Fate Therapuetics, located outside of San Diego in La Jolla, California, announced today that the first patient has been treated in a clinical trial for hematopoietic stem cell support. The Phase 1b study is testing FT1050, a proprietary small molecule stem cell modulator (SCM) which is being administered in a dual cord blood transplant for hematologic malignancy. Among other properties, FT1050 has been designed to activate specific pathways that determine the "fate" (the direction of differentiation and ultimate cell type, i.e.) of a stem cell, the purpose of which in this particular context is to increase hematopoietic stem cell number and function in the treatment of hematologic malignancies such as leukemia and lymphoma in adult patients who have undergone nonmyeloablative conditioning. The study is being conducted at the Dana-Farber Cancer Institute in Boston, where FT1050 is being administered during the standard course of dual umbilical cord blood transplants.

As Dr. Paul Grayson, president and CEO of Fate Therapeutics, explains, "The mission of Fate Therapeutics is to develop small molecules and biologics that modulate adult stem cells within the body for regenerative medicine. As our first SCM clinical candidate, FT1050 represents the initial step in our approach – using a small molecule to treat cells ex vivo but creating an in vivo regenerative effect. With FT1050, we are trying to affect stem cell biology in the body, improving the reconstitution of a patient’s blood and immune system."

According to Dr. Corey Cutler, assistant professor of medicine at Harvard Medical School and the director of the clinical study at Dana-Farber, "For patients who need hematopoietic stem cell support, time is of the essence. However, many patients do not have a suitably matched donor, either from a sibling or from an unrelated volunteer in the worldwide registries. Because umbilical cord blood units are readily available from cord blood banks, and the matching criteria for cord blood are less stringent than with adult donors, the ability to increase cord blood use by enhancing its efficiency has the potential to help thousands of patients waiting for a match." Twelve patients are expected to be enrolled in the trial for FT1050, which has been demonstrated to mediate not only stem cell differentiation pathways but also the ability of stem cells to "home in" on, and target, the bone marrow, thereby repopulating the patient’s own blood and immune system.

Patients with hematologic malignancies such as leukeia and lymphoma who do not respond to conventional therapies are often treated with intensive radiation, chemotherapy and additional forms of high-dose immunotherapy which often destroy the patient’s healthy blood and immunological systems in addition to the cancer cells. Bone marrow restoration through hematopoietic reconstitution is therefore necessary for the survival of such patients. In this as well as other types of clinical settings, adult stem cells obtained from umbilical cord blood have a number of therapeutic and logistical advantages over bone marrow or peripheral blood transplants, including but not limited to ease of matching HLA (human leukocyte antigen) markers as well as "faster availability, lower incidence and severity of acute graft-versus-host disease, lower risk of transmitting infections by latent viruses, lack of donor attrition and no risk to the donor", among other advantages, as described in the official press release of Fate Therapeutics. Additionally, as described on the company’s website, when compared to bone marrow and peripheral blood transplants, "cord blood is less immunogenic, which means it is less likely to be rejected by the patient’s immune system", and "cord blood is more readily available, which reduces medical costs and procedures necessary with obtaining stem cells from bone marrow or a patient’s or donor’s blood." Additionally, "cord blood has been used in hematopoietic stem cell support since 1988", and its safety and efficacy are well documented in the medical literature.

As also stated in the press release, "FT1050 was discovered by Leonard Zon, M.D., director of the Stem Cell Program at Children’s Hospital Boston and a scientific founder of Fate Therapeutics and is part of an exclusive license granted to Fate by Children’s Hospital Boston and Massachusetts General Hospital."

(Please see the related news article on this website, entitled, "Children’s Hospital of Boston and Fate Therapeutics Sign IP Deal", dated May 20, 2009).

In a strong sign of discontent, contrasting sharply with the enthusiasm that accompanied President Obama’s putative reversal of embryonic stem cell federal funding restrictions earlier this year, embryonic stem cell scientists have now concluded that Obama’s new policy would have the opposite effect and would instead impose new restrictions.

At the crux of the argument is the new set of guidelines proposed by the National Institutes of Health which would render ineligible for federal funding most of the current embryonic stem cell research that is already in progress and which is already receiving either federal or private funding. Contrary to popular misconception, the Bush administration did not forbid embryonic stem cell research altogether, and embryonic stem cell research has been alive and well throughout the U.S. for years, even predating the Bush administration. Now, however, under the Obama administration, the anticipated increase in the number of embryonic stem cell lines that would be eligible for federal funding is now instead jeopardized by new NIH guidelines which would actually decrease the number of eligible embryonic stem cell lines, thereby having the exact opposite effect of that which embryonic stem cell scientists had expected. In fact, under the new NIH guidelines, most of the embryonic stem cell research which is currently already in progress would suddenly be rendered ineligible and would have to be shut down.

According to Amy Comstock Rick, chief executive of the Coalition for the Advancement of Medical Research, "We’re very concerned. If they don’t change this, very little current research would be eligible. It’s a huge issue." As Dr. Lawrence Goldstein, director of the stem cell program at the University of California at San Diego, adds, "It’s not that past practices were shoddy. But they don’t necessarily meet every letter of the new guidelines moving forward. We’d have to throw everything out and start all over again."

One particularly contentious point in the new NIH guidelines pertains to issues of informed consent. Couples who donate their embryos for research would now be required to sign a consent form acknowledging that they were fully informed of other options, such as the possibility of donating their embryos to other couples for the purpose of allowing the embryos to grow and be born as children. Currently, not all IVF (in vitro fertilization) clinics present such options to couples, and those clinics which do discuss such options with their clients do not always have the information specified in writing.

As Dr. George Daley of the Harvard Stem Cell Institute explains, "They take 2009 standards and attempt to apply them retroactively, which isn’t really a standard that would allow most of the preexisting lines to be acceptable for NIH funding. This is essentially moving the goal post."

According to Dr. Patrick Taylor, deputy counsel of Children’s Hospital in Boston, whose critique of the proposed NIH guidelines appeared last month in the journal Cell Stem Cell, "If applied retroactively, the proposed guidelines would render ineligible most stem cell lines."

Raynard Kington, acting director of the NIH, declined further comment other than to state, "We know issues like this, among many issues, have been raised, and we will take them into consideration."

NIH published their first proposed draft of the new guidelines on April 17. The final version is expected to be released by July 7.

(Please see the following related news articles on this website: "NIH Issues Guidelines Restricting Embryonic Stem Cell Research", dated April 17, 2009; "Members of The President’s Council on Bioethics Object to Obama’s Stem Cell Policy", dated March 26, 2009; "A High-Profile Proponent of Embryonic Stem Cell Research Sharply Criticizes Obama’s Policy", dated March 13, 2009; "Obama Signs Law Restricting Federal Funding of Embryonic Stem Cell Research", dated March 11, 2009; "Obama Rescinds Bush-Era Executive Order Pushing for More Ethical Stem Cell Research", dated March 10, 2009; "Obama Decrees Changes in Embryonic Stem Cell Research, Though Not What One Might Expect", dated March 9, 2009; and "Former Director of N.I.H. Explains Why Embryonic Stem Cells are Obsolete", dated March 4, 2009).

The biotech company Fate Therapeutics has announced an IP agreement that involves technology licensed primarily from Children’s Hospital of Boston as well as technology developed at Massachusetts General Hospital, also of Boston. Based in San Diego and known for what it calls its "adult stem cell biology engine", Fate Therapeutics has entered into a number of IP agreements in recent months, and this is the seventh in a series of licensing deals between Fate and various research or academic institutions. Although the precise details were not disclosed, the latest agreement involves technology for supporting hematopoietic stem cell development. Dr. Len Zon, director of the stem cell program at Children’s Hospital and a co-founder of Fate Therapeutics, develped the technology.

Fate Therapeutics had previously licensed technology from Mass General which was developed by Dr. David Scadden, another co-founder of Fate Therapeutics who also co-founded and co-directs the Harvard Stem Cell Institute and who is also currently director of the Center for Regenerative Medicine at Mass General Hospital. According to Seema Basu, senior business strategy and licensing manager with the Office of Corporate Sponsored Research and Licensing at Mass General Hospital, "Depending on how the clinical development pans out, they could have different applications. There are many steps to that system’s biology, and they all complement each other. A lot will pan out once Fate does more clinical development. We’re excited that a therapeutic company is trying to take this technology into clinical development."

Founded in 2007, Fate Therapeutics was originally organized from research that had been conducted at Mass General, Stanford University, Harvard University, the University of Washington and The Scripps Research Institute. Although the company’s primary focus is adult stem cells, it is also developing iPS (induced pluripotent stem) cell technology. While iPS cells are not, in the technically strict sense of the term, "adult stem cells" – because iPS cells are derived from adult somatic cells (which are merely ordinary, mature, differentiated cells and are not stem cells) – the more important point is that iPS cells, like adult stem cells, are also not derived from embryonic stem cells even though iPS cells exhibit the same pluripotency as embryonic stem cells.

According to Fate president and CEO Paul Grayson, "Over the past two years, Fate Therapeutics has amassed extensive intellectual property assets as a foundation for our adult stem cell biology engine. The agreement we signed today with Children’s Hospital and the technologies associated with it continue to expand our engine and accelerate the company’s core mission to develop small molecules and biologics that modulate adult stem cells for regenerative medicine."

As the name implies, the company uses small molecules and biologics to guide and direct the "fate" – i.e., the ultimate direction and differentiation type – of cell development. Such techniques apply not only to adult stem cells but also to mature adult somatic (non-stem cell) cells which can be modulated and reprogrammed back to a more primitive state in which the cells exhibit a pluripotency similar to that of embryonic stem cells. As stated on the company’s website, "Fate Therapeutics is focusing on adult stem cells and induced pluripotent stem (iPS) cells. Adult stem cells naturally exist in tissues or organs and are responsible for maintaining and repairing the tissue in which they are found. iPS cells are stem cells created from fully mature differentiated cells, like a skin cell, and promise to be of great use for drug discovery and development and personalized cell replacement therapies."

As also stated on their website, "Fate’s scientific founders have identified and characterized key stem cell pathways, such as Wnt, Hedgehog and Notch, which are known to regulate cell fate and play key roles in tissue repair and regeneration and iPS cell creation." By harnessing the molecular mechanisms of such cellular pathways, Fate is developing therapeutic programs that have clinical applications not only across the broad spectrum of regenerative medicine, such as in the treatment of traumatic injury and degenerative diseases, but also in other fields such as metastatic cancer and hematological diseases. In a company statement, Fate therapeutics announced that, "The discovery of a number of conserved mechanisms from developmental biology and tissue repair has led to the identification of small molecules and biologics that can direct stem cell proliferation and function. Fate is developing these small molecule and biologic stem cell modulators to modulate the activity of adult stem cells to stimulate healing or block cancer growth."

Shortly after Fate’s founding in 2007, Dr. Sheng Ding, associate professor of chemistry and cell biology at The Scripps Research Institute who is also one of Fate’s co-founders, explained that Fate Therapeutics "is really about a collection of small molecules and protein therapeutics for modulating stem cell fate in vivo. That’s a totally different approach", he says, from other stem cell companies that "are using cells, and are primarily focused on cell-based therapies."

In April of this year, Fate Therapeutics and the Boston-based company Stemgent announced a strategic alliance, known as Catalyst, which is "a collaborative one-of-a-kind program to provide pharmaceutical and biotechnology companies with the most advanced induced pluripotent stem (iPS) cell technology platform for drug discovery and development", as described on the website of Fate Therapeutics. The novel technology utilizes protein-based reprogramming methods developed by Dr. Sheng Ding which constitute "a technique that effectively eliminates any risk of genetic modification" and which is free of oncogenic and viral reprogramming factors.

(Please see the related news article on this website, entitled, "First Patient Treated in Clinical Trial for Hematopoietic Stem Cells", dated May 27, 2009).

Researchers in Germany and Sweden have demonstrated that G-CSF improves intelligence – at least in laboratory rats.

Also known as colony-stimulating factor 3 (CSF3), the popular G-CSF (granulocyte-colony stimulating factor) has long been understood to play an important role in a variety of immunological and hematological functions, and to some extent in CNS (central nervous system) functions. Now, however, a new study sheds further light on the important role of G-CSF in maintaining healthy neurological function.

Led by Dr. Kai Diederich of the Department of Neurology at the University of Munster in Germany, and Dr. Nina Hellstrom of the Institute for Clinical Neuroscience in Gothenburg, Sweden, scientists have found that G-CSF improves intellectual function in laboratory rats, when also combined with a challenging environment. More specifically, the researchers were able to demonstrate that G-CSF enhances learning and memory, but only when the G-CSF is combined with cognitive training.

The scientists administered G-CSF to rats who were "engaged in spatial learning in an 8-arm radial maze." The G-CSF was administered to the rats both before and during spatial learning, which was followed by the assessment of memory formation and hippocampal neurogenesis. Using a radial 8-arm maze with food positioned at the distal end of 4 baited arms, while the other 4 arms remained unbaited, the scientists reported that, "Our data show that treatment with the hematopoietic factor G-CSF combined with cognitive training improves long-term spatial memory and promotes the survival of newborn hippocampal neurons." In particular, the scientists were able to demonstrate that G-CSF performs a number of neurological functions which include, among other tasks, facilitating the survival of neuronal precursor cells, recruiting new neurons into the dentate gyrus, and solidifying spatial long-term memory formation when combined with environmental hippocampal stimulation.

In fact, the scientists reported that G-CSF "significantly" improves spatial learning, when combined with the other very important half of the equation, which is, namely, "cognitive training". An enriched and challenging environment, in other words, in which the brain is continuously stimulated to learn, is equally as important as is the G-CSF, on which the authors comment that, "The mechanism whereby learning increases cell survival has not been fully identified yet. A ‘use it or lose it’ principle is thought to underlie the survival of hippocampal neurons." The authors further add that, "Spatial learning is initially dependent on the hippocampus, which appears to prepare contents for long-term storage in the neocortex. Newborn neurons in the hippocampus could contribute to learning and memory formation. Furthermore, neuronal turnover may provide plasticity for information storage that more differentiated neurons cannot. Consistent with this idea, the survival of young adult-born neurons can be increased by learning and enriched environments."

This study illuminates the many complex properties of G-CSF as one of several peripheral circulating peptides that influence and determine CNS structural morphology and function. As the scientists explain, G-CSF not only has specific receptors in the brain but is also produced by the brain and has been shown to induce neurogenesis, neuroplasticity and neuronal complexity, specifically in the hippocampus – a region of the limbic system which plays a key role in long-term memory and spatial navigation. As the authors further explain, "G-CSF may promote the surviving of newborn cells trough its well-investigated anti-apoptotic effects as well as trough its prominent actions in proliferation and differentiation of neural cells." In this manner, the scientists conclude that, "The finding of the present study suggests that the combination of hippocampus-dependent learning and G-CSF treatment may facilitate the integration of adult-born neurons into existing neural networks and therefore insure their survival."

Simultaneously a hormone, a glycoprotein, a neuropeptide, a cytokine and a hematopoietic growth factor, G-CSF had already been recognized as an important component of many physiological processes, though its role in specific neurophysiological processes had not yet been fully defined. As its name implies, G-CSF was previously understood to stimulate granulocyte (white blood cell) production in the bone marrow, from which the granulocytes migrate into the bloodstream. G-CSF was also known to stimulate stem cell production in the bone marrow, and to enhance the differentiation, proliferation, function and survival of mature neutrophils and neutrophil precursor cells – a particularly predominant type of white blood cell which is an essential component of the immune system. G-CSF is naturally and endogenously produced by a variety of tissue types throughout the human body, although it is also manufactured synthetically and prescribed as a drug.

This new study now allows greater insight into the important role that G-CSF plays in neuronal health, which had been studied to some extent though it was not as well understood as the role of G-CSF in immunological and hematological function. Previously, G-CSF has been studied almost exclusively in animal models of various types of neurological diseases such as stroke, Parkinson’s disease, Alzheimer’s and amyotrophic lateral sclerosis (Lou Gehrig’s disease), in which treatment with G-CSF has been found to ameliorate cognitive deficits, especially in the animal models of Alzheimer’s disease and stroke. As the investigators of this study report in their paper, "Although recent studies have begun to explore G-CSF-related mechanisms of action in various disease models, little is known about its function in the healthy brain. A more detailed understanding of the physiological role of G-CSF in the healthy brain may, however, open new insights into disease-relevant mechanisms. We therefore investigated the effect of peripheral administered G-CSF on learning and memory formation and the generation and survival of newborn hippocampal neurons in healthy rats."

As the scientists conclude, "Overall, the findings from the present study support the hypothesis that G-CSF can enhance learning and memory formation. Most importantly because of its easy applicability and its history as a well-tolerated hematological drug, learning enhancement by G-CSF opens up new neurological treatment opportunities in conditions where learning and memory-formation deficits occur."

The article was published in PLoS ONE by the Public Library of Science, an international, peer-reviewed, open access online publication.

Scientists have demonstrated the ability of human cord blood stem cells to regenerate damaged liver tissue in mice. Led by Dr. Ping Zhou, the study was conducted by researchers at the UC-Davis Medical Center in Sacramento in collaboration with scientists at the Washington University School of Medicine in St. Louis and the Krembil Center for Stem Cell Biology at the Robarts Research Institute in Ontario, Canada.

Human cord blood stem cells (hCBSCs) are already known to generate hepatocyte-like cells, and human patients who receive autologous bone marrow transplants as a treatment for liver failure have been found to exhibit clinical improvement in pilot trials. It had not been previously demonstrated, however, whether the hCBSC-derived cells are capable of transdifferentiating directly into hepatocytes, or if other mechanisms are at work that merely allow for the fusion of the cells with recipient hepatocytes.

In the current study, Dr. Zhou and his colleagues investigated the action of hCBSCs with beta-glucoronidase-deficient nonobese diabetic/severe combined immunodeficient/ mucopolysaccharidosis type VII (NOD/SCID/MPSVII) mice to whom carbon tetrachloride had been administered to induce liver damage. Using human umbilical cord blood stem cells that had been selected for aldehyde dehydrogenase activity, which correlates with high stem cell activity, the scientists found that the human progenitor cells with high aldehyde dehydrogenase activity engrafted into the damaged liver tissue with an efficiency rate of 3% to 14.2%, while actual fusion of the human cells to the mouse cells was found to be very rare. Additionally, it was observed that the cells in the target mouse tissue expressed a number of human hepatic markers such as albumin, hepatocyte nuclear factor 1 protein, and liver-specific alpha 1-antitrypsin messenger RNA, and the majority of the albumin-expressing cells of human origin also contained mouse genetic material, thereby further indicating engraftment of the human cells to the mouse tissue. As the researchers noted, the procedure thereby "improved recovery of the mice from toxic insult".

As the authors concluded, "hCBSCs or their progeny may home to the injured liver and release trophic factors that hasten tissue repair, whereas fusion of these cells with hepatocytes may occur rarely and contribute to a lesser extent to liver repair."

One reviewer of the study, in StemCellPatents.com, further suggests the supplemental administration of G-CSF (granulocyte-colony stimulating factor), a known stem cell mobilizer which was already shown by Piscaglia et al. in Italy to accelerate liver regeneration. Also recommended is the continued investigation of CD34+ adult stem cells, found in abundance in umbilical cord blood, which have already yielded positive results in the treatment of liver failure as demonstrated by Pai et al. in London in 2008.

In 2007, when Marsh Mayfly suffered a tendon injury, it seemed as though her career was over. But after receiving adult stem cell therapy and taking some time off to have a foal, the 12-year-old horse returned to the circuit with renewed strength and vigor. Last month she won the Burnham Market CIC and then took third place in the advanced section at the Belton Trials.

It was after finishing in 4th place at the Chatsworth International in 2007 that Marsh Mayfly, also known as "Flower", began developing inflammation in her right foreleg. According to the horse’s owner and breeder, Ann Lawson, "Flower is a brave horse with a wonderful temperament. Show jumping is her weak point but she jumped beautifully at Chatsworth only to pull up lame. We were understandably devastated but our vet Andrew Miller remained optimistic and recommended stem cell therapy. We duly proceeded with the treatment and also decided to put Flower in foal."

According to Dr. Miller, equine veterinarian from the Ark Vet Centre in Lockerbie, "Scans showed fiber damage in the mare’s off fore superficial digital flexor tendon. Stem cell therapy offers a good prognosis for this type of injury and was the ideal treatment protocol in the circumstances. Ann’s desire to put Flower in foal also tied in well with the required rehabilitation program following treatment."

The company VetCell Bioscience developed the equine autologous adult stem cell procedure in the U.K., where such therapy is routine practice at most equine veterinary locations, and is even covered by most equine insurance policies. Unlike other companies such Vet-Stem in the U.S., which uses mesenchymal stem cells (MSCs) derived from the adipose (fat) tissue of animals, VetCell uses MSCs that are derived from the animal’s own bone marrow which is extracted from the horse’s sternum. The MSCs are then isolated, expanded to more than 10 million cells, re-suspended in bone marrow supernatant which is rich in growth factors and other chemical nutrients, and then the cells are injected directly into the site of the injury where the cells regenerate the tendon tissue and also prevent the formation of scar tissue, which is often a main hindrance to healing and the cause of future reinjury. Physical rehabilitation and a controlled exercise program are also important to the recovery of the horse, and periodic MRI (magnetic resonance imaging) scans are taken to monitor the healing. As Ann Lawson describes, "We adhered to the rehabilitation program religiously until it came to the cantering when Flower was just too large for any faster work. On June 3rd she gave birth to Perry, a colt foal by the dressage stallion Pro Set. After weaning we started exercise again, including a weekly workout in our local equine pool at Pine Lodge."

The horse began competing again in April. According to Marsh Mayfly’s rider, Ruth Edge, "She gave me wonderful rides at Burnham Market and at Belton and felt fit, keen and full of power. She’s such a generous horse and it’s great to be back on board. Luhmuhlen is next on the calendar and I’m looking forward to it."

VetCell Bioscience specializes in the development and commercialization of new biotechnologies for veterinarian musculoskeletal regeneration. VetCell was formed in partnership with the Royal Veterinary College and the Institute for Orthopaedic and Musculoskeletal Science, and is a trading company within MedCell Bioscience, its parent company, which develops musculoskeletal regenerative therapeutics for human clinical treatment. As stated on their website, "VetCell has rapidly commercialised a technique for the multiplication of equine stem cells which can be used in the treatment of tendon and ligament injury. This service is now available to veterinary surgeons in the U.K. and internationally. VetCell has also developed a simple method for separating and storing stem cells from the umbilical cords of foals." Although VetCell specializes in the treatment of horse injuries, they are also expanding their services and products to therapeutic applications for dogs, cats and other domestic species. Headquartered in Cambridge, England with laboratories in Edinburgh, Scotland, MedCell and VetCell also have offices in Germany, Spain, China, Australia, South America, Canada and the United States.