Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Grant Type: 
New Cell Lines
Grant Number: 
RL1-00649
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 737 720
Disease Focus: 
Amyotrophic Lateral Sclerosis
Autism
Blood Disorders
Neurological Disorders
Pediatrics
Rett's Syndrome
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 

Human embryonic stem cells (hESC) hold great promise in regenerative medicine and cell replacement therapies because of their unique ability to self-renew and their developmental potential to form all cell lineages in the body. Traditional techniques for generating hESC rely on surplus IVF embryos and are incompatible with the generation of genetically diverse, patient or disease specific stem cells. Recently, it was reported that adult human skin cells could be induced to revert back to earlier stages of development and exhibit properties of authentic hES cells. The exact method for “reprogramming” has not been optimized but currently involves putting multiple genes into skin cells and then exposing the cells to specific chemical environments tailored to hES cell growth. While these cells appear to have similar developmental potential as hES cells, they are not derived from human embryos. To distinguish these reprogrammed cells from the embryonic sourced hES cells, they are termed induced pluripotent stem (iPS) cells. Validating and optimizing the reprogramming method would prove very useful for the generation of individual cell lines from many different patients to study the nature and complexity of disease. In addition, the problems of immune rejection for future therapeutic applications of this work will be greatly relieved by being able to generate reprogrammed cells from individual patients. We have initiated a series of studies to reprogram human and mouse fibroblasts to iPS cells using the genes that have already been suggested. While induction of these genes in various combinations have been reported to reprogram human cells, we plan to optimize conditions for generating iPS cells using methods that can control the level of the “reprogramming” genes, and also can be used to excise the inducing genes once reprogramming is complete; thus avoiding unanticipated effects on the iPS cells. Once we have optimized the methods of inducing human iPS cells from human fibroblasts, we will make iPS cells from patients with 2 different neurological diseases. We will then coax these iPS cells into specific types of neurons using methods pioneered and established in our lab to explore the biological processes that lead to these neurological diseases. Once we generate these cell based models of neural diseases, we can use these cells to screen for drugs that block the progress, or reverse the detrimental effects of neural degeneration. Additionally, we will use the reprogramming technique to study models of human blood and liver disease. In these cases, genetically healthy skin cells will be reprogrammed to iPS cells, followed by introduction of the deficient gene and then coaxed to differentiate into therapeutic cell types to be used in transplantation studies in animal models of these diseases. The ability of the reprogrammed cell types to rescue the disease state will serve as a proof of principle for therapeutic grafting in

Statement of Benefit to California: 

It has been close to a decade since the culture of human embryonic stem (hES) cells was first established. To this day there are still a fairly limited number of stem cell lines that are available for study due in part to historic federal funding restrictions and the challenges associated with deriving hES cell lines from human female egg cells or discarded embryos. In this proposal we aim to advance the revolutionary new reprogramming technique for generating new stem cell lines from adult cells, thus avoiding the technical and ethical challenges associated with the use of human eggs or embryos, and creating the tools and environment to generate the much needed next generation of human stem cell lines. Stem cells offer a great potential to treat a vast array of diseases that affect the citizens of our state. The establishment of these reprogramming techniques will enable the development of cellular models of human disease via the creation of new cell lines with genetic predisposition for specific diseases. Our proposal aims to establish cellular models of two specific neurological diseases, as well as developing methods for studying blood and liver disorders that can be alleviated by stem cell therapies. California has thrived as a state with a diverse population, but the stem cell lines currently available represent a very limited genetic diversity. In order to understand the variation in response to therapeutics, we need to generate cell lines that match the rich genetic diversity of our state. The generation of disease-specific and genetically diverse stem cell lines will represent great potential not only for CA health care patients but also for our state’s pharmaceutical and biotechnology industries in terms of improved models for drug discovery and toxicological testing. California is a strong leader in clinical research developments. To maintain this position we need to be able to create stem cell lines that are specific to individual patients to overcome the challenges of immune rejection and create safe and effective transplantation therapies. Our proposal advances the very technology needed to address these issues. As a further benefit to California stem cell researchers, we will be making available the new stem cell lines created by our work.

Grant Type: 
New Cell Lines
Grant Number: 
RL1-00678
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 369 800
Disease Focus: 
Huntington's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Cell Line Generation: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Closed
Public Abstract: 

Huntington’s disease (HD) is a devastating neurodegenerative disease with a 1/10,000 disease risk that always leads to death. These numbers do not fully reflect the large societal and familial cost of HD, which requires extensive caregiving and has a 50% chance of passing the mutation to the next generation. Current treatments treat some symptoms but do not change the course of disease. Symptoms of the disease include movement abnormalities, inability to perform daily tasks and and psychiatric problems. A loss os specific regions of the brain are observed. The mutation for HD is an expansion of a region of repeated DNA in the HD gene and the longer the repeat, in general the earlier the onset of disease. While the length of this polyglutamine repeat largely determines the age-of-onset, there is variance in onset age that is not accounted for by repeat length but is determined by genetic and environmental factors. In addition, the symptoms can vary significantly among patients in a non-repeat dependent manner. To assist in preventing onset of HD, there is a great need to identify genes that are involved in why one individual with 45 repeats will manifest symptoms at age 40 while another manifests symptoms at age 70. Further, there is a lack of early readouts to determine when to begin HD treatments. Because the disease mutation is known, preimplantation genetic diagnosis (PGD) is possible and mutant Htt embryos are available. Stem cell lines can be derived from PGD embryos with varying repeat lengths and genetic backgrounds to provide new methods to identify genetic modifiers and readouts of disease progression. The development of pluripotent stem cells, termed induced pluripotent stem cells (iPS) cells, derived directly from HD patient fibroblasts, would also provide new methods for these analyses. Chemical compound screens to identify drugs that protect against the effect of mutant Htt protein expression in patient derived hESCs cells would allow evaluation of drug responses in on cells having different genetic backgrounds Ultimately, the iPS cells can provide a way to transplant neurons or neuronal support cells from affected individuals or from unaffected family members having a normal range repeat. Such cells would help reduce immune rejection effects likely to occur with transplantation, however, while patient-derived cells overcome the problems of immune rejection, the mutant protein is still expressed. To overcome this problem we will genetically modify these stem cells to reduce the mutant protein and produce a normal gene. Beyond the immediate application to HD, the development of these models is applicable to a range of neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases.

Statement of Benefit to California: 

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. Further, as the disease progressives, individuals require institutional care facilities 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. Further, hESCs from HD patients will help us understand the factors that dictate the course of the disease and provide a resource for drug development. For the potential of hESCs in HD to be realized, a very forward approach such as that proposed will allow experienced investigators in HD and stem cell research and clinical trials to come together and create cell lines to more fully mimic the diseases neurons and allow for future treatment options. The federal constraints on hESCs create a critical need for the development of treatments using hESCs supported and staffed with non-federal funds. We have proposed goals and strategies for generating new stem cells derived from patient preimplantation diagnosis embryos and patient fibroblasts. We have put in place critical milestones to be met We will build on existing regional stem cell resources . Anticipated benefits to the citizens of California include: 1) development of new stem cell lines that will allow us to more closely model the disease for mechanistic studies and drug screening, 2) improved methods for following the course of the disease in order to treat HD as early as possible before symptoms are manifest; 3) development of new cell-based treatments for Huntington's disease with application to other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases that affect thousands of individuals in California; 4) development of intellectual property that could form the basis of new biotech startup companies; and 5) improved methods for drug development that could directly benefit citizens of the state.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00345
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$2 396 932
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Cord Injury
Spinal Muscular Atrophy
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Cervical spinal cord injuries result in a loss of upper limb function because the cells within the spinal cord that control upper limb muscles are destroyed. The goal of this research program is to create a renewable human source of these cells, to restore upper limb function in both acute and chronic spinal cord injuries. There are two primary challenges to the realization of this goal: 1) a source of these human cells in high purity, and 2) functional integration of these cells in the body after transplantation.

Human embryonic stem cells (hESCs) can form any cell in the body, and can reproduce themselves almost indefinitely to generate large quantities of human tissue. One of the greatest challenges of hESC research is to find ways to restrict hESCs such that they generate large amounts on only one cell type in high purity such that they could be used to replace lost cells in disease or trauma. Our laboratory was the first laboratory in the world to develop a method to restrict hESCs such that they generate large amounts of only one cell type in high purity. That cell type is called an oligodendrocyte, which insulates connections in the spinal cord to allow them to conduct electricity. Transplantation of these cells was useful for treating spinal cord injuries in rats if the treatment was given one week after the injury. That treatment is being developed for use in humans.

Recent studies in our laboratory indicate that we have succeeded in restricting hESCs to generate large quantities of a different cell type in the spinal cord, that which controls upper limb muscles. We have generated large quantities of these human cells, grown them with human muscle, and demonstrated that they connect and control the human muscle. The cells also express markers that are appropriate for this cell type.

Here we propose to generate these cells in high purity from hESCs and genetically modify them so that they can be induced to grow over inhibitory environments that exist in the injured spinal cord. We will then determine whether these human cells have the ability to regenerate the injured tissue in the spinal cord, and restore lost function. All of our studies will be conducted in an FDA-compliant manner, which will speed the translation of our results to humans if we are successful. The studies outlined in this proposal represent a novel approach to treating spinal cord injury, which might work for both acute and chronic injuries.

Statement of Benefit to California: 

This research plan will position California for international competitiveness in this emerging area of biotechnology, as our research strategy addresses critical scientific problems limiting the development of this sector in California and abroad. High purity cultures of hESC-derivatives enable transplantation approaches to disease, drug discovery, and predictive toxicology. This research plan will lead to the development and thorough characterization of a renewable source of human motor neurons that enables these 3 strategies as they pertain to acute spinal cord injury, chronic spinal cord injury, amyotrophic lateral sclerosis, polio, and spinal muscular atrophy. Clinically relevant scientific advance leads to the development of biotechnology companies, creating jobs and taxation. The treatment and care of individuals with disease or trauma-induced disorders of the central nervous system represents a significant economic burden to the State of California. If successful, our research plan will form the basis of a clinical strategy to improve the function and quality of life of spinal cord injured individuals, which may lessen the cost that the State bears in terms of patient care.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00125
Investigator: 
ICOC Funds Committed: 
$3 035 996
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Stroke
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Understanding differentiation of human embryonic stem cells (hESCs) provides insight into early human development and will help directing hESC differentiation for future cell-based therapies of Parkinson’s disease, stroke and other neurodegenerative conditions.

The PI’s laboratory was the first to clone and characterize the transcription factor MEF2C, a protein that can direct the orchestra of genes to produce a particular type of cell, in this case a nerve cell (or neuron). We have demonstrated that MEF2C directs the differentiation of mouse ES cells into neurons and suppresses glial fate. MEF2C also helps keep new nerve cells alive, which is very helpful for their successful transplantation. However, little is known about the role of MEF2C in human neurogenesis, that is, its ability to direct hESC differentiation into neuronal lineages such as dopaminergic neurons to treat Parkinson’s disease and its therapeutic potential to promote the generation of nerve cells in stem cell transplantation experiments. The goal of this application is to fill these gaps.

The co-PI’s laboratory has recently developed a unique procedure for the efficient differentiation of hESCs into a uniform population of neural precursor cells (NPCs), which are progenitor cells that develop from embryonic stem cells and can form different kinds of mature cells in the nervous system. Here, we will investigate if MEF2C can instruct hESC-derived NPCs to differentiate into nerve cells, including dopaminergic nerve cells for Parkinson’s disease or other types of neurons that are lost after a stroke. Moreover, we will transplant hESC-NPCs engineered with MEF2C to try to treat animal models of stroke and Parkinson’s disease. We will characterize known and novel MEF2C target genes to identify critical components in the MEF2C transcriptional network in the clinically relevant cell population of hESC-derived neural precursor cells (hESC-NPCs).

Specifically we will: 1) determine the function of MEF2C during in vitro neurogenesis (generation of new nerve cells) from hESC-NPCs; 2) investigate the therapeutic potential of MEF2C engineered hESC-NPCs in Parkinson’s and stroke models; 3) determine the MEF2C DNA (gene) binding sites and perform a “network” analysis of MEF2C target genes in order to understand how MEF2C works in driving the formation of new nerve cells from hESCs.

Statement of Benefit to California: 

Efficient and controlled neuronal differentiation from human embryonic stem cells (hESCs) is mandatory for developing future clinical cell-based therapies. Strategies to direct differentiation towards neuronal vs. glial fate are critical for the development of a uniform population of desired neuronal specificities (e.g., dopaminergic neurons for Parkinson’s disease (PD)). Our laboratory was the first to clone and characterize the transcription factor MEF2C, the major isoform of MEF2 found in the developing brain. Based on our encouraging preliminary results that were obtained with mouse (m)ESC-derived and human fetal brain-derived neural precursors, we propose to investigate if MEF2C enhances neurogenesis from hESCs. In addition to neurogenic activity, we have shown that MEF2C exhibits an anti-apoptotic (that is, anti-death) effect and therefore increases cell survival. This dual function of MEF2C is extremely valuable for the purpose of transplantation of MEF2C-engineererd neural precursors. Additionally, we found MEF2 binding sites in the Nurr1 promoter region, which in the proper cell context, should enhance dopaminergic (DA) neuronal differentiation. We hypothesize that hESC-derived neural precursors engineered with MEF2C will selectively differentiate into neurons, which will be resistant to apoptotic death and not form tumors such as teratomas.

We believe that our proposed research will lead us to a better understanding of the role of MEF2C in hESC differentiation to neurons. These results will lead to novel and effective means to direct hESCs to become neurons and to resist cell death. This information will ultimately lead to novel, stem cell-based therapies to treat stroke and neurodegenerative diseases such as Parkinson’s.

We also believe that an effective, straightforward, and broadly understandable way to describe the benefits to the citizens of the State of California that will flow from the stem cell research we propose to conduct is to couch the work in the familiar, everyday business concept of “Return on Investment.” The novel therapies and reconstructions that will be developed and accomplished as a result of our research program and the many related programs that will follow will provide direct benefits to the health of California citizens. In addition, this program and its many complementary programs will generate potentially very large, tangible monetary benefits to the citizens of California. These financial benefits will derive directly from two sources. The first source will be the sale and licensing of the intellectual property rights that will accrue to the state and its citizens from this and the many other stem cell research programs that will be financed by CIRM. The second source will be the many different kinds of tax revenues that will be generated from the increased bio-science and bio-manufacturing businesses that will be attracted to California by the success of CIRM.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00135
Investigator: 
ICOC Funds Committed: 
$2 566 701
Disease Focus: 
Immune Disease
Multiple Sclerosis
Neurological Disorders
Stroke
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Strokes that affect the nerves cells, i.e., “gray matter”, consistently receive the most attention. However, the kind of strokes that affecting the “wiring” of the brain, i.e., “white matter”, cause nearly as much disability. The most severe disability is caused when the stroke is in the wiring (axons) that connect the brain and spinal cord; as many as 150,000 patients are disabled per year in the US from this type of stroke. Although oligodendrocytes (“oligos”) are the white matter cells that produce the lipid rich axonal insulator called myelin) are preferentially damaged during these events, stem cell-derived oligos have not been tested for their efficacy in preclinical (animal) trials. These same white matter tracts (located underneath the gray matter, called subcortical) are also the primary sites of injury in MS, where multifocal inflammatory attack is responsible for stripping the insulating myelin sheaths from axons resulting in axonal dysfunction and degeneration. Attempts to treat MS-like lesions in animals using undifferentiated stem cell transplants are promising, but most evidence suggests that these approaches work by changing the inflammation response (immunomodulation) rather than myelin regeneration. While immunomodulation is unlikely to be sufficient to treat the disease completely, MS may not be amenable to localized oligo transplantation since it is such a multifocal process. This has led to new emphasis on approaches designed to maximize the response of endogenous oligo precursors that may be able to regenerate myelin if stimulated. We hypothesize that by exploiting novel features of oligo differentiation in vitro (that we have discovered and that are described in our preliminary data) that we will be able to improve our ability to generate oligo lineage cells from human embryonic stem cells and neural stem cells for transplantation, and also to develop approaches to maximize oligo development from endogenous precursors at the site of injury in the brain. This proposal will build on our recent successes in driving oligo precursor production from multipotential mouse neural stem cells by expressing regulatory transcription factors, and apply this approach to human embryonic and neural stem cells to produce cells that will be tested for their ability to ameliorate brain damage in rodent models of human stroke. Furthermore, we hope to develop approaches that may facilitate endogenous recruitment of oligo precursors to produce mature oligos, which may prove a viable regenerative approach to treat a variety of white matter diseases including MS and stroke.

Statement of Benefit to California: 

Diseases associated with disruption of oligodendrocyte function and integrity (such as subcortical ischemic stroke and multiple sclerosis) are major causes of morbidity and mortality. Stroke is the third leading cause of death and the leading cause of permanent disability in the United States, costing over $50 billion dollars annually, as approximately 150,000 chronic stroke patients survive the acute event and are left with permanent, severe motor and/or sensory deficits. While much less common, multiple sclerosis (MS) is the primary non-traumatic cause of neurologic disability in young adults. Most patients are diagnosed in their 20s-40s and live for many decades after diagnosis with increasing needs for expensive services, medications and ultimately long-term care. Existing strategies for stem cell based therapies include both strategies to replace lost cells and to augment regeneration after injury, but most of these efforts have emphasized the role of undifferentiated stem cells in treatment despite the realization that the main nexus of injury in both diseases is frequently a differentiated cell type – the oligodendrocyte. This project will use new insights into the development of oligodendrocytes from the laboratories of the investigators to find ways to improve production of oligodendrocytes from human ES cells and human neural stem cells, test whether these cells can improve the clinical outcome in rodent models of stroke and MS after transplantation and search for new molecular treatments that would augment the regeneration of oligodendrocytes from resident brain stem cells after injury. This is the first step to translating the basic fundamental understanding of oligodendrocyte development into viable therapies for important human diseases that are major burdens on the citizens of California.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00111
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$2 516 613
Disease Focus: 
Neurological Disorders
Stroke
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 

Human embryonic stem cells (hESCs) have the potential to become all sorts of cells in human body including nerve cells. Moreover, hESCs can be expanded in culture plates into a large quantity, thus serving as an ideal source for cell transplantation in clinical use. However, the existing hESC lines are not fully characterized in terms of their potential to become specific cell types such as nerve cells. It is also unclear if the nerve cells that are derived from hESCs are totally normal when tested in cell transplantation experiments. One of the goals for our proposal is to compare the quality and the potential of eight lines of hESCs in their capacity to become nerve cells. To measure if the nerve cells that are derived from hESCs are normal when compared to the nerve cells in normal human beings, we will examine the levels of gene expression and the mechanisms that control gene expression in hESC-derived nerve cells. Specifically, we will examine the pattern of DNA modification, namely DNA methylation, in the DNA of nerve cells. This DNA modification is involved in the inhibition of gene expression. It is known that if DNA methylation pattern is abnormal, it can lead to human diseases including cancer and mental retardation disorders. We will use a DNA microarray technology to identify DNA methylation pattern in the critical regions where gene expression is controlled. Our recent results suggest that increased DNA methylation is observed in hESC-derived nerve cells. In this proposal, we will also test if we can balance the level of DNA methylation through pharmacological treatment of enzymes that are responsible for DNA methylation. Finally, we will test if hESC-derived nerve cells can repair the brain after injury . A mouse stroke model will be used for testing the mechanisms stem cell-mediated repair and recovery in the injured brain and for selecting the best nerve cells for cell transplantation. Our study will pave the way for the future use of hESC-derived nerve cells in clinical treatment of nerve injury and neurodegenerative diseases such as stroke and Parkinson’s disease.

Statement of Benefit to California: 

Neurodegenerative diseases such as stroke are the leading cause of adult disability. Stroke produces an area of damage in the brain which frequently causes the loss of crucial brain functions such as sensory and movement control, language skills, and cognition capability. Stem cell transplantation has emerged as a method that may improve recovery in these brain areas. Studies of stem cell transplantation after stroke have been limited because many of the transplanted cells do not survive, the appropriate regions for transplantation have not been identified, and the mechanisms by which transplanted stem cells improve recovery have not been determined. Also, there have been no studies of human embryonic stem cell transplantation after stroke. For the use of stem cell therapy in stroke patients, human embryonic stem cell lines have to be grown and tested for their efficacy in repairing the brain after stroke. We have recently found that the process of growing human embryonic stem cells in culture introduces genetic modifications in some of these cell lines that may decrease survival of the cells in the brain and impair their ability to repair the injured brain. The experiments in this grant will determine which human embryonic stem cell lines do not undergo this negative genetic modification. The optimum human embryonic stem cell lines will then be systematically tested for the location in the stroke brain that produces survival and integration, and the mechanisms of repair that these cells mediate in the brain after stroke. These studies will specifically test the role of human embryonic stem cells in improving sensory and movement functions after stroke. In summary, these studies will establish protocols for the proper growth of human embryonic stem cell lines, the lines that are most effective for repairing the brain after stroke, and the principles behind how human embryonic stem cells repair the brain. These results are applicable to other kinds of neurodegenerative conditions, such as Parkinsons, Alzheimer’s and Huntington’s diseases, and to the growth and culture of human embryonic stem cells in general for repair of disease of other human tissues.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00131
Investigator: 
ICOC Funds Committed: 
$2 445 716
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

schemia-induced paraplegia often combined with a qualitatively defined increase in muscle tone (i.e. spasticity and rigidity) is a serious complication associated with a temporary aortic cross-clamping ( a surgical procedure to repair an aortic aneurysm). In addition to spinal ischemic injury-induced spasticity and rigidity a significant population of patients with traumatic spinal injury develop a comparable qualitative deficit i.e. debilitating muscle spasticity. At present there are no effective treatment which would lead to a permanent amelioration of spasticity and rigidity and corresponding improvement in ambulatory function. In recent studies, by using rat model of spinal ischemic injury we have demonstrated that spinal transplantation of rat or human neurons leads to a clinically relevant improvement in motor function and correlates with a long term survival and maturation of grafted cells. More recently we have demonstrated a comparable maturation of human spinal precursors grafted spinally in immunosupressed minipig. In the proposed set of experiments we wish to characterize a therapeutical potential of human blastocyst-derived neuronal precursors when grafted into previously ischemia- injured rat or minipig spinal cord. Defining the potency of spinally grafted hESC-derived neuronal precursors in two in vivo models of spinal ischemic injury serves to delineate the differences and/or uniformity in the cell maturation when cells are transplanted in 2 different animals species and can provide an important data set for future implications of such a therapies in human patients.

Statement of Benefit to California: 

Traumatic or ischemic spinal cord injury affect a significant number of people and in majority of cases can lead to a variable degree of motor dysfunction (such as paraparesis or paraplegia) and often combined with increased muscle tone (i.e. spasticity and rigidity). In contrast to other organ systems the central nervous system and spinal cord in particular has minimal or no neuron-regenerative capacity and therefore if a significant population of spinal cord neurons or fibers is lost the resulting deficit is permanent and irreversible. At present there is no effective therapy which would lead to a clinically relevant neurological improvement in patients with ischemia or trauma-induced paraplegia. Initial experimental data using paraplegic rats show that spinal grafting of rat or human neuronal precursors can provide a significant amelioration of spasticity and lead to improved ambulatory function. In the proposed set of experiments we wish to characterize a therapeutical potential of human blastocyst-derived neuronal precursors when grafted into previously ischemia- injured rat or minipig spinal cord. If proven effective such a treatment can potentially be used in patients with spinal ischemic paraplegia or in patients with other spinal injury-related dysfunction associated with a region-specific neuronal loss.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00115
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$2 879 210
Disease Focus: 
Amyotrophic Lateral Sclerosis
Genetic Disorder
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Human embryonic stem cells (hESCs) are pluripotent entities, capable of generating a whole-body spectrum of distinct cell types. We have developmental procedures for inducing hESCs to develop into pure populations of human neural stem cells (hNS), a step required for generating authentic mature human neurons. Several protocols have currently been developed to differentiate hESCs to what appear to be differentiated dopaminergic neurons (important in Parkinson’s disease (PD) and cholinergic motor neurons (important in Amyolateral Sclerosis (ALS) in culture dishes. We have developed methods to stably insert new genes in hESC and we have demonstrated that these transgenic cells can become mature neurons in culture dishes. We plan to over express alpha synuclein and other genes associated with PD and superoxide dismutase (a gene mutated in ALS) into hESCs and then differentiate these cells to neurons, and more specifically to dopaminergic neurons and cholinergic neurons using existing protocols. These transgenic cells can be used not only for the discovery of cellular and molecular causes for dopaminergic or cholinergic cell damage and death in these devastating diseases, but also can be used as assays to screen chemical libraries to find novels drugs that may protect against the degenerative process. Until recently the investigation of the differentiation of these human cells has only been observed in culture dishes or during tumor formation. Our recent results show that hESC implanted in the brains of mice can survive and become active functional human neurons that successfully integrate into the adult mouse forebrain. This method of transplantation to generate models of human disease will permit the study of human neural development in a living environment, paving the way for the generation of new models of human neurodegenerative and psychiatric diseases. It also has the potential to speed up the screening process for therapeutic drugs.

Statement of Benefit to California: 

We plan to develop procedures to induce human ES cells into mature functioning neurons that carry genes that cause the debilitating human neurological diseases, Parkinson’s disease and Amyolateral Sclerosis (ALS). We will use the cells to reveal the genes and molecular pathways inside the cells that are responsible for how the mutant genes cause damage to specific types of brain cells. We also will make the cells available to other researchers as well as biotech companies so that other investigators can use these cells to screen small molecule and chemical libraries to discover new drugs that can interfere with the pathology caused by these mutant cells that mimic human disease, in hopes of accelerating the pace of discovery.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00346
Investigator: 
ICOC Funds Committed: 
$2 507 223
Disease Focus: 
Epilepsy
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Parkinson’s disease (PD) is caused by degeneration of a specific population of dopamine-producing nerve cells in the brain and is chronic, progressive, and incurable. Loss of dopamine-containing cells results in profound physiological disturbances producing tremors, rigidity, and severe deterioration of gate and balance. In the United States, approximately 1.5 million people suffer with PD and it is estimated that 60,000 new cases are diagnosed each year. Drugs can modify some of the disease symptoms, but many patients develop disabling drug-induced movements that are unresponsive to medication. Deep brain stimulation can alleviate motor symptoms in some patients but is not a cure. We plan an entirely novel approach to treat PD. We propose to utilize a specific class of inhibitory nerve cells found in the embryonic brain, known as MGE cells, as donor transplant cells to inhibit those brain regions whose activity is abnormally increased in PD. In preliminary studies we have demonstrated that this approach can relieve symptoms in an animal model of PD. To turn this approach into a patient therapy, we will need to develop methods to obtain large numbers of human cells suitable for transplantation. This proposal seeks to address this problem by producing unlimited numbers of exactly the right type of MGE nerve cell using human embryonic stem cells.

The inhibitory nerve cells we seek to produce will reduce brain activity in target regions. They may therefore be used to treat other conditions characterized by excessive brain activity, such as epilepsy. Epilepsy can be a life threatening and disabling condition. Nearly two million Americans suffer with some form of epilepsy. Unfortunately, modulation of brain excitability using antiepileptic drugs can have serious side-effects, especially in the developing brain, and many patients can only be improved by surgically removing areas of the brain containing the seizure focus. Using MGE cells made from human embryonic stem cell lines, we hope to develop a novel epilepsy treatment that could replace the need for surgery or possibly even drug therapy.

We propose an integrated approach that combines the complementary expertise of four UCSF laboratories to achieve our goals. We have already determined that mouse MGE cells can improve the symptoms of PD and epilepsy when grafted into animal models. We now need to develop methods to obtain large numbers of human cells suitable for grafting. We need to ensure that when delivered, the cells will migrate and integrate in the target brain regions, and we need to evaluate therapeutic efficacy in animal models of Parkinson’s disease and epilepsy. This proposal addresses these goals. If successful, this accomplishment will set the stage for studies in primates and hasten the day when MGE cells may be used as patient therapy for a wide variety of debilitating neurological disorders.

Statement of Benefit to California: 

This collaborative proposal promises to accelerate progress toward a novel cell based therapeutic agent with potentially widespread benefit for the treatment of a variety of grave neurological disorders. The promise of this work to eventually help our patients is our primary motivation. Additionally, our studies, if successful, could form the basis of a new stem cell technology to produce unlimited numbers of cellular therapeutic products of uniform quality and effectiveness. The production of neurons from stable nerve cell lines derived from human embryonic stem cells is a much-needed biotechnology and a central challenge in embryonic stem (ES) cell biology. Current methods are inefficient at producing neurons that can effectively migrate and integrate into adult brain, and available cell lines generally lack the ability to differentiate into specific neuronal subtypes. Moreover, while many cells resist neuronal differentiation others often take on a glial cell fate. Identification of key factors driving ES cells into a specific neuronal lineage is the primary focus of the current proposal, and if achieved, will generate valuable intellectual property. As such, it may attract biotechnology interest and promote local business growth and development. Moreover, the inhibitory nerve cell type that is the goal of this proposal would be a potentially valuable therapeutic agent. This achievement could attract additional funding from state or industry to begin primate studies and ultimately convert any success into a safe and effective product for the treatment of patients. To produce and distribute stable medicinal-grade cells of a purity and consistency appropriate for therapeutic use will require partnering with industry. Industry participation would be expected to provide economic benefits in terms of job creation and tax revenues. Hopefully, there may ultimately be health benefits for the citizens of California who are suffering from neurological disease.

Grant Type: 
Comprehensive Grant
Grant Number: 
RC1-00116
Investigator: 
ICOC Funds Committed: 
$2 512 664
Disease Focus: 
Aging
Alzheimer's Disease
Genetic Disorder
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Cell Line Generation: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Closed
Public Abstract: 

Alzheimer’s Disease (AD) is a progressive incurable disease that robs people of their memory and ability to think and reason. It is emotionally, and sometimes financially devastating to families that must cope when a parent or spouse develops AD. Unfortunately, however, we currently lack an understanding of Alzheimer’s Disease (AD) that is sufficient to drive the development of a broad range of therapeutic strategies. Compared to diseases such as cancer or heart disease, which are treated with a variety of therapies, AD lacks even one major effective therapeutic approach. A key problem is that there is a paucity of predictive therapeutic hypotheses driving the development of new therapies. Thus, there is tremendous need to better understand the cellular basis of AD so that effective drug and other therapies can be developed. Several key clues come from rare familial forms of AD (FAD), which identify genes that can cause disease when mutant and which have led to the leading hypotheses for AD development. Recent work on Drosophila and mouse models of Alzheimer’s Disease (AD) has led to a new suggestion that early defects in the physical transport system that is responsible for long-distance movements of vital supplies and information in neurons causes neuronal dysfunction. The type of neuronal failure caused by failures of the transport systems is predicted to initiate an autocatalytic spiral of biochemical events terminating in the classic pathologies, i.e., plaques and tangles, and the cognitive losses characteristic of AD. The problem, however, is how to test this new model and the prevailing “amyloid cascade” model, or indeed any model of human disease developed from studies in animal models, in humans. It is well known that mouse models of AD do not fully recapitulate the human disease, perhaps in part because of human-specific differences that alter the details of the biochemistry and cell biology of human neurons. One powerful approach to this problem is to use human embryonic stem cells to generate human neuronal models of hereditary AD to test rigorously the various hypotheses. These cellular models will also become crucial reagents for finding and testing new drugs for the treatment of AD.

Statement of Benefit to California: 

Alzheimer’s Disease (AD) is emotionally devastating to the families it afflicts as well as causing substantial financial burdens to individuals, to families, and to society as a whole. In California, the burden of Alzheimer’s Disease is substantial, so that progress in the development of therapeutics would make a significant financial impact in the state. Although there are not a great deal of data about the burden of AD in California specifically, the population of California is 12% of that of the United States and most information suggests that California has a “typical” American burden of this disease. For example, information from the Alzheimer’s Association (http://www.alz.org/alzheimers_disease_alzheimer_statistics.asp) reveals: 1) An estimated 4.5 million Americans have Alzheimer’s disease, which has more than doubled since 1980. This creates an estimated nationwide financial burden of direct and indirect annual costs of caring for individuals with AD of at least $100 billion. Thus, a reasonable estimate is that California has more than half a million AD patients with an estimated cost to California of $12 billion per year! 2) One in 10 individuals over 65 and nearly half of those over 85 are affected, which means that as our population ages, we will be facing a tidal wave of AD. Current estimates are that with current rates of growth that the AD patient population will double or triple in the next 4 decades. 3) The potential benefit of research such as that proposed in this grant application is that finding a treatment that could delay onset by five years could reduce the number of individuals with Alzheimer’s disease by nearly 50 percent after 50 years. This would be significant since a person with Alzheimer’s disease will live an average of eight years and as many as 20 years or more from the onset of symptoms. Finding better treatments will thus have significant financial benefits to California. 4) After diagnosis, people with Alzheimer’s disease survive about half as long as those of similar age without AD or other dementia. 5) In terms of financial impact on California families, the statistics (http://www.alz.org/alzheimers_disease_alzheimer_statistics.asp) are that more than 7 out of 10 people with Alzheimer’s disease live at home. Almost 75 percent of their care is provided by family and friends. The remainder is “paid’ care costing an average of $19,000 per year. Families pay almost all of that out of pocket. The average cost for nursing home care is $42,000 per year but can exceed $70,000 per year in some areas of the country. The average lifetime cost of care for an individual with Alzheimer’s is $174,000. Thus, any progress in developing better therapy for AD will have a substantial positive impact to California.

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