onset is 60, and the risk of developing it increases with age. Symptoms of Parkinsons include tremor, shaking in the hands, arms, legs, jaw or head; impaired balance or postural instability; slowness of movement; and stiffness of the limbs and trunk.

There is currently no cure for Parkinsons.

While the disease is moderately hereditary, scientists have yet to fully understand the mechanisms of inheritance. The researchers note the DNA mutations that produce the enzyme glucocerebrosidase (GBA) have been linked to a five-fold increased risk of developing Parkinsons, but only 30 percent of people with this mutation have been shown to get the disease by age 80. This suggests that genetic and non-genetic factors cause Parkinsons. In studying the identical twins, scientists were able to analyze these mechanisms.

The scientists made induced pluripotent stem (iPS) cells from skin samples from both twins to generate a cellular model of Parkinsons in a dish, recreating the outstanding features of the disease specifically the dopamine and a-synuclein deficiency.

Scientists saw that the neurons from the twin affected by Parkinsons produced less dopamine and had higher levels of an enzyme called monomine oxidase B (MAO-B), as well as a poorer ability to connect with each other, compared to the twin that did not have the disease.

The findings suggest a possible therapy for Parkinsons: treating neurons with molecules that reduce the activity of MAO-B and GBA, while normalizing -synuclein and dopamine levels.

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Researchers create stem cell model of Parkinsons disease in a dish

45 minutes ago by Nicole Giese Rura

Induced neural stem cells (iNSCs) created from adult cells hold promise for therapeutic transplantation, but their potential in this capacity has been limited by failed efforts to maintain such cells in the desirable multi-potent NSC state without continuous expression of the transcription factors used initially to reprogram them.

Now, Whitehead Institute scientists have created iNSCs that remain in the multi-potent state without ongoing expression of reprogramming factors. This allows the iNSCs to divide repeatedly to generate cells in quantities sufficient for therapy.

"Therapeutically, it's important to make neural stem cells because they can self-renew and make lots of cells," says Whitehead Institute Founding Member Rudolf Jaenisch, who is also a professor of biology at MIT. "If you just make mature neurons, which has been done by others, you never get enough cells."

To make iNSCs via direct lineage conversion researchers use viruses to insert a cocktail of transcription factors into the genome of mouse adult skin cells. A drug triggers these transcription factors to turn on genes active in neural stem cells. This direct conversion, known as transdifferentiation, bypasses the step of pushing the cells first through an embryonic stem-cell-like state.

In previous research, iNSCs remained addicted to the drug and reprogramming transcription factors; if either the drug or the factors was removed, the cells revert to skin cells.

"If the reprogramming factors are still active, it's horrible for the cells," says John Cassady, a scientist in Jaenisch's lab. "The cells would be unable to differentiate and the resulting cells would not be therapeutically useful."

In a paper published online this week in the current issue of the journal Stem Cell Reports, Cassady and other Whitehead scientists describe how they prevented the cells' relapse without keeping the reprogramming factors active. First, the cells were grown in a special medium that selects for neural stem cells. Then, the drug is removed. Instead of reverting into skin cells, the iNSCs remain in a multi-potent state that can differentiate into neurons and glia cells. Cassady also refined the reprogramming cocktail to contain eight transcription factors, which produces iNSCs that are transcriptionally and epigenetically similar to mouse neural stem cells.

Cassady notes that a random sample of skin cells can contain neural precursor cells, which can more easily make the transition to iNSCs. To eliminate the possibility that his method might actually rely on cells having this sort of "head start", Cassady converted fully mature immune system cells called B-lymphocytes, which have a very specific genetic marker, to iNSCs. The resulting cells had the profile of their new identity as iNSCs, yet retained their B-lymphocyte genetic marker, showing that Cassady's method could indeed convert non-neural cells to iNSCs.

Although promising, all of the work to date has been conducted in mouse cells. According to Cassady, researchers should next test this protocol in human cells to see if it can successfully produce the cell populations necessary for therapeutic use.

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Direct generation of neural stem cells could enable transplantation therapy

PUBLIC RELEASE DATE:

6-Nov-2014

Contact: David McKeon dmckeon@nyscf.org 212-365-7440 New York Stem Cell Foundation @nyscf

New York, NY (November 6, 2014) - A team of scientists led by The New York Stem Cell Foundation (NYSCF) Research Institute successfully created a human stem cell disease model of Parkinson's disease in a dish. Studying a pair of identical (monozygotic) twins, one affected and one unaffected with Parkinson's disease, another unrelated Parkinson's patient, and four healthy control subjects, the scientists were able to observe key features of the disease in the laboratory, specifically differences in the patients' neurons' ability to produce dopamine, the molecule that is deficient in Parkinson's disease. In addition, the scientists also identified a potential strategy for developing novel therapies for Parkinson's disease.

Attributed to a combination of genetic and nongenetic factors, Parkinson's disease has no completely effective therapy or cure. Parkinson's disease is moderately heritable, but the mechanisms of this inheritance are not well understood. While genetic forms of the disease exist, sporadic forms are far more common.

"The unique scenario of identical twins, one with this disease and one without, allowed our scientists an unprecedented look into the mechanisms of Parkinson's disease," said Susan L. Solomon, NYSCF Chief Executive Officer. "Advanced stem cell research techniques allow us to push the boundaries of science and see what actually goes wrong at the cellular level, step by step during the disease process."

DNA mutations resulting in the production of a specific enzyme called glucocerebrosidase (GBA) have been linked to a five-fold greater risk of developing Parkinson's disease; however, only 30% of individuals with this mutation have been shown to develop Parkinson's disease by the age of 80. This discordance suggests that multiple factors contribute to the development of Parkinson's disease, including both genetic and non-genetic factors. To date, there has been no appropriate model to identify and test multiple triggers leading to the onset of the disease.

In this study, published today in Cell Reports, a set of identical twins, both with a GBA mutation, provided a unique opportunity to evaluate and dissect the genetic and non-genetic contributions to the development of Parkinson's disease in one twin, and the lack of disease in the other. The scientists made induced pluripotent stem (iPS) cells from skin samples from both twins to generate a cellular model of Parkinson's in a dish, recapitulating key features of the disease, specifically the accumulation of -synuclein and dopamine deficiency.

Upon analyzing the cell models, the scientists found that the dopamine-producing neurons from both twins had reduced GBA enzymatic activity, elevated -synuclein protein levels, and a reduced capacity to synthesize and release dopamine. In comparison to his unaffected brother, the neurons generated from the affected twin produced less dopamine, had higher levels of an enzyme called monoamine oxidase B (MAO-B), and poor ability to connect with each other. Treating the neurons with molecules that lowered the activity of MAO-B together with overexpressed GBA normalized -synuclein and dopamine levels in the cell models. This suggests that a combination therapy for the affected twin may be possible by simultaneously targeting these two enzymes.

"The subject of Parkinson's disease discordant twins gave us an incredible opportunity to utilize stem cell models of disease in a dish to unlock some of the biological mechanisms of disease," said Dr. Scott Noggle, NYSCF Vice President, Stem Cell Research and The NYSCF - Charles Evans Senior Research Fellow for Alzheimer's Disease. "Working with these various different groups and scientists added to the depth and value of the research and we hope our findings will be applicable to other Parkinson's disease patients and other neurodegenerative disorders."

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Scientists create Parkinson's disease in a dish

OpRegen consists of animal product-free retinal pigment epithelial (RPE) cells with high purity and potency that were derived from human embryonic stem cells (hESCs). Cell Cure will conduct the trial in Israel where OpRegen will be transplanted as a single dose into the subretinal space of the eye to test the safety and efficacy of the product. Patient enrollment is expected to begin in 2014 following approval of the trial by the Israel Ministry of Health.

About the OpRegenClinical Trial

Cell Cures Phase I/IIa clinical trial is a dose escalation safety and preliminary efficacy study of hESC-derived Retinal Pigment Epithelial (RPE) cells transplanted subretinally in patients with advanced dry-form AMD called geographic atrophy. The open-label, single center, nonrandomized trial will evaluate three different dose regimens of 50,000 to 500,000 cells. A total of 15 patients will be enrolled. The patients will be 55 years of age and older, with non-neovascular (dry-AMD) who have funduscopic findings of GA in the macula with absence of additional concomitant ocular disorders. The eye most affected by the disease will be treated with the contralateral eye being the control. Following transplantation, the patients will be followed for 12 months at specified intervals, to evaluate the safety and tolerability of OpRegen. A secondary objective of the clinical trial will be to examine the ability of transplanted OpRegen to engraft, survive, and induce changes in visual acuity. In addition to thorough characterization of visual function, a battery of defined ophthalmic imaging modalities will be used to quantify structural changes and rate of GA expansion. The study will be performed at Hadassah Ein Kerem Medical Center in Jerusalem, Israel.

The FDAs acceptance of our IND for the Phase I/IIa trial of OpRegen is a significant milestone for our company, and in the broader development of therapies based on human embryonic stem cells for the treatment of major diseases, said Benjamin Reubinoff, MD, PhD, Chief Scientific Officer of Cell Cure and Chairman of Obstetrics and Gynecology and Director of the Hadassah Human Embryonic Stem Cell Research Center at Hadassah Medical Center, Jerusalem, Israel. We look forward to initiating this first-of-its-kind study, and to continuing the clinical development of OpRegen.

Cell Cures Phase I/IIa study of OpRegen has been designed to provide preliminary, objective functional and structural data on the ability of hESC-RPE cell transplantation to slow the progression of geographic atrophy, in addition to safety data, added Prof. Eyal Banin, Head of the Center for Retinal and Macular Degenerations at the Department of Ophthalmology of Hadassah University Medical Center, Jerusalem, Israel who together with Prof. Reubinoff helped develop this novel treatment over the last decade. We are truly excited that this unique, hESC-based therapy will finally be tested in patients with dry-AMD which severely impacts the quality of life of the elderly, and for which no approved therapy yet exists, Dr. Banin stated.

Information about the trial will be made available at ClinicalTrials.gov website of the National Institutes of Health http://www.clinicaltrials.gov/ct2/home. Additional information will be made available on Cell Cures website at http://www.cellcureneurosciences.com/.

About Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is one of the major diseases of aging and is the leading eye disease responsible for visual impairment of older persons in the US, Europe and Australia. AMD affects the macula, which is the part of the retina responsible for sharp, central vision that is important for facial recognition, reading and driving. There are two forms of AMD. The dry form (dry-AMD) advances slowly and painlessly but may progress to geographic atrophy (GA) in which RPE cells and photoreceptors degenerate and are lost. Once the atrophy involves the fovea (the center of the macula), patients lose their central vision and may develop legal blindness. There are about 1.6 million new cases of dry-AMD in the US annually, and as yet there is no effective treatment for this condition. The yearly economic loss to the gross domestic product in the United States from dry-AMD has been estimated to be $24.4 billion. The market opportunity for a treatment for GA has been estimated at over $5 billion globally. About 10% of patients with dry-AMD develop wet (or neovascular) AMD, the second main form of this disease, which usually manifests acutely and can lead to severe visual loss in a matter of weeks. Wet-AMD can be treated with currently marketed VEGF inhibitors. However, such products typically require frequent repeated injections in the eye, and patients often continue to suffer from continued progression of the underlying dry-AMD disease process. Current annual sales of VEGF inhibitors for the treatment of the wet form of AMD are estimated to be about $7 billion worldwide.

The root cause of the larger problem of dry-AMD is believed to be the dysfunction of RPE cells. Therefore, one of the most exciting new therapeutic strategies for dry-AMD is the transplantation of healthy young RPE cells to support and replace those lost with age. Pluripotent stem cells, such as hESCs, can potentially provide a means of manufacturing such healthy RPE cells on an industrial scale.

About OpRegen

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BioTimes Subsidiary Cell Cure Neurosciences Receives FDA Authorization to Initiate Phase I/IIa Trial of Embryonic ...

Shinya Yamanaka ( , Yamanaka Shin'ya?, born September 4, 1962) is a Japanese Nobel Prize-winning stem cell researcher.[1][2][3] He serves as the director of Center for iPS Cell Research and Application and a professor at the Institute for Frontier Medical Sciences at Kyoto University; as a senior investigator at the UCSF-affiliated J. David Gladstone Institutes in San Francisco, California; and as a professor of anatomy at University of California, San Francisco (UCSF). Yamanaka is also a past president of the International Society for Stem Cell Research (ISSCR).

He received the Wolf Prize in Medicine in 2011 with Rudolf Jaenisch;[6] the Millennium Technology Prize in 2012 together with Linus Torvalds. In 2012 he and John Gurdon were awarded the Nobel Prize for Physiology or Medicine for the discovery that mature cells can be converted to stem cells.[7] In 2013 he was awarded the $3 million Breakthrough Prize in Life Sciences for his work.

Yamanaka was born in Higashisaka Japan in 1962. After graduating from Tennji High School attached to Osaka Kyoiku University,[8] he received his M.D. at Kobe University in 1987 and his PhD at Osaka City University Graduate School in 1993. After this, he went through a residency in orthopedic surgery at National Osaka Hospital and a postdoctoral fellowship at the Gladstone Institute of Cardiovascular Disease, San Francisco.

Afterwards he worked at the Gladstone Institutes in San Francisco, USA and Nara Institute of Science and Technology in Japan. Yamanaka is currently Professor at Kyoto University, where he directs its Center for iPS Research and Application. He is also a senior investigator at the Gladstone Institutes as well as the director of the Center for iPS Cell Research and Application.[9]

Between 1987 and 1989, Yamanaka was a resident in orthopedic surgery at the National Osaka Hospital. His first operation, was removing a benign tumor from his friend Shuichi Hirata, a task he could not complete after one hour, when a skilled surgeon would take ten minutes or so. Some seniors referred to him as "Jamanaka", a pun on the Japanese word for obstacle.[10]

From 1993 to 1996, he was at the Gladstone Institute of Cardiovascular Disease. Between 1996 and 1999, he was an assistant professor at Osaka City University Medical School, but found himself mostly looking after mice in the laboratory, not doing actual research.[10]

His wife advised him to become a practicing doctor, but instead he applied for a position at the Nara Institute of Science and Technology. He stated that he could and would clarify the characteristics of embryonic stem cells, and this can-do attitude won him the job. From 19992003, he was an associate professor there, and started the research that would later win him the 2012 Nobel Prize. He became a full professor and remained at the institute in that position from 20032005. Between 2004 and 2010, Yamanaka was a professor at the Institute for Frontier Medical Sciences.[11] Currently, Yamanaka is the director and a professor at the Center for iPS Cell Research and Application at Kyoto University.

In 2006, he and his team generated induced pluripotent stem cells (iPS cells) from adult mouse fibroblasts.[1] iPS cells closely resemble embryonic stem cells, the in vitro equivalent of the part of the blastocyst (the embryo a few days after fertilization) which grows to become the embryo proper. They could show that his iPS cells were pluripotent, i.e. capable of generating all cell lineages of the body. Later he and his team generated iPS cells from human adult fibroblasts,[2] again as the first group to do so. A key difference from previous attempts by the field was his team's use of multiple transcription factors, instead of transfecting one transcription factor per experiment. They started with 24 transcription factors known to be important in the early embryo, but could in the end reduce it to 4 transcription factors Sox2, Oct4, Klf4 and c-Myc.[1]

Yamanaka practiced judo (2dan black belt) and played rugby as a university student. He also has a history of running marathons. After a 20-year gap, he competed in the inaugural Osaka Marathon in 2011 as a charity runner with a time of 4:29:53. He also took part in the 2012 Kyoto Marathon to raise money for iPS research, finishing in 4:03:19. He also ran in the second Osaka Marathon on November 25, 2012.[12]

In 2007, Yamanaka was recognized as a "Person Who Mattered" in the Time Person of the Year edition of Time Magazine.[13] Yamanaka was also nominated as a 2008 Time 100 Finalist.[14] In June 2010, Yamanaka was awarded the Kyoto Prize for reprogramming adult skin cells to pluripotential precursors. Yamanaka developed the method as an alternative to embryonic stem cells, thus circumventing an approach in which embryos would be destroyed.

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Shinya Yamanaka - Wikipedia, the free encyclopedia

IPS Stem Cells: New Ethical Quandaries By Sally Lehrman

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When scientists learned how to turn back the clock in a young skin cell, to bring it back to an early-stage cell that could become any other type in the body, both they and ethicists rejoiced. The reprogrammed cell was pluripotent, much like an embryonic stem cell. Maybe even better, it also might be prompted to jump from one cell type to another.

One day, these induced pluripotent stem cells -- iPS cells for short -- might be able to correct any number of life-threatening and disabling conditions. Much sooner, these cells will almost certainly serve as extremely useful models for studying disease.

The researchers used viruses to deliver three to four new genes into the cell nucleus. And with the new information, the skin cells reprogrammed themselves. They behaved almost exactly like embryonic stem cells, which are derived from fertilized eggs. But with these reprogrammed cells, people thought, there would be no moral and political controversy. No embryo would be destroyed.

Recently, new studies have taken the work a step further. Researchers used synthetic RNA instead of viruses to get new instructions into the cell nucleus. This sped up the process and lessened the possibility of side effects such as cancer when the cells finally become a treatment for patients. (They're called RNA-induced pluripotent cells.)

But as researchers and ethicists take a closer look at these iPS cells, they are realizing that the issues posed are as thorny as ever. In fact, the issues may be even more urgent because the new techniques are so much easier and cheaper. The concerns fall into three main areas.

First, the possibility of human cloning from one person's skin cells or human reproduction from cells made into sperm and egg. The possibility is far-off, but real. Scientists already have reported progress that could lead to either. One could become a parent at any age, using tissue from someone either living or dead.

More immediate concerns have to do with control of the original tissue donation and the purposes to which it is applied.

For instance, privacy. Because of the desire to use these cells to study or treat diseases such as Parkinson's, juvenile diabetes or Alzheimer's, it will be important to know the donor's health history. The donor's personal information and health history must always be linked to the cells. It may be impossible to maintain donor privacy.

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The long-term goal of Dr. Ikeda's lab is to develop efficient and safe gene and cell therapy platforms for individualized medicine. Dr. Ikeda's main research interests include induced pluripotent stem (iPS) cell technology as a novel diabetes therapy; adeno-associated virus (AAV) vector-mediated gene therapy for diabetes and cardiovascular disease; and intrinsic immunity against HIV and retroviral infection.

Towards patient-specific iPS cells for a novel cell therapy for type I diabetes

Dr. Ikeda's research interests include:

Gene and cell therapy for diabetes. Induced pluripotent stem (iPS) cell technology enables derivation of pluripotent stem cells from nonembryonic sources. Successful differentiation of autologous iPS cells into islet-like cells could allow in vitro modeling of patient-specific disease pathogenesis and future clinical cell therapy for diabetes. However, an efficient methodology is not available for the generation of glucose-responsive insulin-producing cells from iPS cells in vitro.

Recently, the lab has examined the efficiency of iPS differentiation into glucose-responsive insulin-producing cells using a modified stepwise protocol with indolactam V and GLP-1 and demonstrated successful generation of islet-like cells, which expressed pancreas-specific markers. Importantly, the iPS-derived islet-like cells secreted C peptide in a glucose-dependent manner. The lab is currently working on reprogramming diabetic patient-derived cells into genomic modification-free iPS cells using nonintegrating vectors, as well as studying the therapeutic effects of iPS-derived insulin-producing islet-like cells in a diabetic mouse model.

Additionally, the lab has developednovel pancreatic gene delivery vectors and is currently studying the therapeutic effects of pancreatic overexpression of factors known to accelerate beta cell regeneration and neogenesis in diabetic mouse models.

Gene therapy for hypertensive heart disease. Altered myocardial structure and function secondary to hypertensive heart disease are leading causes of heart failure and death. A frequent clinical phenotype of cardiac disease is diastolic dysfunction associated with high blood pressure, which over time leads to profound cardiac remodeling, fibrosis and progression to congestive heart failure.

B-type natriuretic peptide (BNP) has blood pressure lowering, anti-fibrotic and anti-hypertrophic properties, making it an attractive therapeutic for attenuating the adverse cardiac remodeling associated with hypertension. However, use of natriuretic peptides for chronic therapy has been limited by their extremely short in vivo half-life. Recently, the lab usedmyocardium-tropic adeno-associated virus serotype 9 (AAV9)-based vectors and demonstrated long-term cardiac BNP expression in spontaneous hypertensive rats. Sustained BNP expression significantly lowered blood pressure for up to nine months and improved the cardiac functions in hypertensive heart disease.

The lab is currently examining the feasibility of this strategy in a large animal model for future clinical applications, as well as further developing a gene therapy strategy for hypertensive heart disease using other therapeutic genes.

Pathogenesis of HIV and retroviruses. Mammalian cells have evolved several strategies to limit viral production. For instance, type 1 interferons stimulate a series of cellular factors that block viral gene expression by degrading viral RNA or inhibiting protein translation.

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The New York Stem Cell Foundation (NYSCF) Research Institute, through the launch of its repository in 2015, will provide for the first time the largest-ever number of stem cell lines available to the scientific research community. Initially, over 600 induced pluripotent stem (iPS) cell lines and 1,000 cultured fibroblasts from over 1,000 unique human subjects will be made available, with an increasing number available in the first year. To collect these samples, NYSCF set up a rigorous human subjects system that protects patients and allows for the safe and anonymous collection of samples from people interested in participating in research.

A pilot of over 200 of NYSCF's iPS cell lines is already searchable on an online database. The pilot includes panels of iPS cell lines generated from donors affected by specific diseases such as type 1 diabetes, Parkinson's disease, and multiple sclerosis, as well as a diversity panel of presumed healthy donors from a wide range of genetic backgrounds representing the United States Census. These panels, curated to provide ideal initial cohorts for studying each area, include subjects ranging in age of disease onset, and are gender matched. Other panels that will be available in 2015 include Alzheimer's disease, schizophrenia, Juvenile Batten disease, and Charcot-Marie-Tooth disease.

"NYSCF's mission is to develop new treatments for patients. Building the necessary infrastructure and making resources available to scientists around the world to further everyone's research are critical steps in accomplishing this goal," said Susan L. Solomon, CEO of The New York Stem Cell Foundation.

NYSCF has developed the technology needed to create a large collection of stem cell lines representing the world's population. This platform, known as the NYSCF Global Stem Cell ArrayTM, is an automated robotic system for stem cell production and is capable of generating 200 iPS cell lines a month from patients with various diseases and conditions and from all genetic backgrounds. The NYSCF Global Stem Cell ArrayTM is also used for stem cell differentiation and drug screening.

Currently available in the online database that was developed in collaboration with eagle-i Network, of the Harvard Catalyst, is a pilot set of approximately 200 iPS cell lines and related information about the patients. This open source, open access resource discovery platform makes the cell lines and related information available to the public on a user-friendly, web-based, searchable system. This is one example of NYSCF's efforts to reduce duplicative research and enable even broader collaborative research efforts via data sharing and analysis. NYSCF continues to play a key role in connecting the dots between patients, scientists, funders, and outside researchers that all need access to biological samples.

"The NYSCF repository will be a critical complement to other existing efforts which are limited in their ability to distribute on a global scale. I believe that this NYSCF effort wholly supported by philanthropy will help accelerate the use of iPS cell based technology," said Dr. Mahendra Rao, NYSCF Vice President of Regenerative Medicine.

To develop these resources, NYSCF has partnered with over 50 disease foundations, academic institutions, pharmaceutical companies, and government entities, including the Parkinson's Progression Markers Initiative (PPMI), PersonalGenomes.org, the Beyond Batten Disease Foundation, among several others. NYSCF also participates in and drives a number of large-scale multi stakeholder initiatives including government and international efforts. One such example is the Cure Alzheimer's Fund Stem Cell Consortium, a group consisting of six institutions, including NYSCF, directly investigating, for the first time, brain cells in petri dishes from individual patients who have the common sporadic form of Alzheimer's disease.

"We are entering this next important phase of using stem cells to understand disease and discover new drugs. Having collaborated with NYSCF extensively over the last five years on the automation of stem cell production and differentiation, it's really an exciting moment to see these new technologies that NYSCF has developed now being made available to the entire academic and commercial research communities," said Dr. Kevin Eggan, Professor of Stem Cell and Regenerative Biology at Harvard University and Principal Investigator of the Harvard Stem Cell Institute.

NYSCF's unique technological resources have resulted in partnerships with companies to develop both stem cell lines and also collaborative research programs. Over the past year, NYSCF has established collaborations with four pharmaceutical companies to accelerate the translation of basic scientific discoveries into the clinic. Federal and state governments are also working with NYSCF to further stem cell research in the pursuit of cures. In 2013, NYSCF partnered with the National Institutes of Health (NIH) Undiagnosed Disease Program (UDP) to generate stem cell lines from 100 patients in the UDP and also collaborate with UDP researchers to better understand and potentially treat select rare diseases.

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NYSCF Research Institute announces largest-ever stem cell repository

Antonio Regalado for MIT Technology Review 2014-10-15 19:15:44 UTC

When stem cells were first culled from human embryos sixteen years ago, scientists imagined they would soon be treating diabetes, heart disease, stroke, and many other diseases with cells manufactured in the lab.

It's all taken longer than they thought. But now, a Massachusetts biotech firm has reported results from the largest, and longest, human test of a treatment based on embryonic stem cells, saying it appears safe and may have partly restored vision to patients going blind from degenerative diseases.

Results of three-year study were described Tuesday in the Lancet by Advanced Cell Technology and collaborating eye specialists at the Jules Stein Eye Institute in Los Angeles who transplanted lab-grown cells into the eyes of nine people with macular degeneration and nine with Stargardt's macular dystrophy.

The idea behind Advanced Cell's treatment is to replace retinal pigment epithelium cells, known as RPE cells, a type of caretaker tissue without which a person's photoreceptors also die, with supplies grown in laboratory. It uses embryonic stem cells as a starting point, coaxing them to generate millions of specialized retina cells. In the study, each patient received a transplant of between 50,000 and 150,000 of those cells into one eye.

The main objective of the study was to prove the cells were safe. Beyond seeing no worrisome side effects, the researchers also noted some improvements in the patients. According to the researchers half of them improved enough to read two to three extra lines on an eye exam chart, results Robert Lanza, chief scientific officer of Advanced Cell, called remarkable.

"We have people saying things no one would make up, like 'Oh I can see the pattern on my furniture, or now I drive to the airport," he says. "Clearly there is something going on here."

Lanza stressed the need for a larger study, which he said the company hoped to launch later this year in Stargardt's patients. But if the vision results seen so far continue, Lanza says "this would be a therapy."

Some eye specialists said it's too soon to say whether the vision improvements were real. The patients weren't examined by independent specialists, they said, and eyesight in patients with low vision is notoriously difficult to measure. That leaves plenty of room for placebo effects or unconscious bias on the part of doctors.

"When someone gets a treatment, they try really hard to read the eye chart," says Stephen Tsang, a doctor at Columbia University who sees patients losing their vision to both diseases. It's common for patients to show quick improvements, he says, although typically not as large as what Advanced Cell is reporting.

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Stem Cell Eye Treatment May Restore Vision

A treatment based on embryonic stem cells clears a key safety hurdle, and might help restore vision.

When stem cells were first culled from human embryos sixteen years ago, scientists imagined they would soon be treating diabetes, heart disease, stroke, and many other diseases with cells manufactured in the lab.

Its all taken longer than they thought. But today, a Massachusetts biotech firm reported results from the largest, and longest, human test of a treatment based on embryonic stem cells, saying it appears safe and may have partly restored vision to patients going blind from degenerative diseases.

Results of three-year study were described today in the Lancet by Advanced Cell Technology and collaborating eye specialists at the Jules Stein Eye Institute in Los Angeles who transplanted lab-grown cells into the eyes of nine people with macular degeneration and nine with Stargardts macular dystrophy.

The idea behind Advanced Cells treatment is to replace retinal pigment epithelium cells, known as RPE cells, a type of caretaker tissue without which a persons photoreceptors also die, with supplies grown in laboratory. It uses embryonic stem cells as a starting point, coaxing them to generate millions of specialized retina cells. In the study, each patient received a transplant of between 50,000 and 150,000 of those cells into one eye.

The main objective of the study was to prove the cells were safe. Beyond seeing no worrisome side effects, the researchers also noted some improvements in the patients. According to the researchers half of them improved enough to read two to three extra lines on an eye exam chart, results Robert Lanza, chief scientific officer of Advanced Cell, called remarkable.

We have people saying things no one would make up, like Oh I can see the pattern on my furniture, or now I drive to the airport, he says. Clearly there is something going on here.

Lanza stressed the need for a larger study, which he said the company hoped to launch later this year in Stargardts patients. But if the vision results seen so far continue, Lanza says this would be a therapy.

Some eye specialists said its too soon to say whether the vision improvements were real. The patients werent examined by independent specialists, they said, and eyesight in patients with low vision is notoriously difficult to measure. That leaves plenty of room for placebo effects or unconscious bias on the part of doctors.

When someone gets a treatment, they try really hard to read the eye chart, says Stephen Tsang, a doctor at Columbia University who sees patients losing their vision to both diseases. Its common for patients to show quick improvements, he says, although typically not as large as what Advanced Cell is reporting.

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Stem Cells Seem Safe in Treating Eye Disease

PUBLIC RELEASE DATE:

24-Sep-2014

Contact: Krista Conger kristac@stanford.edu 650-725-5371 Stanford University Medical Center @sumedicine

Over 500 million people worldwide carry a genetic mutation that disables a common metabolic protein called ALDH2. The mutation, which predominantly occurs in people of East Asian descent, leads to an increased risk of heart disease and poorer outcomes after a heart attack. It also causes facial flushing when carriers drink alcohol.

Now researchers at the Stanford University School of Medicine have learned for the first time specifically how the mutation affects heart health. They did so by comparing heart muscle cells made from induced pluripotent stem cells, or iPS cells, from people with the mutation versus those without the mutation. IPS cells are created in the laboratory from specialized adult cells like skin. They are "pluripotent," meaning they can be coaxed to become any cell in the body.

"This study is one of the first to show that we can use iPS cells to study ethnic-specific differences among populations," said Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute and professor of cardiovascular medicine and of radiology.

"These findings may help us discover new therapeutic paths for heart disease for carriers of this mutation," said Wu. "In the future, I believe we will have banks of iPS cells generated from many different ethnic groups. Drug companies or clinicians can then compare how members of different ethnic groups respond to drugs or diseases, or study how one group might differ from another, or tailor specific drugs to fit particular groups."

The findings are described in a paper that will be published Sept. 24 in Science Translational Medicine. Wu and Daria Mochly-Rosen, PhD, professor of chemical and systems biology, are co-senior authors of the paper, and postdoctoral scholar Antje Ebert, PhD, is the lead author.

ALDH2 and cell death

The study showed that the ALDH2 mutation affects heart health by controlling the survival decisions cells make during times of stress. It is the first time ALDH2, which is involved in many common metabolic processes in cells of all types, has been shown to play a role in cell survival. In particular, ALDH2 activity, or the lack of it, influences whether a cell enters a state of programmed cell death called apoptosis in response to stressful growing conditions.

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Stanford scientists use stem cells to learn how common mutation in Asians affects heart health

Over 500 million people worldwide carry a genetic mutation that disables a common metabolic protein called ALDH2. The mutation, which predominantly occurs in people of East Asian descent, leads to an increased risk of heart disease and poorer outcomes after a heart attack. It also causes facial flushing when carriers drink alcohol.

Now researchers at the Stanford University School of Medicine have learned for the first time specifically how the mutation affects heart health. They did so by comparing heart muscle cells made from induced pluripotent stem cells, or iPS cells, from people with the mutation versus those without the mutation. IPS cells are created in the laboratory from specialized adult cells like skin. They are "pluripotent," meaning they can be coaxed to become any cell in the body.

"This study is one of the first to show that we can use iPS cells to study ethnic-specific differences among populations," said Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute and professor of cardiovascular medicine and of radiology.

"These findings may help us discover new therapeutic paths for heart disease for carriers of this mutation," said Wu. "In the future, I believe we will have banks of iPS cells generated from many different ethnic groups. Drug companies or clinicians can then compare how members of different ethnic groups respond to drugs or diseases, or study how one group might differ from another, or tailor specific drugs to fit particular groups."

The findings are described in a paper that will be published Sept. 24 in Science Translational Medicine. Wu and Daria Mochly-Rosen, PhD, professor of chemical and systems biology, are co-senior authors of the paper, and postdoctoral scholar Antje Ebert, PhD, is the lead author.

ALDH2 and cell death

The study showed that the ALDH2 mutation affects heart health by controlling the survival decisions cells make during times of stress. It is the first time ALDH2, which is involved in many common metabolic processes in cells of all types, has been shown to play a role in cell survival. In particular, ALDH2 activity, or the lack of it, influences whether a cell enters a state of programmed cell death called apoptosis in response to stressful growing conditions.

The use of heart muscle cells derived from iPS cells has opened important doors for scientists because tissue samples can be easily obtained and maintained in the laboratory for study. Until recently, researchers had to confine their studies to genetically engineered mice or to human heart cells obtained through a heart biopsy, an invasive procedure that yields cells which are difficult to keep alive long term in the laboratory.

"People have studied the enzyme ALDH2 for many years in animal models," said Ebert. "But there are many significant differences between mice and humans. Now we can study actual human heart muscle cells, conveniently grown in the lab."

The iPS cells in this study were created from skin samples donated by 10 men, ages 21-22, of East Asian descent.

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Stem cells used to learn how common mutation in Asians affects heart health

ALAMEDA, Calif.--(BUSINESS WIRE)--BioTime, Inc. (NYSE MKT: BTX) announced that its subsidiary Asterias Biotherapeutics, Inc. (OTCBB: ASTY) has reached an agreement with Cancer Research UK and Cancer Research Technology (CRT), the charitys development and commercialization arm, to conduct a clinical trial of Asterias novel immunotherapy treatment AST-VAC2 in subjects with non-small cell lung cancer.

AST-VAC2 is a non-patient specific (allogeneic) cancer vaccine designed to stimulate patients immune systems to attack telomerase, a protein that is expressed in over 95 percent of cancers but is rarely expressed in normal adult cells.

The vaccine was developed following successful early phase clinical trials of a similar, patient specific (autologous) Asterias vaccine, called AST-VAC1, which was derived from patients blood cells and tested in prostate cancer and acute myeloid leukemia.

Unlike AST-VAC1, and other autologous (patient specific) vaccines that are developed from a patients own cells, AST-VAC2 is derived from human embryonic stem cells (hESCs), meaning it can be produced on a large scale and stored ready for use, rather than having to produce a specific version of the drug for each patient.

The trial of AST-VAC2 will evaluate the safety and toxicity of the vaccine, feasibility, stimulation of patient immune responses to telomerase and AST-VAC2, and clinical outcome after AST-VAC2 administration in patients with resected early-stage lung cancer and in patients with advanced forms of the disease.

Pedro Lichtinger, Asterias chief executive officer, said: The Asterias collaboration with Cancer Research UKs Drug Development Office and CRT represents a major step in advancing our proprietary dendritic cell platform for the potential benefit of patients.

AST-VAC2 is based on a specific mode of action that is complementary and potentially synergistic to other immune therapies. We are delighted to partner with Cancer Research UK to advance this important platform through Phase 1/2 clinical trials. Cancer Research UKs Drug Development Office has the global recognition of having the quality, capability and track record of successfully advancing development programs. We are excited about the possibility of favorably impacting the lives of patients across multiple cancers and are proud to be working with Cancer Research UK.

Under the agreement, Asterias will complete development of the manufacturing process for AST-VAC2. Cancer Research UK will then produce the vaccine and conduct the phase 1/2 clinical trial in the United Kingdom. On completion of the clinical trial, Asterias will have an exclusive first option to acquire a license to the data from the trial on pre-agreed terms including an upfront payment, milestones and royalties on sales of products. If Asterias declines this option, CRT will then have an option to obtain a license to Asterias intellectual property to continue the development and commercialization of AST-VAC2 and related products in exchange for a revenue share to Asterias of development and partnering proceeds.

Dr. Jane Lebkowski, president of research and development at Asterias, said: The use of human embryonic stem cells to derive allogeneic dendritic cells for cancer immunotherapy has the potential to dramatically improve the scalability, consistency, and feasibility of cellular cancer vaccines. We believe this collaboration will enable the acceleration of clinical studies of AST-VAC2 and the collection of important proof-of-concept data for the entire human embryonic stem cell-derived dendritic cell immunotherapy platform.

About Lung Cancer

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BioTime Subsidiary, Asterias Biotherapeutics, and Cancer Research UK and Cancer Research Technology Partner for ...

PUBLIC RELEASE DATE:

5-Sep-2014

Contact: Lisa Newbern lisa.newbern@emory.edu 404-727-7709 Emory Health Sciences

Creating induced pluripotent stem cells or iPS cells allows researchers to establish "disease in a dish" models of conditions ranging from Alzheimer's disease to diabetes. Scientists at Yerkes National Primate Research Center have now applied the technology to a model of Huntington's disease (HD) in transgenic nonhuman primates, allowing them to conveniently assess the efficacy of potential therapies on neuronal cells in the laboratory.

The results were published in Stem Cell Reports.

"A highlight of our model is that our progenitor cells and neurons developed cellular features of HD such as intranuclear inclusions of mutant Huntingtin protein, which most of the currently available cell models do not present," says senior author Anthony Chan, PhD, DVM, associate professor of human genetics at Emory University School of Medicine and Yerkes National Primate Research Center. "We could use these features as a readout for therapy using drugs or a genetic manipulation."

Chan and his colleagues were the first in the world to establish a transgenic nonhuman primate model of HD. HD is an inherited neurodegenerative disorder that leads to the appearance of uncontrolled movements and cognitive impairments, usually in adulthood. It is caused by a mutation that introduces an expanded region where one amino acid (glutamine) is repeated dozens of times in the huntingtin protein.

The non-human primate model has extra copies of the huntingtin gene that contains the expanded glutamine repeats. In the non-human primate model, motor and cognitive deficits appear more quickly than in most cases of Huntington's disease in humans, becoming noticeable within the first two years of the monkeys' development.

First author Richard Carter, PhD, a graduate of Emory's Genetics and Molecular Biology doctoral program, and his colleagues created iPS cells from the transgenic monkeys by reprogramming cells derived from the skin or dental pulp. This technique uses retroviruses to introduce reprogramming factors into somatic cells and induces a fraction of them to become pluripotent stem cells. Pluripotent stem cells are able to differentiate into any type of cell in the body, under the right conditions.

Carter and colleagues induced the iPS cells to become neural progenitor cells and then differentiated neurons. The iPS-derived neural cells developed intracellular and intranuclear aggregates of the mutant huntingtin protein, a classic sign of Huntington's pathology, as well as an increased sensitivity to oxidative stress.

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Disease in a dish approach could aid Huntington's disease discovery