Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Grant Type: 
SEED Grant
Grant Number: 
RS1-00377
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$619 223
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Our understanding of the effect of immunosuppressive agents on stem cell proliferation and differentiation in the central nervous system is limited. Indeed, even the necessity for long-term immunosuppression to promote the survival of stem cells grafted into the “immunoprivileged” central nervous system (CNS) is unknown. Grafting multipotent stem cells into the injured CNS often results in a failure of the cells to survive. If the cells survive, often they differentiate into astrocytes, a cell-type not considered beneficial. We recently grafted human stem cells (hCNS-SC) into spinal injured mice and observed behavioral improvements coupled with differentiation of these human cells into neurons and oligodendrocytes. We also observed mouse-human synapse formation and remyelination. The mice we used lacked a functional immune system, enabling us to grafting human cells into the mice without the use of immunosuppressants. When these same cells were grafted into spinal injured rats with a normal immune system, we had to immunosuppress the animals. Exposure of these human stem cells to immunosuppressive drugs resulted poor cell survival. The cells that did survive predominantly differentiated into astrocytes. Did the immunosuppressive drugs we used alter the ability of the human stem cells to differentiate into useful cells?

All cell-based therapeutic approaches are dependent upon either immunosuppression in an otherwise normal animal or testing for proof of principal in an immunodeficient animal model. This has quite significant implications for animal experiments or human trials, where continuous immunosuppression is required to obtain successful graft survival. No one knows if there are direct effects of immunosuppressant drugs on neural stem cells.

Stem cells may also respond differently to immunosuppression depending on their “ontogenetic” age (embryonic vs. fetal vs. adult). There is a common perception that “young” ES cells will have greater potential than “older” stem cells. Stem cells isolated at different ontogenetic stages might respond differently to immunosuppression.

We predict that the immunosuppressive drugs will exert direct effects on stem cell proliferation, gene expression, and fate determination, both in cell culture and when grafted into animals with spinal cord injury. We will also test if “ontogenetic” age alters the responsiveness of stem cells.

Statement of Benefit to California: 

The California Institute for Regenerative Medicine (CIRM) recognizes that the field of stem cell biology is in its infancy. CIRM has requested a broad range of research to fill in key gaps in our understanding of basic stem cell biology and the possible use of these cells as therapeutics. Grants are to be judged on impact (extent the proposed research addresses an important problem; significantly moves the field forward scientifically; moves the research closer to therapy; and changes the thinking or experimental practice in the field), quality (is proposed research planned carefully to give a meaningful result; are possible difficulties are acknowledge; does the timetable allows for achieving significant research) and innovation (to what extent the research approach is original, breaks new ground, and brings novel ideas to bear on an important problem).

We believe that the projects proposed here target several of the areas CIRM cites as beneficial to the State of California. This proposal addresses the critical area of immunosuppression and stem cell survival in animal transplantation models. Future therapies using human stem cells will have to surmount the possible rejection by the host of cells derived from another source. If traditional immunosuppressive drugs are to be used, we will need to understand whether these drugs have a direct effect on stem cell proliferation and fate determination (or differentiation). Furthermore, these projects will allow for a direct comparison of stem cells from different ontogenetic stages and the ability to improve functional outcome after spinal cord injury. Thus we may gain insight into whether embryonic derived stem cells are more useful than adult derived stem cells as a therapeutic tool.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00215
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$564 309
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

In this application, we propose to identify small molecule compounds that can stimulate human embryonic stem cells to become dopamine-producing neurons. These neurons degenerate in Parkinson’s disease, and currently have very limited availability, thus hindering the cell replacement therapy for treating Parkinson’s disease.

Our proposed research, if successful, will lead to the identification of small molecule compounds that can not only stimulate cultured human embryonic stem cells to become DA neurons, but may also stimulate endogenous brain stem cells to regenerate, since the small molecule compounds can be made readily available to the brain due to their ability to cross the blood-brain barrier. In addition, these small molecule compounds may serve as important research tools, which can tell us the fundamental biology of the human embryonic stem cells.

Statement of Benefit to California: 

The proposed research will potentially lead to a cure for the devastating neurodegenerative, movement disorder, Parkinson’s disease. The proposed research will potentially provide important research tools to better understand hESCs. Such improved understanding of hESCs may lead to better treatments for a variety of diseases, in which a stem-cell based therapy could make a difference.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00170
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$500 000
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurological disease that leads to the degeneration of motor neurons in the brain and in the spinal cord. There are currently 20,000 ALS patients in the United States, and 5,000 new patients are diagnosed every year. Unfortunately no cure has been found for ALS. The only medication approved by the FDA to treat ALS can only slow the disease’s progression and prolong life by a few months in some patients. Thus it is critical to explore other therapeutic strategies for the treatment of ALS such as cell replacement strategy.

Because of the ability to generate many different cell types, human embryonic stem cells (hESCs) may potentially serve as a renewable source of cells for replacing the damaged cells in diseases. However, transplanting ESCs directly may cause tumor growth in patients. To support cell transplants, it is important to develop methods to differentiate hESCs into the specific cell types affected by the disease. In this application, we propose to develop an effective method to differentiate hESCs into corticospinal motor neurons (CSMNs), the neurons in the cerebral cortex that degenerate in ALS. We will test whether these CSMNs generated from hESCs in culture conditions can form proper connections to the spinal cord when transplanted into mouse brains.

To direct hESCs to become the CSMNs, it is critical to establish a reliable method to identify human CSMNs. Recent progress in developmental neuroscience have identified genes that are specifically expressed in the CSMNs in mice. However no information is available for identifying human CSMNs. We hypothesize that CSMN genes in mice will be reliable markers for human CSMNs. To test this hypothesis we will investigate whether mouse CSMN markers are specifically expressed in the human CSMNs.

The therapeutic application of hESCs to replace damaged CSMNs in ALS depends on the ability to direct hESCs to develop into CSMNs. Currently a reliable condition to direct hESCs to differentiate into CSMNs has not been established. We will attempt to differentiate hESCs into CSMNs based on the knowledge gained from studying the development of nervous system. We will achieve this goal in two steps: first we will culture hESCs in a condition to make them become progenitors cells of the most anterior region of the brain; then we will culture these progenitors to become neurons of the cerebral cortex, particularly the CSMNs. We will study the identities of these neurons using the CSMN markers that we have proposed to identify.

To apply the cell replacement strategy to treat ALS, it will be critical to test if human CSMNs generated from cultured hESCs can form proper connections in an animal model. We will transplant the CSMNs developed from hESCs into the brains of mice and test whether they can form connections to the spinal cord.

When carried out, the proposed research will directly benefit cell replacement therapy for ALS.

Statement of Benefit to California: 

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurological disease that leads to the degeneration of motor neurons in the brain and in the spinal cord. There are currently 20,000 ALS patients in the United States, and 5,000 new patients are diagnosed every year. Unfortunately no cure has been found for ALS. The only medication approved by the FDA to treat ALS can only slow the disease’s progression and prolong life by a few months in some patients. Thus it is critical to explore other therapeutic strategies for the treatment of ALS such as cell replacement strategy.

Because of the ability to generate many different types of cells, human embryonic stem cells (hESCs) may potentially serve as a renewable source of cells for replacing the damaged cells in diseases. However, transplanting ESCs directly may cause tumor growth in patients. To support cell transplants, it is important to develop methods to differentiate hESCs into the specific cell types affected by the disease. In this application, we propose to develop an effective method to differentiate hESCs into corticospinal motor neurons (CSMNs), the neurons in the cerebral cortex that degenerate in ALS. We will test whether these CSMNs generated from hESCs in culture conditions can form proper connections to the spinal cord when transplanted into mouse brains.

Everyday, 15 people die from ALS. For patients diagnozied with ALS, time is running out very fast. It is critical to explore novel therapeutic strategies for this rapidly progressive and fatal disease. The research proposed in this application may provide the basis for a novel cell replacement therapy for ALS, thus it will greatly benefit the State of California and everyone in the State.

Grant Type: 
Basic Biology II
Grant Number: 
RB2-01628
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 458 000
Disease Focus: 
Neurological Disorders
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 

Pluripotent stem cells have a remarkable potential to develop into virtually any cell type of the body, making them a powerful tool for the study or direct treatment of human disease. Recent demonstration that induced pluripotent stem (iPS) cells may be derived from differentiated adult cells offers unprecedented opportunities for basic biology research, regenerative medicine, disease modeling, drug discovery and toxicology. For example, using patient-derived iPS cells, one can model diseases in vitro and screen for drugs in ways never before possible, enabling the identification of promising new therapeutic candidates earlier in the drug discovery process. In addition, iPS cell derivatives represent an ideal source for autologous cell replacement therapies, as they would not be rejected upon transplantation back into the patient.

While it is clear that iPS cells hold great promise for finding therapies for diseases, there are significant hurdles that need to be overcome before full clinical potential is realized. The mechanism of iPS cell derivation is largely elusive, and the process used to generate them is very inefficient and needs to be improved in significant ways. Currently, iPS cells are generated by forced expression of four molecular factors using genome-integrating viruses. This may lead to mutations and altered differentiation potential of iPS cells, as well as tumorogenesis if transplanted back into the patient. The inefficient and stochastic nature of the reprogramming process indicates that additional, as yet unidentified mechanisms may exist and contribute to iPS cell generation. Finally, increasing the efficiency of current iPS cell derivation protocols will increase the ability to generate large panels of patient-specific iPS cell lines.

We propose to use a human cell-based assay to identify small molecules that can enhance the efficiency of iPS cell generation. Our strategy will allow us to identify small molecules that target events essential for derivation of iPS cells, as well as those that replace one or more of the four virally-delivered factors. We will use the identified small molecules to discover regulatory pathways and molecular targets involved in induction of pluripotency, gaining valuable insight into the mechanism of cellular reprogramming. Application of these small molecules themselves, as well as novel approaches derived from mechanism of action studies, will help overcome issues associated with viral integration and has the potential to transform personalized cell-replacement therapies as well as accelerate drug discovery based on iPS cell-derived disease models.

Statement of Benefit to California: 

California’s health care system faces significant challenges as millions of children and adults suffer from a host of incurable illnesses. It is expected that health care costs will continue to rise as California’s citizenry ages and requires treatments for age-related, chronic metabolic, cardiovascular, and neurodegenerative disorders. Both the measureable economic impact on California’s health care system and the incalculable emotional suffering of affected individuals, their families and communities, make it an imperative to develop novel therapeutic treatments to address these mounting medical and economic societal challenges.

Recognizing the potential utility of novel stem cell technologies to address California’s unmet medical needs, California voters approved Proposition 71 which created the California Institute for Regenerative Medicine (CIRM), an agency that administers funds to support stem cell research that has the greatest potential for development of novel regenerative medical treatments and cures. The CIRM Basic Biology Awards II program is intended to fund studies that will lay the foundation for future stem cell-based translational and clinical advances. In keeping with this mission, our proposed research program aims to discover new methods for producing human induced pluripotent stem cells (iPS cells) on an industrial scale and in an efficient manner; and to develop a better understanding of the mechanisms underlying cellular reprogramming. As such, our research program will help accelerate the realization of the full potential of iPS cells in cell-based regenerative medicine therapies and drug discovery.

Our proposed research program will benefit the State of California and its citizens in several ways. Firstly, our research program will lay the foundation for future stem cell-based clinical and translational advances to treat and manage one of California’s most pressing unmet medical needs. Secondly, execution of our research program will create new jobs in the academic, biotechnology and pharmaceutical sectors throughout California. Funding from CIRM will be expanded with additional funding from the applicant to augment achievement of the aims of this project. CIRM funding will leverage other sources of investment in this project to help ensure California’s continued future as a world leader in biomedical innovation and translational medicine for the benefit of human health. Lastly, our proposed research program will stimulate California’s economy by creating new enabling tools and technologies that can be broadly adopted across the life science industry, thus promoting development across the academic institutions and biopharmaceutical companies that create biomedical discoveries and advances. These activities will continue to strengthen California’s leadership position at the forefront of the stem cell and regenerative medical revolution of the 21st century.

Grant Type: 
Basic Biology II
Grant Number: 
RB2-01637
Investigator: 
ICOC Funds Committed: 
$1 522 800
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 

Approaches to repair the injured brain or even prevent age-related neurodegeneration are in their infancy but there is growing interest in the role of neural stem cells in these conditions. Indeed, there is hope that some day stem cells can be used for the treatment of spinal cord injury, stroke, or Parkinson’s disease and stem cells are even mentioned in the public with respect to Alzheimer’s disease. To utilize stem cells for these conditions and, equally important to avoid potential adverse events in premature clinical trials, we need to understand the environment that supports and controls neural stem cell survival, proliferation, and functional integration into the brain. This “neurogenic” environment is controlled by local cues in the neurogenic niche, by cell-intrinsic factors, and by soluble factors which can act as mitogens or inhibitory factors potentially over longer distances. While some of these factors are starting to be identified very little is known why neurogenesis decreases so dramatically with age and what factors might mediate these changes. Because exercise or diet can increase stem cell activity even in old animals and lead to the formation of new neurons there is hope that neurogenesis in the aged brain could be restored to that seen in younger brains and that stem cell transplants could survive in an old brain given the right “young” environmental factors. Indeed, our preliminary data demonstrate that systemic factors circulating in the blood are potent regulators of neurogenesis. By studying how the most promising of these factors influence key aspects of the neurogenic niche in vitro and in vivo we hope to gain an understanding about the molecular interactions that support stem cell activity and the generation of new neurons in the brain. The experiments supported under this grant will help us to identify and understand the minimal signals required to regulate adult neurogenesis. These findings could be highly significant for human health and biomedical applications if they ultimately allow us to stimulate neurogenesis in a controlled way to repair, augment, or replace neural networks that are damaged or lost due to injury and degeneration.

Statement of Benefit to California: 

In California there are hundreds of thousands of elderly individuals with age-related debilitating brain injuries, ranging from stroke to Alzheimer’s and Parkinson’s disease. Approaches to repair the injured brain or even prevent age-related neurodegeneration are in their infancy but there is growing interest in the role of neural stem cells in these conditions. However, to potentially utilize such stem cells we need to understand the basic mechanisms that control their activity in the aging brain. The proposed research will start to address this problem using a novel and innovative approach and characterize protein factors in blood that regulate stem cell activity in the old brain. Such factors could be used in the future to support stem cell transplants into the brain or to increase the activity of the brain’s own stem cells.

Grant Type: 
Basic Biology II
Grant Number: 
RB2-01602
Investigator: 
ICOC Funds Committed: 
$1 387 800
Disease Focus: 
Epilepsy
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

There are now viable experimental approaches to elucidate the genetic and molecular mechanisms that underlie severe brain disorders through the generation of stem cells, called iPS cells, from the skin of patients. Scientists are now challenged to develop methods to program iPS cells to become the specific types of brain cells that are most relevant to each specific brain disease. For instance, there is evidence that defects in cortical interneurons contribute to epilepsy, autism and schizophrenia. The experiments proposed in this grant application aim to understand basic mechanisms that underlie the development of cortical interneurons. We are discovering regulatory elements (called enhancers) in the human genome that control gene expression in developing interneurons. We have three experimental Aims. In Aim 1, we will study when and where these enhancers are expressed during mouse brain development. We will concentrate on identifying enhancers that control gene expression during development of specific types of cortical interneurons, although we hope to use this approach for additional cell types. Once we identify and characterize where and when these enhancers are active, in Aim 2 we will use the enhancers as tools in human stem cells to produce specific types of cortical interneurons in the test tube. The enhancers will be used to express proteins in the stem cells that will enable us purify only those cells that have specific properties (e.g. properties of cortical interneurons). In Aim 3 we will explore whether the human brain produces cortical interneurons in the same way as the mouse brain; this information is essential to identify molecular markers on the developing interneurons that could be used for further characterization and purification of the interneurons that we care generating in Aim 2. We want to emphasize that while the experiments focus on cortical interneuron subtypes, our work has general implications for the other types of brain cells our labs study, such as cortical and striatal neurons. In sum, the basic science mechanisms that we will discover will provide novel insights into how to generate specific types of neurons that can be used to study and treat brain diseases.

Statement of Benefit to California: 

Large numbers of California residents are stricken with severe medical disorders affecting the function of their brain. These include epilepsy, Parkinson’s Disease, Alzheimer’s Disease, Huntington’s Disease, Autism and Schizophrenia. For instance, a recent report from the Center for Disease Control and Prevention [www.cdc.gov/epilepsy/] estimates that 1 out of 100 adults have epilepsy. In California, epilepsy is one of the most common disabling neurological conditions, with approximately 140,000 affected individuals. The annual cost estimates to treat epilepsy range from $12 to $16 billion in the U.S. Currenlty up to one-third of these patients are not receiving adequate treatment, and may benefit from a cell-based transplantation therapy that we are currently exploring with our work in mice.
There are now viable experimental approaches to elucidate the genetic and molecular mechanisms that underlie these neuropsychiatric disorders through the generation a stem cells, called iPS cells, from the skin of patients. Scientists are now challenged to develop methods to program iPS cells to become the specific types of brain cells that are most relevant to each specific brain disease. For instance, there is evidence that defects in cortical interneurons contribute to epilepsy, autism and schizophrenia. The experiments proposed in this grant application aim to understand basic mechanisms that underlie the development of cortical interneurons. We are discovering regulatory elements (called enhancers) in the human genome that control gene expression in developing interneurons. Our experiments will help us understand fundamental mechanisms that govern development of these cells. Furthermore, we have designed experiments that harness these enhancers to drive the production of specific subtypes of these cells from human stem cells. This will open the door to making these types of neurons from iPS cells to study human disease, and potentially to the production of these neurons for transplantation into patients whose interneurons are deficient in regulating their brain function. Furthermore, the approach we describe is general and readily applicable to the generation of other brain cells. Thus, the results from these studies will provide essential and novel basic information for understanding and potentially treating severe brain disorders.

Grant Type: 
Basic Biology II
Grant Number: 
RB2-01496
Investigator: 
Type: 
PI
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$1 284 921
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Collaborative Funder: 
Japan
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

Multipotent Neural Stem Cells (NSC) can be derived from adult central nervous system (CNS) tissue, embryonic stem cells (ESC), or iPSC and provide a partially committed cell population that has not exhibited evidence of tumorigenesis after long term CNS transplantation. Transplantation of NSC from these different sources has been shown by multiple investigators in different CNS injury and disease paradigms to promote recovery or ameliorate disease. Additionally, both {REDACTED} groups have shown that human NSCs transplanted in the subacute period after spinal cord injury promote functional recovery. While the role of the host immune response has been considered in the context of immune-rejection, predominantly regarding the T-cell response, the consequence of an ongoing inflammatory response within the context of the tissue microenvironment for cell fate, migration, and integration/efficacy has been largely overlooked. Critically, the tumorigeneis, fate, migration, and integration/repair potential of a stem cell is driven by: 1) the intrinsic properties of cell programming, e.g., the type and source of cell / means used to derive the cell, and maintenance/differentiation of the cell in vitro; and 2) the extrinsic factors the cell encounters. Variations in the intrinsic properties of the cell may affect the potential of that cell for uncontrolled proliferation or the response of the cell to extrinsic factors that it later encounters, defining its fate, migration, and integration/repair potential. The {REDACTED} group has demonstrated that iPS-derived neurospheres (iPS-NS) exhibit a surprisingly large degree of variation in tumorigenesis potential after CNS transplantation, which is correlated with tissue source as well as differentiation and NS forming capacity. Moreover, the intrinsic properties of hNSC populations derived from different cell sources have not been broadly characterized; in fact, {REDACTED} has published the first data in the field demonstrating the differences in fate and integration/repair potential between primary and secondary neurospheres generated via in vitro differentiation of mouse or human ESC and iPSC. In parallel, {REDACTED} has shown profound differences in the response of NSC derived from human tissue versus hESC to extrinsic signals. Together, these data suggest that both characterization of the intrinsic properties of NSCs derived from different sources is essential for our understanding of the basic biology of these cells. Investigation of molecules and signaling pathways directing hNSC fate choices in the injured CNS microenvironment will yield new insight into the mechanisms of fate and migration decisions in these cell populations.

Statement of Benefit to California: 

Multipotent Neural Stem Cells (NSC) can be derived from adult central nervous system (CNS) tissue, embryonic stem cells (ESC), or induced pluripotent cells (iPSC) and provide a partially committed cell population that has not exhibited evidence of tumorigenesis after long term CNS transplantation. Transplantation of NSC from these different sources has been shown by multiple investigators in different CNS injury and disease paradigms to promote recovery or ameliorate disease. Accordingly, stem cell based therapeutics such as these have the potential to treat a variety of traumatic, congenital, and acquired human conditions. However, while much progress has been made, translational research with human stem cell populations will remain limited by the progress of the fundamental understanding of the basic biology of these cells. The {REDACTED} group has pioneered understanding the critical role of timing in considering cell transplantation therapies. More recently, this group has focused on the neural induction of mouse- and human-derived iPSC and tested the potential of these cell populations for spinal cord injury treatment in animal models. {REDACTED} has established the NOD-scid mouse as a model for experimental neurotransplantation for xenograft studies, characterizing the relationship between transplant timing, engraftment outcome, cell fate, host remyelination, and functional recovery. Recently, this group has focused on how the innate inflammatory response influences cell fate and migration. In this collaborative proposal, researchers from California and Japan propose to combine their expertise to characterize and investigate some of the most fundamental aspects of the intrinsic properties of, and extrinsic factors influencing, human induced pluripotent (hiPSC) and human embryonic (hESC) stem cells, pooling knowledge and expertise in stem cell and animal model paradigms. The experiments proposed investigate the basic cellular and molecular mechanisms underlying the role of the host environment in stem cell fate regulation, and the relationship between reprogramming and tumorigenic/fate potential of hiPS-NSC in vitro and after transplantation, and key to this collaborative effort, the interface of these two aspects of basic stem cell biology. Critically, this international collaboration combines the expertise of two of the most advanced laboratories in translational stem cell biology to address several key unresolved questions in the control of cell fate, and will promote sharing of resources, data, and techniques between these labs to advance the field. Ultimately, the collaborative work proposed may permit the development of strategies to refine cellular reprogramming techniques, alter in vitro differentiation strategies, or manipulate the microenvironment to maximize the window for potential stem cell-based neurotherapeutics.

Grant Type: 
Disease Team Research I
Grant Number: 
DR1-01480
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Neurological Disorders
Stroke
Collaborative Funder: 
Germany
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

A stroke kills brain cells by interrupting blood flow. The most common “ischemic stroke” is due to blockage in blood flow from a clot or narrowing in an artery. Brain cells deprived of oxygen can die within minutes. The loss of physical and mental functions after stroke is often permanent and includes loss of movement, or motor, control. Stroke is the number one cause of disability, the second leading cause of dementia, and the third leading cause of death in adults. Lack of movement or motor control leads to job loss and withdrawal from pre-stroke community interactions in most patients and institutionalization in up to one-third of stroke victims. The most effective treatment for stroke, thrombolytics or “clot-busters”, can be administered only within 4.5 hours of the onset of stroke. This narrow time window severely limits the number of stroke victims that may benefit from this treatment. This proposal develops a new therapy for stroke based on embryonic stem cells. Because our (and others’) laboratory research has shown that stem cells can augment the brain’s natural repair processes after stroke, these cells widen the stroke treatment opportunity by targeting the restorative or recovery phase (weeks or months after stroke instead of several hours).

Embryonic stem cells can grow in a culture dish, but have the ability to produce any tissue in the body. We have developed a technique that allows us to restrict the potential of embryonic stem cells to producing cell types that are found in the brain, making them “neural stem cells”. These are more appropriate for treating stroke and may have lower potential for forming tumors. When these neural stem cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs. Based on these findings, we propose in this grant to further develop these neural stem cells into a clinical development program for stroke in humans at the end of this grant period.

This proposal develops a multidisciplinary team that will rigorously test the effectiveness of stem cell delivery in several models of stroke, while simultaneously developing processes for the precise manufacture, testing and regulatory approval of a stem cell therapy intended for human use. Each step in this process consists of definite milestones that must be achieved, and provides measurable assessment of progress toward therapy development. To accomplish this task, the team consists of stroke physician/scientists, pharmacologists, toxicologists, experts in FDA regulatory approval and key collaborations with biotechnology firms active in this area. This California-based team has a track record of close interactions and brings prior stroke clinical trial and basic science experience to the proposed translation of a stem cell therapy for stroke.

Statement of Benefit to California: 

The State of California has made a historic investment in harnessing the potential of stem cells for regenerative therapy. While initially focused on developing new stem cell technologies, CIRM has recognized that translational progress from laboratory to clinic must also be fostered, for this is ultimately how Californians will benefit from their investment. Our focus on developing a neuro-restorative therapy for treatment of motor sequelae following sub-cortical stroke contains several benefits to California. The foremost benefit will be the development of a novel form of therapy for a major medical burden: The estimated economic burden for stroke exceeds $56.8 billion per year in the US, with 55% of this amount supporting chronic care of stroke survivors (1). While the stroke incidence markedly increases in the next half-century, death rates from stroke have declined. These statistics translate into an expected large increase in disabled stroke survivors (1) that will have a significant impact on many aspects of life for the average Californian. Stroke is the third greatest cause of death, and a leading cause of disability, among Californians. Compared to the nation, California has slightly above average rates for stroke (2). Treatments that improve repair and recovery in stroke will reduce this clinical burden.

The team that has been recruited for this grant is made of uniquely qualified members, some of whom were involved in the development, manufacturing and regulatory aspects of the first clinical trial for safety of neural stem cells for stroke. Thus not only is the proposed work addressing a need that affects most Californians, it will result in the ability to initiate clinical studies of stem cells for stroke recovery from a consortium of academic and biotechnology groups in California.

1. Carmichael, ST. (2008) Themes and strategies for studying the biology of stroke recovery in the poststroke epoch. Stroke 39(4):1380-8.

2. Reynen DJ, Kamigaki AS, Pheatt N, Chaput LA. The Burden of Cardiovascular Disease in California: A Report of the California Heart Disease and Stroke Prevention Program. Sacramento, CA: California Department of Public Health, 2007.

Grant Type: 
Disease Team Research I
Grant Number: 
DR1-01471
Investigator: 
ICOC Funds Committed: 
$5 694 308
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Amyotrophic lateral sclerosis (ALS), a lethal disease lacking effective treatments, is characterized by the loss of upper and lower motor neurons. 5-10% of ALS is familial, but the majority of ALS cases are sporadic with unknown causes. The lifetime risk is approximately 1 in 2000. This corresponds to ~30,000 affected individuals in the United States and ~5000 in the Collaborative Funding Partner country. There is currently only one FDA-approved compound, Rilutek, that extends lifespan by a maximum of three months. Although the causes of ALS are unknown and the presentation of the disease highly variable, common to all forms of ALS is the significant loss of motor neurons leading to muscle weakness, paralysis, respiratory failure and ultimately death. It is likely that many pathways are affected in the disease and focusing on a single pathway may have limited impact on survival. In addition, as ALS is diagnosed at a time that significant cell loss has occurred, an attempt to spare further cell loss would have significant impact on survival.
Several findings support the approach of glial (cells surrounding the motor neurons) transplants. Despite the relative selectivity of motor neuron cell death in ALS, published studies demonstrate that glial transporters critical for the appropriate balance of glutamate surrounding the motor neurons are affected both in animal models and in tissue from sporadic and familial ALS. The significance of non-neuronal cells in the disease process has been well characterized using SOD1 mouse models representing many of the key aspects of the human disease. In addition, transplantation using glial-restricted precursors (GRPs) that differentiate into astrocytes in SOD1 mutant rats has been shown to increase survival. Motor neurons have a process, the axon, up to a meter in length which connects the cell body to its target, the muscle. The ability to appropriately rewire and ensure functional connections after motor neuron replacement remains a daunting task with no evidence to date that this will be possible in humans. Therefore, we will focus on the development of an ALS therapy based on hES-derived astrocyte precursor cell transplants to prevent the progression of ALS.
Our proposed project will develop clinical grade stem-cell derived astrocyte precursor transplants for therapy in a prospective Phase I clinical trial. We will: 1) generate astrocyte precursors from three different sources of human embryonic stem cell (hESC) lines; 2) identify the hESC line and glial progenitor combination that has the best characteristics of minimal toxicity, best efficiency in generating astrocytes, and reducing disease phenotypes in vivo in a rat model of ALS; 3) manufacture the appropriate cells in a GMP facility required by the FDA; 4) work with our established clinical team to design a Phase I safety trial; and 5) submit an application for an invesitgational new drug (IND) within the next four years.

Statement of Benefit to California: 

Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's Disease) is a common and devastating adult motor neuron disease that afflicts many Californians. In the absence of a cure, or an effective treatment, the cost of caring for patients with ALS is substantial, and the consequences on friends and family members similarly takes a devastating toll. Our goal is to develop a safe and effective cell transplant therapy for ALS by starting with human embryonic stem cells. If successful, this advance will hopefully diminish the cost of caring for the many Californians with ALS, extend their useful lives, and improve their quality of life. In addition, the development of this type of therapeutic approach in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop these types of therapies in California with consequent economic benefit.

Grant Type: 
Basic Biology I
Grant Number: 
RB1-01358
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 407 076
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Parkinson’s disease (PD) is a neurodegenerative movement disorder that affects 1 in 100 people over the age of 60, one million people in the US and six million worldwide. Patients show a resting tremor, slowness of movement (bradykinesia), postural instability and rigidity. Parkinson's disease results primarily from the loss of neurons deep in the middle part of the brain (the midbrain), in particular neurons that produce dopamine (referred to as “dopaminergic”). There are actually two groups of midbrain dopaminergic (DA) neurons, and only one, those in the substantia nigra (SN) are highly susceptible to degeneration in Parkinson’s patients. There is a relative sparing of the second group and these are called ventral tegmental area (VTA) dopaminergic neurons. These two groups of neurons reside in different regions of the adult ventral midbrain and importantly, they deliver dopamine to their downstream neuronal targets in different ways. SN neurons deliver dopamine in small rapid squirts, like a sprinkler, whereas VTA neurons have a tap that provides a continuous stream of dopamine.

A major therapeutic strategy for Parkinsons’ patients is to produce DA neurons from human embryonic stem cells for use in transplantation therapy. However early human trials were disappointing, since a number of patients with grafts of human fetal neurons developed additional, highly undesirable motor dyskinesias. Why this occurred is not known, but one possibility is that the transplant mixture, which contained both SN and VTA DA neurons, provided too much or unregulated amounts of DA (from the VTA neurons), overloading or confusing the target region in the brain that usually receives dopamine from SN neurons in small, regular quantities. Future human trials will likely utilize DA neurons that have been made from human embryonic stem cells (hES). Since stem cells have the potential to develop into any type of cell in the body, these considerations suggest that we should devise a way to specifically produce SN neurons and not VTA neurons from stem cells for use in transplantation. However, although we can produce dopaminergic neurons from hES cells, to date the scientific community cannot distinguish SN from VTA neurons outside of their normal brain environment and therefore has no ability to produce one selectively and not the other. We do know, however, that these two populations of neurons normally form connections with different regions in the brain, and we propose to use this fact to identify molecular markers that distinguish SN from VTA neurons and to determine optimal conditions for the differentiation of hES to SN DA neurons, at the expense of VTA DA neurons. Our studies have the potential to significantly impact transplantation therapy by enabling the production of SN over VTA neurons from hES cells, and to generate hypotheses about molecules that might be useful for coaxing SN DA neurons to form appropriate connections within the transplanted brain.

Statement of Benefit to California: 

The goal of our work is to further optimize our ability to turn undifferentiated human stem cells into differentiated neurons that the brain can use as replacement for neurons damaged by disease. We focus on Parkinson’s disease, a neurodegenerative disease that afflicts 4-6 million people worldwide in all geographical locations, but which is more common in rural farm communities compared to urban areas, a criteria important for California's large farming population. In Parkinson’s patients, a small, well-defined subset of neurons, the midbrain dopaminergic neurons have died, and one therapeutic strategy is to transplant healthy replacement neurons to the patient. Our work will further our understanding of the biology of these neurons in normal animals. This will allow us to refine the process of turning human embryonic stem cells onto biologically active dopaminergic neurons that can be used in transplantation therapy. Our work will be of benefit to all Parkinson's patients including afflicted Californians. Further, this project will utilize California goods and services whenever possible.

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