Tag Archives: pluripotent

Novel liver stem cell model could speed up process for developing new drugs

Durham, NC – The path to bringing a new drug to market is, simply put, a rocky one. Not only is it estimated to take over 12 years at an average price tag running anywhere between US $800 million and US $2 billion, but more often than not the new drug never makes it through the process.

But now a research team reports that it has developed a way to speed up the process. Their work, which involves the creation of a highly stable and sensitive liver stem cell model, is reported in the latest issue of STEM CELLS Translational Medicine.

“Liver toxicity is the second most common cause of human drug failure,” explained David Hay, Ph.D., of the University of Edinburgh’s MRC Centre for Regenerative Medicine, who led the team made up of university colleagues and scientists from Bristol-Myers Squibb, Princeton, N.J. “But one major bottleneck in safety testing new drugs has been finding a routine supply of good quality primary human hepatocytes from the desired genetic background.”

Scientists have long believed that finding an efficient way to force pluripotent stem cells (PSCs) to develop into hepatocytes — liver cells — could be the way around the problem. “But faithfully recapitulating human physiology in a dish from a renewable source remains a holy grail for medicine and the pharmaceutical industry,” Dr. Hay noted.

“Many procedures have been described that, to a limited extent, exhibit human-tissue-specific function in vitro but incomplete cellular differentiation and/or the loss of cell phenotype after they differentiate. Using our knowledge in pharmacology, stem cell biology and materials chemistry, we developed a highly stable and sensitive model.”

Their method involved expanding PSCs and driving their differentiation to hepatocytes, then replating them onto a synthetic surface. The results yielded active cell populations that displayed stable function for over two weeks in vitro.

“The scalable nature of our model combined with the interchangeable genetic element demonstrates clear advantages over the erratic supply of highly variable human hepatocytes from deceased specimens,” Dr. Hay added. “We believe our approach is important and will likely contribute to improvements in drug safety testing.”

“This model was compared to human liver cells from deceased donors and found to be equivalent, suggesting that stem cell-derived hepatocyles have potential to improve the preclinical assessment of human liver toxicity,” said Anthony Atala, M.D., Editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.”

The full article, “Developing high fidelity hepatotoxicity models from pluripotent stem cells,” can be accessed at http://www.stemcellstm.com

New method for mass-producing RPE cells paves way to treating age-related blindness

Durham, NC – Scientists have developed a new, simpler way to produce human pluripotent stem cells in quantities large enough that they can be used to develop treatments for age-related macular degeneration — the leading cause of irreversible blindness among the elderly. The results of this new study are published in the current issue of STEM CELLS Translational Medicine.

Age-related macular degeneration (AMD), which affects up to 50 million people worldwide, is associated with the dysfunction and death of retinal pigment epithelial (RPE) cells.

“As a result, there has been significant interest in developing RPE culture systems both to study AMD disease mechanisms and to provide substrate for possible cell-based therapies. Because of their indefinite self-renewal, human pluripotent stem cells (hPSCs) have the potential to provide an unlimited supply of RPE-like cells,” noted Donald Zack, M.D., Ph.D., who with Julien Maruotti, Ph.D., led the team of researchers from the Wilmer Institute, Johns Hopkins University School of Medicine in Baltimore, Md., and the Institute of Vision in Paris in conducting the study.

“However, most of the currently accepted methods in use for deriving RPE cells from hPSC involve time-and-labor-consuming  steps done by hand, and they don’t yield large enough amount of the differentiated cells – which has posed a problem when trying to use them to develop potential new therapies,” Dr. Maruotti added.

The Zack/Maruotti team simplified RPE cell production by modifying a standard protocol for isolating the cells from spontaneously differentiating hPSC monolayers. In the new method, hPSCs were amplified by clonal propagation and the RPE cells enriched by serial passage rather than mechanical picking.

“These modifications eliminate the need for the time- and labor consuming manual steps usually required to culture hPSCs and to purify the RPE population, and thereby provide a readily scalable approach to generate large numbers of high quality RPE cells — up to 36 times more than the best protocols previously reported during the same time interval,” Dr. Zack said.

“This improved process represents a step toward mass production of RPE and could prove useful for applications requiring large number of cells such as cell therapy, drug screening or disease modelling,” said Anthony Atala, M.D., Editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.

NeoStem’s CEO, Dr. Robin L. Smith, Letter to Shareholders

NEW YORK , Jan. 3, 2012 /PRNewswire/ —

Dear NeoStem Shareholders,

We would like to take a moment to both look back at 2011 – a transformative year for NeoStem (NYSE Amex: NBS) – and to look ahead to near term catalysts that we expect to move the company forward in 2012 and beyond.

We have closed two acquisitions – Progenitor Cell Therapy, LLC (“PCT”) and Amorcyte, LLC (“Amorcyte”).

We believe our therapeutic product development team is very close to accomplishing its aggressive goal of getting a first patient enrolled in our AMR-001 Phase 2 clinical trial for the treatment of AMI with the clinical sites beginning to open.  This brings us closer to achieving our goal of enrollment of the targeted 160 patients in the study over the next year or so with first data follow-up six months after the last patient is enrolled (roughly mid-2013).

Our cell therapy manufacturing business is growing and client satisfaction confirms our belief and excitement that we have unique skills and people (expertise, quality and work ethic) to serve as a platform to be a global leader in the cell therapy space.

We raised $16.5 million in gross proceeds in 2011 for working capital, including research and development of our cell therapeutic candidates.

We received awards of over $1.7 million in Department of Defense funding for development of our VSELTM Technology to treat osteoporosis and $245,176 from the National Institutes of Health (NIH) with Excell Therapeutics to progress our T regulatory program in Lupus.

We co-hosted a spectacular international conference in partnership with the Vatican’s Pontifical Council for Culture on Adult Stem Cells: Science and the Future of Man and Culture, moving forward the public discussion of adult stem cells and adult stem cell research.

Our cord blood banking enrollment more than doubled over the previous year.

We have been marketing our ownership in Suzhou Erye Pharmaceutical Co. Ltd. subsidiary for possible sale.

We have positioned our intellectual property portfolio to expand beyond the current indications and give us a strong position in the cell therapy arena.

We continue to make great headway in integrating IT systems, legal, finance, and marketing for our multiple entities to achieve cost savings and maximize efficiencies.

NeoStem gained a significant pharmaceutical partnership with Becton Dickinson through our co-ownership of Athelos, Inc. (80% NeoStem, 20% BD). We are actively pursuing additional strategic relationships with major pharmaceutical and biotechnology companies in 2012.

We look forward to keeping you updated and encourage your questions via the contact information below. I also encourage you to learn more by visiting our company websites, www.neostem.com, www.amorcyte.com, and www.progenitorcelltherapy.com, our social media outlets, and our company blog at thechairmansblog.com/robin-l-smith. Thank you for your continued support of NeoStem and our ongoing transformation.

Sincerely,

Dr. Robin L. Smith
Chairman and CEO

About NeoStem, Inc.
NeoStem, Inc. (“NeoStem”) is a leader in the development and manufacture of cell therapies. NeoStem has a strategic combination of revenues, including that which is derived from the contract manufacturing services performed by Progenitor Cell Therapy, LLC, a NeoStem company. That manufacturing base is one of the few cGMP facilities available for contracting in the burgeoning cell therapy industry, and it is the combination of PCT’s core expertise in manufacturing and NeoStem’s extensive research capabilities that positions the company as a leader in cell therapy development. Amorcyte, Inc., also a NeoStem company, is developing a cell therapy for the treatment of cardiovascular disease. Amorcyte’s lead compound, AMR-001, represents NeoStem’s most clinically advanced therapeutic, poised to commence enrollment of patients in a Phase 2 trial for the preservation of heart function after a heart attack.  Athelos Corporation, also a NeoStem company, is developing a T-cell therapy for a range of autoimmune conditions with our partner Becton-Dickinson.  NeoStem’s pre-clinical assets include its VSEL™ Technology platform for regenerative medicine, which NeoStem believes is an endogenous pluripotent non-embryonic cell that has the potential to change the paradigm of cell therapy as we know it today.

Stem Cell Possibilities in Autism Research

Dr. Ricardo Dolmetsch and his colleagues have generated stem cells from children with autism allowing them to study how the brain develops in children with ASD.

A conversation with Dr. Thomas Insel, Director, National Institute of Mental Health.

Gladstone scientist converts human skin cells into functional brain cells

July 28, 2011 – A scientist at the Gladstone Institutes has discovered a novel way to convert human skin cells into brain cells, advancing medicine and human health by offering new hope for regenerative medicine and personalized drug discovery and development.

In a paper being published online today in the scientific journal Cell Stem Cell, Sheng Ding, PhD, reveals efficient and robust methods for transforming adult skin cells into neurons that are capable of transmitting brain signals, marking one of the first documented experiments for transforming an adult human’s skin cells into functioning brain cells.

“This work could have important ramifications for patients and families who suffer at the hands of neurodegenerative diseases such Alzheimer’s, Parkinson’s and Huntington’s disease,” said Lennart Mucke, MD, who directs neurological research at Gladstone. “Dr. Ding’s latest research offers new hope for the process of developing medications for these diseases, as well as for the possibility of cell-replacement therapy to reduce the trauma of millions of people affected by these devastating and irreversible conditions.”

The work was done in collaboration with Stuart Lipton, M.D., Ph.D., who directs the Del E. Webb Neuroscience, Aging and Stem Cell Research Center at Sanford-Burnham Medical Research Institute. Dr. Ding, one of the world’s leading chemical biologists in stem-cell science, earlier this year joined Gladstone and the faculty at the University of California San Francisco (UCSF), as a professor of pharmaceutical chemistry. Gladstone, which is affiliated with UCSF, is a leading and independent biomedical-research organization that is using stem-cell research to advance its work in its three major areas of focus: cardiovascular disease, neurodegenerative disease and viral infections.

Dr. Ding’s work builds on the cell-reprogramming work of another Gladstone scientist, Senior Investigator Shinya Yamanaka, MD, PhD. Dr. Yamanaka’s 2006 discovery of a way to turn adult skin cells into cells that act like embryonic stem cells has radically advanced the fields of cell biology and stem-cell research.

Embryonic stem cells—”pluripotent” cells that can develop into any type of cell in the human body—hold tremendous promise for regenerative medicine, in which damaged organs and tissues can be replaced or repaired. Many in the science community consider the use of stem cells to be key to the future treatment and eradication of a number of diseases, including heart disease and diabetes. But the use of embryonic stem cells is controversial—which is one reason why Dr. Yamanaka’s discovery of an alternate way to obtain human stem cells, without the use of embryos, is so important.

Dr. Ding’s work extends Dr. Yamanaka’s by offering still another method for avoiding the use of embryonic stem cells and creating an entirely new platform for fundamental studies of human disease. Rather than using models made in yeast, flies or mice for disease research, all cell-reprogramming technology allows human brain, heart and other cells to be created from the skin cells of patients with a specific disease. The new cells created from the skin cells contain a complete set of the genes that resulted in that disease—representing the potential of a far-superior human model for studying illnesses, drugs and other treatments. In the future, such reprogrammed skin cells could be used to test both drug safety and efficacy for an individual patient with, for example, Alzheimer’s disease.

“This technology should allow us to very rapidly model neurodegenerative diseases in a dish by making nerve cells from individual patients in just a matter of days—rather than the months required previously,” said Dr. Lipton.

In the experiments being reported today, Dr. Ding used two genes and a microRNA to convert a skin sample from a 55-year-old woman directly into brain cells. (MicroRNAs are tiny strands of genetic material that regulate almost every process in every cell of the body.) The cells created by Dr. Ding’s experiments exchanged the electrical impulses necessary for brain cells to communicate things such as thoughts and emotions. Using microRNA to reprogram cells is a safer and more efficient way than using the more common gene-modification approach. In ensuing experiments, Dr. Ding hopes to rely only on microRNAs and pharmaceutical compounds to convert skin cells to brain cells, which should lead to more efficient generation of cells for testing and regenerative purposes.

“This will help us avoid any genome modifications,” said Dr. Ding. “These cells are not ready yet for transplantation. But this work removes some of the major technical hurdles to using reprogrammed cells to create transplant-ready cells for a host of diseases.”

Dr. Ding is a senior investigator at the Gladstone Institute of Cardiovascular Disease and a UCSF professor of pharmaceutical chemistry. Dr. Ding, who performed the work described in this paper at The Scripps Research Institute, has pioneered the development and application of innovative chemical approaches to stem-cell biology and regeneration.

About the Gladstone Institutes
Gladstone is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and biomedical innovation to prevent illness and cure patients suffering from cardiovascular disease, neurodegenerative disease, or viral infections. Gladstone is affiliated with the University of California, San Francisco.

International Stem Cell Corporation Progresses towards Establishment of the Industry’s First Universal Stem Cell Bank, UniStemCell™

OCEANSIDE, Calif.–(BUSINESS WIRE)–International Stem Cell Corporation (OTCBB: ISCO), www.internationalstemcell.com, announced today that it has signed up the first two in vitro fertilization (IVF) clinics and engaged an experienced pharmaceutical industry executive to lead the establishment of the company’s universal stem cell bank, UniStemCell™. International Stem Cell Corporation has made breakthrough stem cell discoveries that result in unique advantages over the only two other proven methods of making human pluripotent stem cells. In particular, for the first time in industry history, this will enable the establishment of a bank containing a manageable number of stem cell lines that will be immunological matches for large patient populations of different ethnic origin.

“By combining the proven oocyte retrieval experience and clinical excellence of California Center for Reproductive Medicine and Acacio Fertility Center with the pharmaceutical and operational experience of Dr. Craw, International Stem Cell Corporation is well positioned to generate the world’s first cGMP quality hpSC lines in 2010.”

The company uses unfertilized eggs (oocytes) to create human “parthenogenic” stem cells (hpSCs). Like embryonic stem cells (ESCs), hpSCs are pluripotent (i.e. have the capacity to become almost any cell type in the body), yet avoid ethical issues associated with use or destruction of viable human embryos. Unlike induced pluripotent stem cells (iPSs), hpSCs do not involve extensive gene manipulation, which may have unknown biological impact. Unlike both ESCs and iPSs, hpSCs can be created in a homozygous form such that each line will be an immunological match for millions of patients.

International Stem Cell Corporation has partnered with two IVF clinics in Southern California, California Center for Reproductive Medicine under the leadership of Dr. Lori Arnold and Acacio Fertility Center under the leadership of Dr. Brian Acacio. Both clinics provide exceptional clinical care for egg donors and IVF patients, not only regionally but across the US and abroad. California Center for Reproductive Medicine and Acacio Fertility Center provide a US source of oocytes under full regulatory and medical oversight that allow for the creation of the first clinical grade hpSC lines anywhere in the world. Dr. Acacio says: “We look forward to participating in this important research with the ultimate goal of each egg donation not only helping a single couple but millions of people with degenerative diseases.” Dr. Arnold says: “While we provide world-class care for our IVF patients, we are excited to add our clinical expertise and join International Stem Cell Corporation in this medical frontier of regenerative medicine.”

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Creation Of Multiple Types Of White Blood Cells Directly From Embryonic And Adult Stem Cells

From MedicalNewsToday.com

In an advance that could help transform embryonic stem cells into a multipurpose medical tool, scientists at the University of Wisconsin-Madison have transformed these versatile cells into progenitors of white blood cells and into six types of mature white blood and immune cells.

While clinical use is some years away, the new technique could produce cells with enormous potential for studying the development and treatment of disease. The technique works equally well with stem cells grown from an embryo and with adult pluripotent stem cells, which are derived from adult cells that have been converted until they resemble embryonic stem cells.

If the adult cells came from people with certain bone marrow diseases, the new technique could produce blood cells with specific defects. It could also be used to grow specific varieties of immune cells that could target specific infections or tumors.

The likely most immediate benefit is cells that can be used for safety screening of new drugs, says study leader Igor Slukvin, an assistant professor in the university’s Department of Pathology and Laboratory Medicine.

“Toxicity to the blood-forming system is a key limit on drug development, so these cells could be used for safety testing in any drug development,” says Slukvin, who performs research at the National Primate Research Center in Madison.

Bone marrow stem cells are already used to screen drugs, but the new technique promises to produce large quantities of cells in a dish that can be more exactly tailored to the task at hand, without requiring a constant supply of bone marrow cells from donors.

The development of stem cells into mature, specialized cells is governed by trace amounts of biological signaling molecules, so Slukvin and colleagues Kyung-Dal Choi and Maxim Vodyanik exposed two types of highly versatile stem cells to various compounds.

Eventually they found a recipe that would cause the cells to move through a process of progressive specialization into a variety of adult cells. Slukvin’s study was published in the Journal of Clinical Investigation.

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Researchers May Have Found Equivalent of Embryonic Stem Cells

By Rob Stein, WashingtonPost.com

Chinese scientists have bred mice from cells that might offer an alternative to human embryonic stem cells, producing the most definitive evidence yet that the technique could help sidestep many of the explosive ethical issues engulfing the controversial field but raising alarm that the advance could lead to human cloning and designer babies.

In papers published online Thursday by two scientific journals, separate teams of researchers from Beijing and Shanghai reported that they had for the first time created virtual genetic duplicates of mice using skin cells from adult animals that had been coaxed into the equivalent of embryonic stem cells.

The findings were welcomed by supporters and opponents of human embryonic stem cell research as a long-sought vital step in proving that the cells could be as useful as embryonic cells for studying and curing many illnesses.

The results come just as the Obama administration has eased federal restrictions on government funding for embryonic stem cell research, and they could influence how to prioritize millions of dollars in new spending in the field.

But because of concerns that the techniques might make cloning and genetic engineering of embryos easier, the work could reignite calls for a ban on attempts to clone people and for restrictions on genetic manipulation of embryos.

“The implications of this are both enormously important and troublesome,” said Robert Lanza, a stem cell researcher at Advanced Cell Technology in Worcester, Mass. “It revives many of the issues raised by reproductive cloning.”

Many scientists believe human embryonic stem cell research could revolutionize medicine by enabling doctors to use genetically matched tissue to treat many diseases. But the field has been mired in controversy because embryos are destroyed to obtain the cells.

In 2006, scientists discovered that they could induce adult cells to regress to a stage that appeared identical to embryonic stem cells, called induced pluripotent stem (iPS) cells. Although scientists have become increasingly adept at creating and manipulating such cells, questions have lingered about whether they are truly equivalent. The new experiments were designed to put the cells to what has long been considered the most rigorous test.

In the studies, published in the journals Nature and Cell Stem Cell, the researchers used viruses to flip genetic switches in the DNA of skin cells from adult mice to turn them into iPS cells in the laboratory. The researchers then injected some of the iPS cells into very early embryos that are capable of forming a placenta but not of fully developing on their own. The resulting embryos were then transferred into the wombs of surrogate mice.

One team of scientists led by Qi Zhou of the Chinese Academy of Sciences created 37 iPS cell lines, three of which produced 27 live offspring, the first of which they named Tiny. One of the offspring, a 7-week-old male, went on to impregnate a female and produce young of its own. Altogether, the researchers bred at least 100 first-generation mice and hundreds of second-generation mice that were nearly identical genetically to the mice from which the iPS cells were derived.

“This gives us hope for future therapeutic interventions using patients’ own reprogrammed cells,” Fanyi Zeng of Shanghai Jiao Tong University, who worked with Zhou, said during a telephone briefing for reporters.

The second group of researchers, led by Shaorong Gao of the National Institute of Biological Sciences in Beijing, created five iPS cell lines, one of which was able to produce embryos that survived until birth. Although four animals were born, only one lived to adulthood. Nevertheless, the work is “proof that iPS cells are functionally equivalent to embryonic stem cells,” Gao said in a telephone interview.

Other researchers agreed, praising the work as a long-awaited confirmation of the cells’ equivalence.

“This clearly says for the first time that iPS cells pass the most stringent test,” said Konrad Hochedlinger, a stem cell researcher at Harvard University.

Opponents of human embryonic stem cell research said the findings provide the latest in a growing body of evidence for why such research is no longer necessary.

“Nobody has been able to find anything that embryonic stem cells can do that these cells can’t do,” said Richard M. Doerflinger of the U.S. Conference of Catholic Bishops. “This was the last remaining barrier.”

The Chinese scientists and others, however, said continued research on embryonic stem cells remains crucial to validate iPS cells and because it remains unclear which cells will turn out to be most useful for different purposes.

But the cells’ ability to produce almost genetically identical offspring raised the fear that rogue scientists might misuse the technique to attempt to clone humans.

“The culture wars are not over,” said Jonathan D. Moreno, a University of Pennsylvania bioethicist. “There was a lot of celebration about the end of the ethical issues with induced pluripotent stem cells. But this is the paradigm case that shows that the old debates are rapidly being transformed into something even more complicated.”

Lanza also raised the prospect that the techniques could one day be used essentially to steal someone’s DNA to make a baby. “With just a little piece of your skin, or some blood from the hospital, anyone could have your child — even an ex-girlfriend or neighbor,” he wrote in an e-mail. “This isn’t rocket science — with a little practice, any IVF clinic in the world could probably figure out how to get it to work.”

In addition, researchers could genetically engineer traits into the cells before using them to create embryos for designer babies.

“For instance, the technology already exists to genetically increase the muscle mass in animals by knocking out a gene known as mystatin, and could be used by a couple who wants a great child athlete,” Lanza wrote.

Others dismissed such concerns, saying many scientific, ethical and regulatory hurdles remain. They said that just because the process works in mice does not necessarily mean it would work in humans, that many states outlaw human cloning and that federal regulators could step in to prevent it.

Scientists Reprogram Clearly Defined Adult Cells Into Pluripotent Stem Cells — Directly And Without Viruses

From ScienceDaily.com

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Scientists Find Differences in Embryonic Stem Cells and Reprogrammed Skin Cells

From Newswise.com

UCLA researchers have found that embryonic stem cells and skin cells reprogrammed into embryonic-like cells have inherent molecular differences, demonstrating for the first time that the two cell types are clearly distinguishable from one another.

The data from the study suggest that embryonic stem cells and the reprogrammed cells, known as induced pluripotent stem (iPS) cells, have overlapping but still distinct gene expression signatures. The differing signatures were evident regardless of where the cell lines were generated, the methods by which they were derived or the species from which they were isolated, said Bill Lowry, a researcher with the Broad Stem Cell Research Center and a study author.

“We need to keep in mind that iPS cells are not perfectly similar to embryonic stem cells,” said Lowry, an assistant professor of molecular, cell and developmental biology. “We’re not sure what this means with regard to the biology of pluripotent stem cells. At this point our analyses comprise just an observation. It could be biologically irrelevant, or it could be manifested as an advantage or a disadvantage.”

The study appears in the July 2, 2009 issue of the journal Cell Stem Cell.

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