Myelomeningocele – also known as spina bifida – is a devastating and costly defect that causes lifelong paralysis as well as bowel and bladder incontinence in newborns. It is one of the most common birth defects worldwide, with four children in the United States born with spina bifida every day. Spina bifida affects the physical, educational, social, and psychological development of these children. Most patients require multiple surgeries and hospitalizations throughout their lives. Physicians are now able to diagnose this disease during pregnancy, and new fetal surgical techniques allow surgeons to safely operate on these children in the womb. This unique fetal surgery was studied in the award winning Management of Myelomeningocele Study (MOMS). The MOMS trial showed – for the first time ever – that the paralysis associated with spina bifida could be improved. Children treated in the womb were more likely to walk independently than those who were repaired after birth. However, the improvements seen were not perfect and the majority of children treated with fetal surgery still had some level of paralysis or lower extremity weakness.
Our research has built upon the success of the MOMS trial to address the residual deficits seen in children even after treatment with fetal surgery. We have developed a placental stem cell based therapy that can be applied at the time of fetal repair, in order to reverse spinal cord damage. After six years of laboratory research investigating different stem cell types and the best way to deliver a stem cell based treatment in the womb, we have discovered a placental stem cell therapy that cures spina bifida in the animal model. Animals treated with these cells can make a full recovery and are able to walk normally without any evidence of lower extremity paralysis. These amazing results require additional testing and FDA approval before the therapy can be used in humans. With this proposal, we will optimize this stem cell product, validate its effectiveness, determine the optimal dose, and confirm its preliminary safety in order to translate this new treatment to clinical trials. Stem cell therapy for spina bifida could cure this devastating disease, alleviating a massive burden on children, families, and society.
Spina bifida is one of the most common, costly, and disabling birth defects. Within the United States, four children per day are born with this devastating disease. In California, the 5-year statewide incidence of spina bifida was 6.8 cases per 10,000 live births between 1999 and 2003, significantly higher than the Healthy People 2010 target of 3 per 10,000 births. Additionally, spina bifida disproportionately affects Americans of Hispanic and Latino descent, who make up 37.6% of California’s population. Given the disproportionately high incidence of children born with spina bifida in California, and the lifelong disability these children live with, spina bifida is a substantial economic burden to the state. The estimated average total lifetime cost to California is approximately $532,000 for each child born with spina bifida. However, for many children, the cost may be several million dollars due to repeat surgical procedures, frequent hospitalizations, and the need for ongoing physical and cognitive rehabilitation. In addition to the direct medical costs associated with spina bifida, the indirect costs include: pain and suffering, cost of specialized childcare, and the lost earning potential of unpaid caregivers, which compound the impact the disease has on California’s economy.
There is currently no cure for spina bifida, and interventions that mitigate the negative consequences of the disease (lower body paralysis, bowel and bladder incontinence) are urgently needed. For the first time, hope for an improved treatment option was provided by the award winning Management of Myelomeningocele Study (MOMS). The MOMS trial was a multicenter randomized controlled trial demonstrating that the paralysis associated with spina bifida might be improved by surgical repair of the defect before birth. This promise of fetal intervention for spina bifida was based on the hypothesis that early in utero treatment would have the potential to fix the defect before permanent spinal cord damage occurred. While the MOMS trial did demonstrate an improvement in the lower extremity paralysis of those patients undergoing in utero repair compared to postnatal repair, these improvements were not universal for all children. This proposal presents an innovative placental stem cell-based therapy to augment fetal repair and further improve and possibly cure the devastating and costly neurologic deficits of spina bifida. A cure for spina bifida would relieve California families and society of the tremendous emotional and economic cost burden of this debilitating disease, and would be life changing for future children afflicted with spina bifida.
Huntington’s disease (HD) is a devastating degenerative brain disease with at least a 1 in 10,000 prevalence that inevitably leads to death. These numbers do not fully reflect the large societal and familial cost of HD, which requires extensive care-giving. HD has no effective treatment or cure and symptoms unstoppably progress for 15-20 years, with onset typically striking in midlife. Because HD is genetically dominant, the disease has a 50% chance of being inherited by the children of patients. Symptoms of the disease include uncontrolled movements, difficulties in carrying out daily tasks or continuing employment, and severe psychiatric manifestations including depression. Current treatments only address some symptoms and do not change the course of the disease, therefore a completely unmet medical need exists. Human embryonic stem cells (hESCs) and their derivatives offer a possible long-term treatment approach that could relieve the tremendous suffering experienced by patients and their families. HD is the 3rd most prevalent neurodegenerative disease, but because it is entirely genetic and the mutation known, a diagnosis can be made with certainty and clinical applications of hESCs may provide insights into treating brain diseases that are not caused by a single, known mutation. Trials in mice where protective factors were directly delivered to the brains of HD mice have been effective, suggesting that delivery of these factors by hESCs may help patients. Transplantation of tissue in HD patients suggests that replacing neurons that are lost may also be effective. The ability to differentiate hESCs into neural populations offers a powerful and sustainable alternative to provide neuroprotection to the brain with the possibility of cell replacement. We have assembled a multidisciplinary team of investigators and consultants with expertise in basic, translational and clinical development and have identified a lead developmental candidate, ESI-017 neural stem cells, that have disease modifying activity in HD mice with sufficient promise to perform systematic efficacy and safety studies in HD mice with cells generated for this project. We will utilize the collaborative research team, additional preclinical and clinical investigators, stem cell experts and FDA consultants to finalize work that will lead to a productive pre-IND meeting with the FDA and a path forward for clinical trials with the neural stem cell development candidate.
The disability and loss of earning power and personal freedom resulting from Huntington's disease (HD) is devastating and creates a financial burden for California. Individuals are struck in the prime of life, at a point when they are their most productive and have their highest earning potential. As the disease progresses, individuals require institutional care at great financial cost. Therapies using human embryonic stem cells (hESCs) have the potential to change the lives of hundreds of individuals and their families, which brings the human cost into the thousands. For the potential of hESCs in HD to be realized, we have brought together a team of investigators highly experienced in HD basic science and preclinical development, stem cell research, HD clinical trials and FDA regulatory activities to evaluate a human stem cell derived neural stem cell line, ESI-107 NSC in HD mouse models. This selection of this development candidate is based on efficacy in behavioral and electrophysiology measurements in a rapidly progressing mouse model of HD. HD is the 3rd most prevalent neurodegenerative disease, but because it is entirely genetic and the mutation known, a diagnosis can be made with certainty and clinical applications of NSCs may provide insights into treating brain diseases that are not caused by a single, known mutation. We have assembled a strong team of California-based investigators to carry out proposed studies to move ESI-017 NSCs to the point of a productive pre-IND meeting with the FDA to ultimately move this clinical product into Investigative New Drug-enabling (IND) activities with the goal of performing clinical trials in HD subjects. Anticipated benefits to the citizens of California include: 1) development of new human stem cell-based treatments for HD with application to other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases that affect thousands of individuals in California; 2) improved methods for following the course of the disease in order to treat HD as early as possible before symptoms are manifest; 3) transfer of new technologies and intellectual property to the public realm with resulting IP revenues coming into the state with possible creation of new biotechnology spin-off companies; and 4) reductions in extensive care-giving and medical costs. It is anticipated that the return to the State in terms of revenue, health benefits for its Citizens and job creation will be substantial.
Over 6 million people in the US suffer from Alzheimer’s disease (AD). There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate nerve cell replacement in aged human brain. Importantly, even if nerve cells could be replaced, the toxic environment of the AD brain which caused the disease in the first place will likely kill any cells that are born into that environment unless they are resistant to those conditions or can be protected by a drug. Therefore, drugs that stimulate the generation of new neurons (neurogenesis) alone will not be effective. A drug with both neurogenic and neuroprotective properties is required. With the ability to use cells derived from human neural precursor cells (hNPCs) derived from human embryonic stem cells (hESCs) as a screen for neurogenic compounds, we have shown that it is possible to identify and tailor drugs for therapeutic use in AD. With the support of CIRM, we have recently made a very potent AD drug candidate that is exceptionally effective in promoting the making of new nerve cells from human embryonic stem cells. It is both neurogenic and has therapeutic efficacy in a rodent model of AD. However, this molecule needs more preclinical development work before it can start the formal FDA pre clinical toxicity screening protocols. This work will optimize the chances for its true therapeutic potential in AD, and presents a unique opportunity to expand the use of hESCs for the development of a therapeutic for a disease for which there is no cure.
Over 6 million people in the US suffer from AD, and unless a viable therapeutic is identified it is estimated that this number will increase to at least 16 million by 2050, with a cost of well over $1 trillion per year, likely overwhelming both the California and national health care systems. There is no treatment to prevent, cure or slow down this condition. In this application we have used the new human stem cell technologies to develop an AD drug candidate that stimulates the multiplication of nerve precursor cells derived from human embryonic stem cells. This approach presents a unique opportunity to expand the use of human embryonic stems cells for the development of a therapeutic for a disease for which there is no cure, and could lead to a paradigm shift in the treatment of neurodegenerative disease. Since our AD drug discovery approach is fundamentally different from the unsuccessful approaches used by the pharmaceutical industry. It could also stimulate new biotech. The work in this proposal addresses one of the most important medical problems of California as well as the rest of the world, and if successful would benefit all.
The proposed alpha clinic will bring together an outstanding team of physician-scientists with substantial clinical trials experience including stem cell and other cellular treatments of blood diseases and others. This team will also draw on our unique regional competitive advantages derived from our history of extensive collaboration with investigators at many nearby first-class research institutions and biotech companies. We propose to include these regional assets in our plans to translate our successful research on basic properties of stem cells to stem cell clinical trials and ultimately to delivery of effective and novel therapies. We propose to build an alpha clinic that serves the stem cell clinical trial needs of our large region where we are the only major academic health center with the needed expertise to establish a high impact alpha clinic. Our infrastructure will initially be developed and then used to support two major high-impact stem cell clinical trials: one in type I diabetes and one in spinal cord injury. Both are collaborations with established and well known companies. The type I diabetes trial will test embryonic stem cell derived cells that differentiate to become the missing beta cells of the pancreas. The cells are contained in a semipermeable bag that has inherent safety because of restriction of cell migration while allowing proper control of insulin levels in response to blood sugar. These hybrid devices are implanted just beneath the skin in patients in these trials. In a second trial of stem cell therapy for spinal cord injury, neuronal stem cells that have been shown to have substantial safety and efficacy in animal models of spinal cord injury and other types of spinal cord trauma or disease will be tested in human patients with chronic spinal cord injury. Both of these trials have the potential to have very substantial and important impact on patients with these diseases and the families and society that supports them. Following on these two trials, we are planning stem cell clinical trials for heart failure, cancer, ALS, and other terrible deadly disorders. Our proposed alpha clinic also benefits from very substantial leveraged institutional commitments, which will allow for an alpha clinic that is sustainable well beyond the five-year grant, which is essential to continue to manage the patients who have participated in the first trials being planned since multi-year followup and tracking is essential scientifically and ethically. We have a plan for our proposed alpha clinic to be sustainable to 10 years and beyond to the point at which these therapies if successful will be delivered to patients in our healthcare system.
Many terrible diseases that afflict the citizens of California and cause substantial economic and emotional disruption to California families can potentially be treated with novel stem cell therapies. These therapies need to be tested in a rigorous and unbiased fashion in clinical trials, which is the focus of our proposed alpha clinic. Our clinic proposes to begin with clinical trials in two major diseases in need of improved treatment: type I diabetes and spinal cord injuries. The type I diabetes clinical trial will test a novel hybrid embryonic stem cell-derived pancreatic cell/encapsulation technology that is implanted just beneath the skin in an out-patient procedure, and is inherently safe because the cells are confined to a semi-permeable bag. The spinal cord injury trial will test the benefit of neural stem cells delivered to the site of injury. Both have substantial positive evidence in animal models and have the potential of leading to major breakthroughs. In addition to providing the infrastructure for these two trials, our proposed alpha clinic will also take advantage of very substantial regional expertise at our partner institutions to test stem cells in other diseases of importance in California including heart failure, ALS, cancer, and many others. Our proposed alpha clinic will also be a major economic as well as medical driver as it leverages substantial institutional and private sector commitment, and has the potential to deliver breakthrough therapies that will be marketed either in a health care system or by private sector companies.
Motor neurons degenerate and die as a consequence of many conditions, including trauma to the spinal cord and its nerve roots and degenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Paralysis and in many cases death may result from a loss of motor neurons. No effective treatments are available for these patients. Most cellular therapy studies for motor neuron disorders are done in rodents. However, because of the dramatic differences between the rodent and human spinal cord, translation of these studies to humans is difficult. In particular, the development of new stem cell based treatments is limited by the lack of large animal models to test promising candidate therapies.
This bottleneck will be addressed by developing a new research tool in which human embryonic stem cell-derived motor neurons are transplanted into the spinal cord of rhesus macaques after injury and surgical repair of motor nerve roots. This injury and repair model mimic many features of motor neuron degeneration in humans. Microscopic studies will determine survival and tissue integration of transplanted human cells in the primate spinal cord tissues. Evaluations of walking, muscle and bladder function, sensation and magnetic resonance imaging (MRI) will test for possible benefits and potential adverse effects. This new research tool will be available for future pre-clinical testing of additional stem cell-based therapies that target motor neuron loss.
Paralysis resulting from motor neuron loss after cauda equina and conus medullaris forms of spinal cord injury and from neurodegenerative conditions, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are devastating and affects thousands of patients and their families in California (CA). These conditions also create a significant financial burden on the state of CA. No effective treatments are available for these underserved patients. Development of a clinically relevant research tool is proposed to evaluate emerging stem cell-based motor neuron replacement therapies in translational studies. No such models are presently available to the global research community. As a result, the proposed research tool, which will remain based in CA, may attract interest across the United States and abroad, potentially being able to tap into a global translational research market of stem cell-based therapies and contribute to a positive revenue flow to CA.
Future benefits to people in CA include: 1) Development and translation of a new CA-based research tool to facilitate and expedite clinical realization of emerging stem cell-based therapies for devastating neurological conditions affecting motor neurons; 2) Reduction of health care costs and care giver costs for chronic motor neuron conditions with paralysis; 3) Potential for revenue from intellectual properties related to new cellular treatments entering clinical trials and human use.
Microglia are a type of immune cell within the brain that profoundly influence the development and progression of many neurological disorders. Microglia also inherently migrate toward areas of brain injury, making them excellent candidates for use in cell transplantation therapies. Despite the widely accepted importance of microglia in neurological disease, methods to produce microglia from stem cells have yet to be reported. Our team has recently developed one of the first protocols to generate microglia from human pluripotent stem cells. We have used several approaches to confirm that the resulting cells are microglia including examination of gene expression and testing of key microglial functions. However, our current protocol uses cell culture supplements that preclude the use of these cells for any future clinical applications in people. The major goal of this proposal is to resolve this problem. We will generate pluripotent human stem cells that have special "reporter" genes that make the cells glow as they become microglia, allowing us to readily monitor and quantify the generation of these important cells. Using these reporter lines we can then streamline the differentiation process and develop improved protocols that could be translated toward eventual clinical use. As a proof-of-principle experiment we will then use the resulting human microglia to study some important questions about the genetic causes and potential treatment of Alzheimer’s disease.
Recent estimates suggest that nearly 2 million Californian adults are currently living with a neurological disorder. While the causes of neurological disease vary widely from Alzheimer’s disease to Stroke to Traumatic Brain Injury, a type of brain cell called microglia has been strongly implicated in all of these disorders. Microglia are often considered the immune cell of the brain, but they play many additional roles in the development and function of the nervous system. In neurological disease, Microglia appear to be involved in a response to injury but they can also secrete factors that exacerbate neurological impairment. Unfortunately, it has been difficult to study human microglia and their role in these diseases because of challenges in producing these cells. Our group recently developed an approach to ‘differentiate’ microglia from human pluripotent stem cells. This enables researchers to now study the role of different genes in human microglial function and disease. Yet our current approach dose not allow these cells to be used for potential clinical testing in patients. Our proposal therefore aims to develop new tools and technology that will allow us to produce clinically-relevant human microglia. These cells will then be used to study the role of a specific microglial gene in Alzheimer’s disease, and may ultimately be useful for developing treatments for the many Californians suffering from neurological disease.
One critical bottleneck in the translation of regenerative medicine into the clinic is the efficient delivery and engraftment of transplanted cells. While direct injection is the least invasive method for cell delivery, it commonly results in the survival of only 5-20% of cells. Studies suggest that delivery within a carrier gel may enhance cell viability, but most of the gels used previously were naturally derived materials that have complex and unknown compositions. In our previous CIRM-funded work, we discovered that pre-encapsulating cells in very weak hydrogels offers the best protection during injection; however, those gels may be too compliant to support long-term cell survival. To address these limitations, we propose the design of a fully defined, customizable, and injectable material that initially forms a weak gel that then stiffens post-injection. We focus our studies on the delivery of human induced pluripotent stem cell-derived neural progenitors for the treatment of spinal cord injury (SCI). There are ~12,000 new SCI patients in the US each year, primarily young adults. SCI commonly results in paralysis, and the estimated lifetime cost for a patient can rise above $4 million dollars. In preclinical models of SCI, stem cell therapies have resulted in partial regeneration; however, reproducible delivery and engraftment of sufficient cells remain difficult and unmet challenges. This award potentially develops transformational regenerative therapies for SCI.
The annual incidence of spinal cord injuries (SCI) in the United States is estimated at 12,000 new cases per year, with motor vehicle crashes accounting for up to a third of these cases. SCI has devastating impacts not only on the quality of life for the victims and their families, but also on their economic security – the estimated lifetime cost of an SCI patient can rise to over $4 million dollars depending on the severity and age at which the injury was sustained, not including the loss of wages and productivity. Although the most prevalent types of SCIs are those sustained at either the cervical or thoracic vertebrae, there are currently no definitive therapies approved for the chronic management of these SCI. Stem cell-based therapies have recently been shown to be mildly successful in several clinical and pre-clinical trials in various injuries and diseases, and a number of trials are ongoing for applications in SCI. In our proposal, we seek to advance the stem cell-based approach to the treatments of SCI. The potential benefit of this proposal to the state of California and its citizens include 1) the provision of a better medical prognosis for patients with spinal cord injuries, 2) the improved quality of life for SCI patients and their families, 3) the reduction of the burden of health care costs, 4) the creation and maintenance of jobs in the stem cell technology field, and 5) preserving California’s prominence in the field of stem cell research.
The intestine performs the essential function of absorbing food and water into the body. Without a functional intestine, children and adults cannot eat normal meals, and these patients depend on intravenous nutrition to sustain life. Many of these patients do not have a neural system that coordinates the function of the intestine. These patients have a poor quality of life, and the cost of medical care is over $200,000 per year for each patient. Stem cell therapies offer potential cures for these patients while avoiding the risks of invasive procedures and hazardous treatments. A novel approach to treat these patients is to use stem cells derived from the patient’s own skin to generate the neural system. This has been shown to be feasible in small animals, and the next step hinges on the demonstration of these results in a large animal model of intestinal dysfunction. We will develop a model in large animals that can be used to test the ability of skin-derived stem cells to form the neural system. Skin-derived stem cells will be isolated from large animal models and human skin to demonstrate their potential to generate a functional neural system. These cells will be transplanted into the animal model to determine the best way for these cells to make the intestine function properly. This research will gather critical information needed to begin a clinical trial using skin-derived cells to treat intestinal dysfunction.
Gastrointestinal dysfunction destroys the lives of thousands of Californians. These Californians have frequent and prolonged hospitalizations and lost wages due to their chronic illness. It is estimated that the health care cost of Californians with gastrointestinal neuromuscular dysfunction is over 400 million dollars annually. Currently, most of these patients are covered by the state’s insurance agency. Stem cell therapies offer potential cures for these patients and reduce this economic burden. The proposed research will obtain critical information needed to begin a clinical trial using skin-derived cells to treat patients with intestinal dysfunction. The California economy will significantly benefit from this research through the reduced costs for health care and increased quality of life of the affected Californians. Additionally, this work will add to the state’s growing stem cell industry and will increase employment opportunities and revenue by the state of California. The educational benefit to Californians involved in this research project will also maintain California’s position in leading the stem cell effort in the future.
Three years ago, with help from CIRM funding, we developed an assay. This is a genomics-base diagnostic assay, similar to those now used for diagnosing cancers; but in our case, it is designed to analyze human ES and iPS cells. The assay is very simple to use; researchers use microarrays to profile the genes that are active in their cells. They upload the microarray data to the website, and in a few minutes they find out whether or not their cells are pluripotent. Our assay is replacing the old method for proving pluripotency, which involves producing tumors in animals. Our assay has been extremely popular, with 9,386 samples analyzed by 581 research groups in 29 countries so far. In this proposal, we plan to take the same concept and apply it to translational stem cell applications. Our new assay will allow researchers to easily detect DNA damage in their stem cells, and will enable the detection of undifferentiated or other abnormal cells (which potentially could form a tumor) in populations used for cell replacement therapy. We are also designing specific assays for quality control of neuronal cells to be transplanted to Parkinson's disease patients and for other neurological therapies. Finally, with our European partners, we will develop an assay for ensuring reliability of drug screening assays using stem cells. Our tools will greatly simplify translation of hESCs and iPSCs to the clinic.
California is at the leading edge of development of stem cell therapies to treat previously untreatable diseases. It is critical at this important stage, when treatments are being transferred from the lab to the clinic, that the cells used for therapy are carefully produced and qualified. Our project combines two of California's best scientific assets: genomics and stem cells. Our quality control assays for stem cell production are based on our long experience in genomic analysis of stem cells and development of genomics-based diagnostic tests. The assays will ensure that stem cells used for therapy are consistently of high quality. This will speed the development of stem cell therapies for Californians.
Cell replacement therapies (CRTs) have considerable promise for addressing unmet medical needs, including incurable neurodegerative diseases. However, several bottlenecks hinder CRTs, especially the needs for improved cell manufacturing processes and enhanced cell survival and integration after implantation. Engineering synthetic biomaterials that present biological signals to support cell expansion, differentiation, survival, and/or integration may help overcome these bottlenecks. Our prior work has successfully generated synthetic biomaterial platforms for the long-term expansion of human pluripotent stem cells (hPSCs) at large scale, efficient differentiation of hPSCs into dopaminergic progenitors and neurons for treating Parkinson’s Disease, and modulation of stem cell function to promote neuronal differentiation within the brain. We now propose to advance this work and engineer two synthetic biomaterial platforms to treat neurodegenerative disease, in particular Parkinson’s Disease and Retinitis Pigmentosa. Specifically, our central goals are to further engineer biomaterial systems for scalable hPSC differentiation into dopaminergic and photoreceptor neurons, and to engineer a second biomaterial system as a biocompatible delivery vehicle to enhance the survival and engraftment of dopaminergic and photoreceptor neurons in disease models. The resulting modular, tunable platforms will have broad implications for other cell replacement therapies to treat human disease.
This proposal addresses critical translational bottlenecks to stem cell therapies that are identified in the RFA, including the development of fully defined, xenobiotic free cell manufacturing systems and the development of clinically relevant technologies to enhance the survival and integration of human stem cell therapies. The proposed platform technologies for expanding and differentiating pluripotent stem cells in a scaleable, reproducible, safe, and economical manner will initially be developed for treating two major neurodegenerative disorders - Parkinson’s Disease and Retinitis Pigmentosa - that affect the well-being of hundreds of thousands of Californians and Americans. In addition, the biomaterial platforms are designed to be modular, such that they can be re-tuned towards other target cells to even more broadly enable cell replacement therapies and enhance our healthcare. This work will thus strongly enhance the scientific, technological, and economic development of stem cell therapeutics in California.
Furthermore, the principal investigator has a strong record of translating basic science and engineering towards clinical development within industry, particularly within California. Finally, this collaborative project will focus research groups with many students on an important interdisciplinary project at the interface of science and engineering, thereby training future employees and contributing to the technological and economic development of California.