Stanford study finds Induced pluripotent stem cells match embryonic stem cells in modeling human disease


Investigators from Stanford University School of Medicine have shown that induced Pluripotent Stem cells (iPSCs), which are made from adult cells through genetic engineering techniques, are a possible alternative to human embryonic stem cells when it comes to modeling those defects caused by a particular genetic condition. The example used in this study was Marfan syndrome, and in this study, iPSCs modeled the disease as well as embryonic stem cells (ESCs). Thus, iPSCs could be used to examine the molecular aspects of Marfan on a personalized basis. Embryonic stem cells, on the other hand, can’t do this because their genetic contents are those of the donated embryo are not the same as the patient’s.

Marfan syndrome is an inherited connective-tissue disorder that occurs in one in 10,000 to one in 20,000 individuals. It results from a large number of defects in one gene called “fibrillarin.” People with Marfan syndrome tend to be very tall and thin, and also tend to suffer from osteopenia, or poor bone mineralization. Medical experts have speculated that Abraham Lincoln, for example, suffered from this disorder. Marfan can also profoundly affect the eyes and cardiovascular system.

This proof-of-principle study, with regards to the utility of iPSCs also has more universal significance; it advances the credibility of using iPSCs to model a broad range of human diseases. iPSCs, unlike ESCs, are easily obtained from virtually anyone and possess a genetic background identical to the patient from which they were derived. Moreover, they carry none of the ethical controversy associated with the necessity of destroying embryos.

“Our in vitro findings strongly point to the underlying mechanisms that may explain the clinical manifestations of Marfan syndrome,” said Michael Longaker, MD, professor of surgery and senior author of the study, which will be published online Dec. 12 in Proceedings of the National Academy of Sciences. Longaker is the Dean P. and Louise Mitchell Professor in the School of Medicine and co-director of the school’s Institute for Stem Cell Biology and Regenerative Medicine. The study’s first author is Natalina Quarto, PhD, a senior research scientist in Longaker’s laboratory.

In this study, both iPSCs and ESCs, and embryonic stem cells that carried a mutation that causes Marfan syndrome showed impaired ability to form bone, and all too readily formed cartilage. These aberrations mirror the most prominent clinical manifestation of the disease.

iPSCs were discovered in 2006, and are derived from fully differentiated tissues such as the skin. However, they harbor the same capacity as embryonic stem cells; namely to differentiate into all the tissues of the body, and replicate for indefinite periods in a cell culture dish. Because iPSCs offer an ethically uncomplicated alternative to ESCs, IPSCs have fueled the hope that they can replace ESCs in scientists’ efforts to analyze, in a dish, those cellular defects ultimately responsible for diseases ranging from diabetes to Parkinson’s and even such complex conditions as cardiovascular disease and autism.

One hope for iPSCs is to be able to differentiate them in a dish into tissues of interest and then study these cells and their characteristics. This would help scientists better understand diseases in a patient-specific way, which would be impossible to do with ESCs unless ESCs were made from donated human eggs that were modified by cloning procedures. Cloning human embryos to the blastocyst stage has yet to occur, which makes this option technically impossible at the present time.

While scientists want to us iPSCs to develop therapeutic applications for regenerative medicine. This strategy, however, is technically more difficult, since scientists will have to develop the capacity first to repair genetic defects within cells before they can be used for regenerative medicine. iPSCs in theory might be a better bet because they are derived from patients’ own cells and, therefore, are less likely to provoke graft rejection than similar tissues produced using a donor embryo’s ESCs.

Unfortunately, several studies have reported subtle differences between iPSCs and ESCs, and these differences imply that the two cell types may not be equivalent. Stem cell experts have wondered whether these differences may render iPSCs inadequate substitutes for ESCs in modeling disease states, but this Stanford study suggests otherwise.

Geron Corporation Announces Phase II Trial for Brain-Specific Anticancer Drug GNR1005


After a successful completion of a Phase I study, Geron Corporation announces the initiation of a phase II trial for its GRN1005 anticancer drug. This drug was designed to specifically treat tumors that have metastasized (spread) to the brain from the lung. This clinical trial is called GRABM-L, which stands for GRN1005 Against Brain Metastases – Lung cancer). This phase II trial is designed to determine the efficacy of GRN1005 in patients with brain metastases arising from non-small cell lung cancer (NSCLC).

GRN1005 is a novel cancer drug that consists of three molecules of the anticancer drug paclitaxel linked to a 19 amino acid peptide (Angiopep-2). This 19-amino acid peptide binds to a receptor called the “lipoprotein receptor-related protein 1” (LRP1), which is one of the most highly expressed receptors on the surface of the blood-brain barrier (BBB). Brain tumor treatment is exceedingly difficult because the central nervous system is surrounded by the BBB. The BBB prevents molecules from entering the brain unless they can bind specific receptors. When GRN1005 binds to the LRP1 receptor, the binding facilitates “receptor-mediated transport,” or transcytosis, across the BBB into the brain tissue. Conveniently, LRP1 is also very heavily expressed in many tumors. Therefore, once GRN1005 enters the brain, it can gain entry into tumor cells. GRN1005 is a “prodrug,” which means that the form that the patient takes is inactive, but the drug becomes active once it enters cells and is cleaved by enzymes called “esterases” to release active paclitaxel from the peptide.

Geron’s Executive Vice President, Head of R&D and Chief Medical Officer, Stephen M. Kelsey, M.D., said: “With the treatment of the first patient in the GRABM-L study, we have initiated both of the planned Phase 2 clinical trials of GRN1005 in patients with cancer metastases in the brain, a significant unmet medical need for which there are currently no approved drug therapies. We have been encouraged by the preliminary evidence of anti-tumor activity against brain metastases observed in the Phase 1 study of GRN1005, and we hope to confirm these results in our Phase 2 trials.”

The purpose of GRABM-L Phase 2 study is to determine the efficacy, safety and tolerability of GRN1005 in patients with brain metastases from Non-Small Cell Lung Cancer. The trial plans to enroll 50 patients, who will receive one intravenous dose of GRN1005 every three weeks (650 mg/m2). The primary efficacy endpoint for the trial is the response of the tumors to the drug during the course of treatment.

Patients with brain cancer, particularly secondary tumors that are the result of metastases, currently have few options. The reason for this treatment dead-end is the difficulty in getting antitumor drugs to effectively cross the blood-brain barrier and enter the tumor. Preclinical and Phase 1 data indicate that GRN1005 not only transports paclitaxel into tumors inside the brain through LRP1-mediated transport, but also has activity against tumors outside the brain.

Data on safety and tolerability, and preliminary evidence of anti-tumor activity of GRN1005 were documented in two separate Phase 1 multi-center, open-label, dose escalation clinical trials, conducted by Angiochem, Inc. In these trials, patients with heavily pre-treated progressing, advance-stage solid tumors and brain metastases (n=56; including NSCLC) and patients with recurrent or progressive malignant glioma (n=63) were treated with GRN1005. Final data were presented at the 2011 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November. The data were encouraging. In patients with brain metastases from solid tumors, overall response rate was 20% (4/20) by one-dimensional assessment when treated with a dose of 650 mg/m2 of GRN1005 administered as single-agent therapy once every three weeks. Anti-tumor activity was observed against metastases inside the brain and in organs outside the brain, such as the liver, lung and lymph nodes.

Geron’s clinical development plan for GRN1005 includes two Phase 2 clinical trials in patients with brain metastases arising from either breast cancer (GRABM-B) or non-small cell lung cancer (GRABM-L). Top-line data from both studies are expected to be available by the end of the second quarter of 2013.

Combination Immunosuppressive Therapy Works Better for Stem Cell Treaments in Amyotrophic Sclerosis Patients


A research team from the University of California, San Diego has successfully grafted human spinal stems into the spinal cords of rats that have a rodent version of the neurodegenerative disease amyotrophic sclerosis (ALS). ALS is also known as Lou Gehrig’s Disease, which is progressive, degenerative, lethal, neuromuscular disease. In this study, the research group tested four different protocols that suppress the immune response to ensure that the transplanted cells were not attacked and rejected by the host animal’s immune system. The goal of this study was to determine which protocol improved the long-term therapeutic effects of the transplanted cells. This study demonstrated that a combined, systematically-delivered immunosuppression regimen of two drugs significantly improved the survival of the human spinal stem cells. Their results are published in the current issue of Cell Transplantation (20:8).

Michael P. Hefferan from the University of California, San Diego Neurodegeneration Laboratory and a corresponding author on the paper said, “There are no therapeutic strategies that successfully modify ALS progression or outcome. “Cell-based transplantation therapies have emerged as potential treatments for several neurological disorders, including ALS. However, cell graft survival seems to greatly depend on an accompanying immunosuppression regimen, yet there are differential responses to identical immunosuppressive therapies.”

The precise reason for this differential response is presently unclear, but the authors of this study suggested several mechanisms, including distinct types of acute and inflammatory responses, might be the primary reason for different efficacies of the same treatment. To address this possibility, the authors tried to optimize an immunosuppressive protocol for transplanting human spinal cord cells into rats that were genetically preprogrammed to develop ALS (ALS G93A rats). Two drugs, tacrolimus (FK506) and mycophenolate, were used to suppress the immune response against the transplanted spinal stem cells. These drugs were either used alone or in combination with each other.

Human spinal stem cells were transplanted before the ALS G93A rats started to show any ALS symptoms (presymptomatic). ALS G93A rats have a mutant superoxide dismutase gene. Superoxide dismutase is an enzyme found in every cell of our bodies and it detoxifies “superoxide radicals.” Superoxide radicals are oxygen molecules with an extra electron (O2-). Superoxide radicals form as a consequence of the chemical reactions cells use to make energy. Fortunately, our cells have enzymes, like superoxide dismutase, to convert superoxide radicals to hydrogen peroxide (H2O2). Hydrogen peroxide is degraded by the enzyme catalase to water and molecular oxygen. Without a functional superoxide dismutase enzyme, these rats sustain extensive cellular damage in their central nervous system, and, consequently, their motor neurons (those neurons responsible for voluntary movement) begin to die off.

Dr. Hefferan explained: “Although FK506 has been used successfully as monotherapy in our previous studies of spinal ischemia, it failed in the present study on ALS. In contrast to ALS, where spinal inflammation continues and likely worsens until endstage, the traumatically-injured spinal cord is typically characterized by an acute inflammatory phase followed by a progressive loss of most inflammatory markers.”

In this research project, those animals that received the combined immunosuppression of both FK506 and mycophenolate did better than those that received either drug alone and much better than those that received no immunosuppressive therapy. In all likelihood, the combination of the two drugs works better because of the longer drug half-life of mycophenolate rather than from its action. The addition of mycophenolate seems to supplement inhibition of T-cell formation, which leads to a robust survival of the grafted stem cells when analyzed three weeks after transplantation. This suggests that the extensive inflammation in the spinal cords of ALS patients requires extensive immunosuppressive therapies for transplanted stem cells to survive and provide regenerative effects.

HIV Drug Maraviroc Reduces Graft-Versus-Host Disease In Stem Cell Transplant Patients


A drug called maraviroc is normally used to treat Human Immunodeficiency Virus (HIV) infections, but work at the University of Pennsylvania suggests that maraviroc redirects the trafficking of immune cells. The significance of these results are profound for transplant patients, since a drug like maraviroc can potentially reduce the incidence of graft-versus-host disease in cancer patients who have received allogeneic (from someone else) stem cell transplantation (ASCT). This research, which was conducted at the Perelman School of Medicine at the University of Pennsylvania, was presented at the 53rd American Society of Hematology Annual Meeting.

Graft-versus-host disease or GvHD occurs as complication after a stem cell or bone marrow transplant. During GvHD, the newly transplanted cells recognize the recipient’s body as foreign and mount an attack against it. Acute cases of GvHD usually occur within the first 3 months after the transplant. Chronic GvHD usually starts more than 3 months after the transplant. GvHD rates vary from 30 – 40% among related bone marrow or stem cells donors and from 60 – 80% between unrelated donors and recipients. The greater the degree of immunological mismatches between the donor and the recipient, the greater the risk of GvHD. After a transplant, the recipient usually takes a battery of drugs that suppress the immune system. These drug treatments help reduce the chances or severity of GvHD.

Standard treatments for GvHD suppress the immune system. Commonly used medicines include methotrexate, cyclosporine, tacrolimus, sirolimus, ATG (Antithymocyte globulin), and alemtuzumab either alone or in combination. High-dose corticosteroids are the most effective treatment for acute GVHD. Antibodies to T cells and other medicines are given to patients who do not respond to steroids. Chronic GvHD treatments include prednisone, (a steroid) with or without cyclosporine. Other treatments include mycophenolate mofetil (CellCept), sirolimus (Rapamycin), and tacrolimus (Prograf). These treatments, if given during the course of the stem cell or bone marrow transplant, reduce but do not eliminate the risk of developing GvHD.

In the current trial, treatment with maraviroc dramatically reduced the incidence of GvHD in organs where it is most dangerous (liver, GI tract, lung, skin — without compromising the immune system and leaving patients more vulnerable to severe infections.

Assistant professor in the division of Hematology-Oncology and a member of the Hematologic Malignancies Research Program at Penn’s Abramson Cancer Center, Ran Reshef, commented: “There hasn’t been a change to the standard of care for GvHD since the late 1980s, so we’re very excited about these results, which exceeded our expectations. Until now, we thought that only extreme suppression of the immune system can get rid of GvHD, but in this approach we are not killing immune cells or suppressing their activity, we are just preventing them from moving into certain sensitive organs that they could harm.”

Reshef and colleagues presented results showing that maraviroc is safe and feasible in stem cell transplant patients who have received stem cells from a healthy donor. A brief course of the drug led to a 73% reduction in severe GvHD in the first six months after transplant, compared with a matched control group treated at Penn during the same time period (6% who received maraviroc developed severe GvHD vs. 22% of other patients receiving standard drug regimens).

Reshef explained, “Just like in real estate, immune responses are all about location, location, location. Cells of the immune system don’t move around the body in a random way. There is a very distinct and well-orchestrated process whereby cells express particular receptors on their surface that allows them to respond to small proteins called chemokines. The chemokines direct the immune cells to specific organs, where they are needed, or in the case of GvHD, to where they cause damage.”

Thirty-eight patients with blood cancers, including acute myeloid leukemia, myelodysplastic syndrome, lymphoma, myelofibrosis, and others, enrolled in the phase I/II trial. All patients received the standard GvHD prevention drugs tacrolimus and methotrexate, plus a 33-day course of maraviroc that began two days before transplant. In the first 100 days after transplant, none of the patients treated with maraviroc developed GvHD in the gut or liver. By contrast, 12.5% of patients in the control group developed GvHD in the gut and 8.3 percent developed it in the liver within 100 days of their transplant.

The differential impact of maraviroc on those organs indicates that the drug is working as expected, by limiting the movement of T lymphocytes to specific organs in the body. Maraviroc works by blocking the CCR5 receptor on the surfaces of lymphocytes. This prevents the lymphocytes from trafficking to certain organs. Maraviroc did not affect GvHD rates in the skin, which might mean that the CCR5 receptor is more important for sending lymphocytes into the liver and the gut than the skin.

After 180 days, the benefit of maraviroc appeared to be partially sustained in patients and the cumulative incidence of gut GvHD rose to 8.8% and the rates of liver GvHD rose only to 2.9%. The cumulative incidence of GvHD in the control group, however, remained higher, at 28.4% for gut and 14.8% for liver GvHD. Based on these data, the research team plans to try a longer treatment regimen with maraviroc to see if longer exposures to maraviroc can its protective effect.

Additionally, maraviroc treatment appeared to neither increase treatment-related toxicities nor alter the relapse rate of their underlying disease. Clearly this drug shows promise for limiting the devastating effects of GvHD in stem transplant patients.

Fate Therapeutics Clinical Trial with FT1050 Improves Stem Cell Engraftment In Umbilical Cord Blood Transplant Recipients


Patients who receive umbilical stem cell treatments after bone marrow-ablating cancer treatments usually have to wait for the cells the “engraft” or proliferate and fill the bone marrow. During this engraftment time, these patients are prone to life-threatening infections, since their immune systems are effectively wiped out. However, a natural compound called FT1050 (marketed as Prohema) might improve the ability of stem cells from umbilical cord blood to engraft in patients. A phase I clinical trial led by Dana-Farber Cancer Institute scientists provides genuine hope that this compound might decrease the engraftment time for umbilical cord stems cells.

FT-1050 (16,16-dimethyl Prostaglandin E2) is the first drug candidate from Fate Therapeutics’ platform of Stem Cell Modulators (SCMs). SCMs are small molecules that influence adult stem cells. By treating stem cell patients with SCMs, physicians hope to guide stem cells treatments toward desired outcomes, and these can include cell regeneration, healing or blocking cancer growth. In the case of blood cell-making stem cells (also known as “hematopoietic stem cells” or HSCs), FT1050 can mediate their ability to home to the bone marrow and eventually repopulate the patient’s blood and immune system. Because FT-1050 seems to affect fundamental pathways present in all blood cell-making stem cells, it could improve the efficiency and success of treatments with stem cells from any source, including from bone marrow, peripheral blood, and umbilical cord blood.

This clinical trial involved 12 patients who underwent reduced-intensity chemotherapy and then received a transplant of cord blood stem cells that had been treated with FT1050. FT1050-treated blood-forming stem cells might solve a long-standing problem with umbilical cord transplants – a relatively small number of stem cells are infused during such procedures, and therefore, they often take longer to engraft (or take root) in patients than do the more numerous stem cells involved in transplants from adult donors. These delays during engraftment can leave patients susceptible to dangerous infections and other complications.

Trial leader Corey Cutler, MD, MPH, of Dana-Farber and Brigham and Women’s Hospital put it this way: “There is a significant need to improve the speed and quality of engraftment of cord-derived stem cells. FT1050 has shown the ability in preclinical research to activate hematopoietic [blood-forming] stem cells so they engraft more quickly and with a higher degree of success.”

Umbilical cord stem cell transplants are an excellent option for patients who do not have a closely-matched adult donor. Since the current pool of potential donors is smaller for non-Caucasians than for Caucasians, members of ethnic minorities tend to receive transplants from cord blood at a higher rate than Caucasians.

The goal of this phase I trial was to assess the safety of FT1050-treated cord blood cells in adult patients who receive umbilical cord blood stem cell transplants. Additionally, this trial determined if the treated cells show accelerated engraftment. In the 12 patients who participated in the trial, engraftment occurred approximately three to four days faster than normal. Also the patient’s levels of particular types of white blood cells (neutrophils) returned to normal in the patients after a median of 17.5 days, which is similar to the rate in standard stem cell transplants. Side effects of the FT1050-treated cord blood cells were minimal, and in none of the study patients did the stem cells fail to engraft.

The phase I trial was sponsored by Fate Therapeutics, Inc., of San Diego, Calif., which is developing ProHema, a biologic product that consists of blood cell-making stem cells treated with FT1050 for patients who require a stem cell transplant. FT1050 was identified by Leonard Zon, MD, a hematologist and director of the Stem Cell Program at Children’s Hospital Boston, who used a chemical screens that was conducted in zebrafish. FT1050 is the first potential therapeutic derived from a zebrafish model to make it to clinical trials.

“We’re encouraged by the results of this study for patients receiving umbilical cord stem cell transplants after reduced-intensity chemotherapy treatment,” Cutler says. “Further studies are planned to test FT1050-treated hematopoietic stem cells in a larger group of these patients.”

StemCells, Inc. Announces Completion of Enrollment of Its First Cohort in Their Chronic Spinal Cord Injury Trial


StemCells, Inc. announced on December 15, 2001 that the first cohort of the Company’s Phase I/II clinical trial in chronic spinal cord injury have been successfully transplanted with the Company’s proprietary HuCNS-SC neural stem cells. This is a landmark clinical trial that has a unique design. What makes this clinical trial unique is the implantation of patients with progressively decreasing severity of spinal cord injury that are treated three sequential cohorts. The first cohort of patients all have spinal cord injury classified as AIS A, which is the most severe type of spinal cord injury as defined by the American Spinal Injury Association Impairment Scale or AIS.

Stephen Huhn MD, FACS, FAAP, Vice President and Head of the CNS Program at StemCells, Inc. made this statement: “We are extremely pleased with our progress in this innovative trial. Having completed dosing of the AIS A cohort, screening for AIS B patients, who have a less severe, incomplete type of spinal cord injury, can now begin. Of course, our first priority is to assess safety in each patient, but we will also be evaluating trial patients for changes in sensation, motor and bowel/bladder function.”

Martin McGlynn, President and CEO of StemCells Inc added, “I am also pleased to announce that, in consultation with the clinical team at Balgrist Hospital (University of Zurich), the Company has decided to open enrollment for the remainder of the trial to patients living in the United States and Canada. We have received a large number of inquiries from patients in both countries, and hopefully this decision will come as good news to the spinal cord injury community, who were greatly disappointed by Geron’s recent decision to discontinue its spinal cord injury trial. We remain optimistic about the prospect of being able to demonstrate safety and clinical utility of our cells in this devastating condition, and are committed to funding our spinal cord injury program until such time as we can come up with a definitive outcome.”

The Phase I/II clinical trial of StemCells, Inc.’s HuCNS-SC purified human adult neural stem cells is designed to assess both safety and preliminary efficacy of this cell line in the treatment of spinal cord injuries. Twelve patients with thoracic (chest-level) neurological injuries at the T2-T11 level are planned for enrollment. The first three patients all have injuries classified as AIS A, in which there is no apparent neurological function below the level of spinal cord injury. The planned second and third cohorts will consist of patients who have spinal cord injuries classified as AIS B and AIS C, which are less severe than AIS A spinal cord injuries and show at least some preservation of sensory or motor function. This trial will assess safety of the cell line and treatment efficacy based on specific criteria. These clinical criteria include changes in sensation, motor and bowel/bladder function. Prior to implanting the next cohort, data from previous cohorts will be reviewed by an independent Data Safety Monitoring Committee.

All patients will receive HuCNS-SC cells through direct transplantation into the spinal cord and will receive initial doses of medicines that suppress the immune system to ensure that the implanted cells do not elicit inflammation or are instantly rejected by the immune system. However, these drug treatments are temporary, since the central nervous system is surrounded by a blood-brain barrier than prevents the immune system from rejecting transplantations into the central nervous system. Temporary treatment with immunosuppressive drugs are necessary at the beginning of the procedure because the implantations breach the blood brain barrier and until this breach heals, the immune system has access to the implantation, but after the breach heals, immunosuppression is no longer necessary. Implanted patients will be evaluated regularly in the period after the transplant in order to monitor and assess the safety of the HuCNS-SC cells and the implantation procedure, and to determine if there are any neurological changes in the patients. The Company intends to follow the effects of this therapy long-term, and a separate four-year observational study will be initiated at the conclusion of this trial.

The trial is being conducted at Balgrist University Hospital, University of Zurich, a world leading medical center for spinal cord injury and rehabilitation. This institution has a global reputation for providing some of the highest quality examinations, treatments and rehabilitation opportunities to patients with serious musculoskeletal conditions. The clinic owes its leading international reputation to its unique combination of specialized medical services. The hospital’s carefully balanced, interdisciplinary network brings together under one roof medical specialties including orthopedics, paraplegiology, radiology, anesthesiology, rheumatology, and physical medicine.

Induced Pluripotent Stem Cells Produce Pigs That are Superior Model Systems for Medical Research


Rodents are the standard laboratory model system for testing the safety of treatments, chemicals and other medically important protocols and devices. Rodents share an immune system that is very similar to the primate immune system, and also share many other biological features with primates. However, all the drugs we ingest usually make a stop at the liver where they are chemically modified, and this modification step differs from rodents to humans. Some drugs are processed in very similar manners in rats, mice and humans, but many other drugs are processed quite differently. In such cases, rodents make poor model systems for how those drugs might affect human patients.

Another case where rodent models are less than exemplary is cancer studies. Experiments on rodents and rodent-derived cell lines have provided vital insights into the genetics, cell biology and molecular biology of cancer, carcinogens, or compounds that cause cancer in living organisms, have very different effects in rodents and humans. For example, some components in coffee appear to be carcinogenic in rodents, but in humans moderate coffee consumption may reduce the risk of cancer.

Another field of research trends to show very different results in humans and rodents and that field is stem cell research. Induced pluripotent stem cells (iPSCs), which are embryonic-like stem cells made from adult cells though genetic engineering techniques, very effectively cause tumors in rodents. However, in 2010, University of Georgia scientists Steve Stice and Franklin West introduced 13 pigs that might show the way toward new regenerative therapies. These pigs have been the subjects of some experiments with iPSCs and the astounding result is that adult-cell-sourced stem cells (iPSCs) don’t form tumors in these pigs.

West, an animal science researcher and assistant professor in the UGA College of Agricultural and Environmental Sciences said: “Pluripotent stem cells have significant potential for stem cell therapies . . . However, tests in mice often resulted in tumor formation that frequently led to death.” Such robust tumor formation raised concerns about the safety of iPSCs and any cells derived from iPSCs. However, to date, the vast majority of these safety tests have been done in rodent models. Given the rodents can show different results in carcinogenesis tests (a test that determines the tendency of a chemical to cause cancer) relative to humans, West and Stice wondered if these differences as translated into tumor tests with iPSCs.

To address this concern, West and Stice, and their research colleagues examined tumor formation in pigs that were actually made from iPSCs. The results were striking. According to West, “Brain, skin, liver, pancreas, stomach, intestine, lung, heart, kidney, muscle, spleen and gonad tissues from all 11 pigs tested showed no evidence of tumors.” The absence of tumor formation in these pigs suggests that iPSCs can safely incorporate into tissues without causing the formation of tumor.

The potential of such animals as model systems for medical purposes is not lost on these scientists. Steve Stice, a Georgia Research Alliance Eminent Scholar in the College of Agricultural and Environmental Sciences, said: “Being able to safely use iPSCs without the potential of causing tumors is essential for this promising stem cell therapy to become a viable treatment option . . . We now have graduate students working on making neural cells from the human and pig stem cells to help further the studies. The human stem cells were effective in a rodent model for stroke, but rodent studies are not rigorous enough to start human clinical trials.”

There are over 700 drug treatments that have gone to human clinical trials for stroke alone based on safety tests that were done on rodents. However once these drugs were brought to clinical trials, they failed all safety tests. These pigs, however, are much more similar to humans when it comes to drug processing and tolerance. Such animals are much better model systems to study strokes than rodents.

West is leading a cooperative project between the UGA Regenerative Bioscience Center and stroke researchers at Georgia Health Sciences University. “This project will improve the speed and efficiency of treatment development for stroke and many other conditions and potentially reduce the number of nonhuman primates used in research,” he said. In addition to this collaboration, Stice and West have now bred the pigs produced from iPSCs and have demonstrated that the stem cells did form germ cells (eggs and sperm), and their genes were passed to their offspring. These data opens the door for better animal-sourced tissue for human regenerative medicine such as islet cells that produce insulin for diabetic patients.

Using iPSC technology, the UGA Regenerative Bioscience Center is working with researchers at Emory University to make pigs whose cells from the pancreas demonstrate decreased rejection in human treatments. Stice noted, “The next step would be to put these pig insulin-producing cells into other animals, potentially dogs or cats suffering from diabetes—to see if it will produce insulin for them without being rejected . . . So, it’s moving forward. Never as fast as we like, but it’s moving.”