Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
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.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00409
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$425 594
Disease Focus: 
Immune Disease
Multiple Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Multiple sclerosis (MS) is the most common neurologic disease affecting young adults under the age of 40 with the majority of MS patients diagnosed in the second or third decade of life. MS is characterized by the gradual loss of the myelin sheath that surrounds and insulates axons that allow for the conduction of nerve impulses – a process known as demyelination. For unknown reasons, the ability to remyelinate axons is impaired in MS patients making recovery of motor skills difficult. Therefore, developing novel and effective approaches to remyelinate axons in MS patients would dramatically improve the quality of life of many MS patients. The experiments described in this research proposal utilize a well-accepted model of MS to further characterize the potential clinical applicability of human embryonic stem cells (hESCs) to remyelinate axons. Such knowledge is crucial in order to increase our understanding of stem cells with regards to treatment of numerous human diseases including MS.

Statement of Benefit to California: 

California is the most populated state in the USA. As such, the costs of medical care for the treatment of patients with chronic diseases such as multiple sclerosis (MS) represents a significant and growing problem. MS is the most common neurologic disease affecting young adults under the age of 40 with the majority of MS patients diagnosed in the second or third decade of life. Given the population of California, there are many MS patients living in the state and the numbers will undoubtedly grow. It is unusual for MS patients to die from the disease and many will live normal life spans but will develop an increasing array of medical problems stemming from the progression of neurologic damage associated with MS. MS is characterized by the gradual loss of the myelin sheath that surrounds and insulates axons that allow for the conduction of nerve impulses – a process known as demyelination. For unknown reasons, the ability to remyelinate axons is impaired in MS patients making recovery of motor skills difficult. Therefore, developing novel and effective approaches to remyelinate axons in MS patients would dramatically alleviate some of the burden placed on the medical community by improving the quality of life of many MS patients. The experiments described in this research proposal utilize a well-accepted model of MS to further characterize the potential clinical applicability of human embryonic stem cells (hESCs) to remyelinate axons. Such knowledge is crucial in order to increase our understanding of stem cells with regards to treatment of human diseases with the ultimate goal of limiting patient suffering and reducing medical costs.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00333
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$642 361
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

The advent of human embryonic stem cells (hESCs) has offered enormous potential for regenerative medicine and for basic understanding of human biology. On the one hand, hESCs can be turned into many different cell types in culture dish, and specific cell types derived from hESCs offer an almost infinite source for cellular replacement therapies. This is the primary reason for which hESCs have received much attention from the general public. On the other hand, scientists can study the properties of hESCs and their derivatives, and determine the effect of genes and molecules on such properties either in culture dish or with transplantation studies in live animals. This second aspect of hESC research would not only significantly enhance our understanding of the function of human genes, but will greatly augment our ability to apply hESCs in transplantation therapies and regenerative medicine. To attain the full potential of hESCs, genetic manipulation of hESCs is essential. In this proposal, we will establish the methods to genetically manipulate an increasingly used, non-federally approved hESC line, the HUES-9, and assess the feasibility to use genetically modified HUES-9 cells in cell transplantation studies to assess the integration of hESCs into the mouse central nervous system. We propose to achieve both homologous recombination (i.e. gene targeting) and transgene expression (with bacterial artificial chromosome), which have complementary utilities in assaying gene function in addition to the opportunity to label hESCs or their derivatives with fluorescent markers. Specifically, with genetic engineering of hESCs we will be able to 1) label hESCs and specific cell types derived from hESCs so that they can be readily followed in culture dish and in animals that have received cellular transplants; 2) disturb an endogenous gene or add more copies of a gene so that the effect of a gene of interest can be assessed (for this purpose, a gene involved in the development of a major motor tract, the corticospinal tract, will be studied). We will then transplant genetically engineered hESCs and their derivatives into the embryonic and adult mouse CNS to assess how well these cells integrate into the mouse CNS, and whether such transplanted animals can serve as valid models to study the effect of genes on hESC function in live animals. In transplantation studies involving adult mouse recipients, injured mouse CNS will be used in addition to intact CNS in order to evaluate the potential of hESCs to integrate into injured CNS, which has direct implications on the therapeutic potential of these cells. In summary, our proposal will establish the methods and tools to genetically manipulate HUES-9 cells, explore a paradigm to study human genes and cells in a context of neural development and cellular therapies, and will pave the way for future studies of genes and pathways in basic biology and regenerative medicine with hESCs.

Statement of Benefit to California: 

The disability, loss of earning power, and loss of personal freedom associated with spinal cord injury is devastating for the injured individual, and creates a financial burden of an estimated $400,000,000 annually for the state of California. Research is the only solution as currently there are no cures for spinal cord injury. My lab studies the underlying mechanisms for axon regeneration failure after spinal cord injury using mouse genetics and animal models of spinal cord injury. The current proposal aims to genetically manipulate human embryonic stem cells, study their potential to integrate into immature and mature central nervous system and analyze the effect of genes on such integration. Achieving genetic modification of hESCs will expedite studies with hESCs to cure a variety of human diseases and injuries including spinal cord injury. Our studies will pave the way for discoveries that might lead to novel treatment strategies for spinal cord injury and other neurological conditions. Effective treatments promoting functional repair will significantly increase personal independence for people with spinal cord injury, increase earning capacity and financial independence, and thus decrease the financial burden for the State of California. More importantly, treatments that enhance functional recovery will improve the quality of life for those who are directly or indirectly affected by spinal cord injuries.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00331
Investigator: 
ICOC Funds Committed: 
$758 999
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder caused by damage of dopamine-producing nerve cells (DA neuron) in patient brain. The main symptoms of PD are age-dependent tremors (shakiness). There is no cure for PD despite administration of levodopa can help to control symptoms.

Most of PD cases are sporadic in the general population. However, about 10-15% of PD cases show familial history. Genetic studies of familial cases resulted in identification of PD-linked gene changes, namely mutations, in six different genes, including α-synuclein, LRRK2, uchL1, parkin, PINK1, and DJ-1. Nevertheless, it is not known how abnormality in these genes cause PD. Our long-term research goal is to understand PD pathogenesis at cellular and molecular levels via studying functions of these PD-linked genes and dysfunction of their disease-associated genetic variants.

A proper experimental model plays critical roles in defining pathogenic mechanisms of diseases and for developing therapy. A number of cellular and animal models have been developed for PD research. Nevertheless, a model closely resembling generation processes of human DA nerve cells is not available because human neurons are unable to continuously propagate in culture. Nevertheless, human embryonic stem cells (hESCs) provide an opportunity to fulfill the task. hESCs can grow and be programmed to generate DA nerve cells. In this study, we propose to create a PD model using hESCs. The strategy is to express PD pathogenic mutants of α-synuclein or LRRK2 genes in hESCs. Mutations in α-synuclein or LRRK2 genes cause both familial and sporadic PD. α-Synuclein is a major component of Lewy body, aggregates found in the PD brain. The model will allow us to determine molecular action of PD pathogenic α-synuclein and LRRK2 mutants during generation of human DA neuron and interactions of PD related genes and environmental toxins in DA neurons derived from hESCs.

Our working hypothesis is that PD associated genes function in hESCs-derived DA neurons as in human brain DA neurons. Pathogenic mutations in combination with environmental factors (i.e. aging and oxidative stress) impair hESCs-derived DA function resulting in eventual selective neuronal death. In this study, we will firstly generate PD cellular models via expressing two PD-pathogenic genes, α-synuclein and LRRK2 in hESCs. We will next determine effects of α-synuclein and LRRK2 on hESCs and neurons derived from these cells. Finally, we will determine whether PD-causing toxins (i.e. MPP+, paraquat, and rotenone) selectively target to DA neurons derived from hESCs. Successful completion of this study will allow us to study the pathological mechanism of PD and to design strategies to treat the disease.

Statement of Benefit to California: 

Parkinson’s disease (PD) is the second leading neurodegenerative disease with no cure currently available. Compared to other states, California is among one of the states with the highest incidence of this particular disease. First, California growers use approximately 250 million pounds of pesticides annually, about a quarter of all pesticides used in the US (Cal Pesticide use reporting system). A commonly used herbicide, paraquat, has been shown to induce parkinsonism in both animals and human. Other pesticides are also proposed as potential causative agents for PD. Studies have shown increased PD-caused mortality is agricultural pesticide-use counties in comparison to those non-use counties in California. Second, California has the largest Hispanic population. Studies suggest that incidence of PD is the highest among Hispanics (Van Den Eeden et al, American Journal of Epidemiology, Vol. 157, pages 1015-1022, 2003). Thus, finding effective treatments of PD will significantly benefit citizen in California.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00288
Investigator: 
ICOC Funds Committed: 
$807 749
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Muscular Atrophy
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

More than 600 disorders afflict the nervous system. Common disorders such as stroke, epilepsy, Parkinson’s disease and autism are well-known. Many other neurological disorders are rare, known only to the patients and families affected, their doctors and scientists who look to rare disorders for clues to a general understanding of the brain as well as for treatments for specific diseases. Neurological disorders strike an estimated 50 million Americans each year, exacting an incalculable personal toll and an annual economic cost of hundreds of billions of dollars in medical expenses and lost productivity. There are many potential applications for using human embryonic stem (hES) cells to treat neurological diseases and injuries; however, a critical barrier to progress in the field is the ability to efficiently and reliably control neuronal differentiation from these cells. The main goal of this proposal is to define the gene regulatory mechanisms that control the acquisition of neuronal fate from hES cells. Longer term, we plan to produce small compounds (drugs) that greatly facilitate this process. Drugs that enhance neuron formation are likely to improve scientists’ ability to manipulate hES cells and create in vitro models for studying neurological diseases. Most importantly, drugs of this type may stimulate endogenous stem cells within adults to self-repair damaged areas of the brain. Because so little is known about how hES cells differentiate into neurons at the molecular level, this grant will focus on understanding how a single neuronal subtype is generated – motor neurons. Why motor neurons? Motor neuron diseases are a group of progressive neurological disorders that destroy cells that control essential muscle activity such as speaking, walking, breathing and swallowing. Eventually, the ability to control voluntary movement can be lost. Motor neuron diseases may be inherited or acquired, and they occur in all age groups. In adults, symptoms often appear after age 40. In children, particularly in inherited or familial forms of the disease, symptoms can be present at birth or appear before the child learns to walk. Is there a treatment? There is no cure or standard treatment for motor neuron diseases. Prognosis varies depending on the type of motor neuron disease and the age of onset; however, many types such as ALS and some forms of spinal muscular atrophy are typically fatal.The experiments in this proposal seek to understand mechanisms that will be directly applicable to hES cells and their use for treating motor neuron diseases. Moreover, the mechanisms controlly motor neuron formation are also likely to be relevant to many other neuronal subtypes. Therefore, these studies should provide essential and general insight into medically deploying strategies for converting hES cells into specific neuronal subtypes and thereby serve as a platform for treating a wide range of neurological diseases.

Statement of Benefit to California: 

The long term goal of this research grant proposal is to understand and treat diseases and injuries of the nervous system using hES cells. Neurological disorders such as stroke, epilepsy, Parkinson’s disease and autism strike an estimated 5 million Californians each year, exacting an incalculable personal toll and an annual economic cost of billions of dollars in medical expenses and lost productivity. Thus, one benefit that will be derived from this area of research is the generation of specific tools and methods for reducing medical costs and increasing the quality of life and level of productivity of afflicted Californians. A second key benefit derived from this research grant proposal is the training of new scientists to serve as educators and researchers for the future, many in the burgeoning area of stem cell biology for which the State of California has emerged as a world’s leader. Finally, the discoveries derived from innovative and multidisciplinary research on hES cells described in this proposal, including the use of chemistry to create drug leads for regulating stem cell differentiation, are likely to lead to important new areas of intellectual property that are essential for creating high quality jobs in the biotechnology and pharmaceutical industries in California.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00247
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$492 750
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Alzheimer disease (AD) is a progressive neurodegenerative disorder that currently affects over 4.5 million Americans. By the middle of the century, the prevalence of AD in the USA is projected to almost quadruple. As current therapies do not abate the underlying disease process, it is very likely that AD will continue to be a clinical, social, and economic burden. Progress has been made in our understanding of AD pathogenesis by studying transgenic mouse models of the disease and by utilizing primary neuronal cell cultures derived from rodents. However, key proteins that are critical to the pathogenesis of this disease exhibit many species-specific differences at both a biophysical and functional level. Additional species differences in other as yet unidentified AD-related proteins are likely to also exist. Thus, there is an urgent need to develop novel models of AD that recapitulate the complex array of human proteins involved in this disease. Cell culture-based models that allow for rapid high-throughput screening and the identification of novel compounds and drug targets are also critically needed. To that end we propose to model both sporadic and familial forms of AD by generating two novel human embryonic stem cell lines (hES cells). Differentiation of these lines along a neuronal lineage will provide researchers with an easily accessible and reproducible neuronal cell culture model of AD. These cells will also allow high-throughput screening and experimentation in neuronal cells with a species-relevant complement of human proteins. In Aim 1 we will develop and characterize hES cell lines designed to model both sporadic and familial forms of AD. To model sporadic AD we will stably transfect HUES7 hES cells (developed by Douglas Melton) with lentiviral constructs coding for human wild type amyloid precursor protein (APP-695) under control of the human APP promoter. APP is well expressed within hES cells and upregulated upon neuronal differentiation. To model familial AD and generate cells that exhibit a more aggressive formation of oligomeric A species we will also develop a second hES cell line stably transfected with human APP that includes the Arctic (E693G) mutation.In Aim 2 we will utilize our wild-type APP hES cells to perform a high-throughput siRNA screen. We will utilize AMAXA reverse-nucleofection in conjunction with a human druggable genome siRNA array (Dharmacon) that targets 7309 genes considered to be potential therapeutic targets. Following transfection conditioned media will be examined by a sensitive ELISA to identify novel targets that modulate A levels. In addition a Thioflavin S assay will determine any effects on A aggregation. Follow-up experiments will confirm promising candidates identified in the high-throughput screen. Taken together these studies aim to establish novel AD-specific hES cell lines and identify promising new therapeutic targets for this devastating disease.

Statement of Benefit to California: 

Alzheimer disease (AD) is a progressive neurodegenerative disorder that currently affects over 500 thousand Californians. As the baby-boomer generation ages the prevalence of AD in California is projected to almost quadruple such that 1 in every 45 individuals will be afflicted. As current therapies do not abate the underlying disease process, it is very likely that AD will continue to be a major clinical, social, and economic burden. Some estimates have even suggested that AD alone may bankrupt the current Californian health care system. Progress has been made in our understanding of AD by studying rodent-based models of the disease. However, key proteins that are critical to the disease exhibit many species-specific differences at both a biophysical and functional level. Thus, there is an urgent need to develop novel models of AD that exhibit the complex array of human proteins involved in this disease. Cell culture-based models that also allow for rapid high-throughput screening and the identification of novel compounds and drug targets are also in critical need. The proposed studies aim to utilize human embryonic stem (hES) cells to establish a novel cell culture based model of Alzheimer’s disease. Once developed these cells will provide Californian researchers with a unique tool to investigate genes and proteins that influence the progress of AD. In this proposal we will also utilize these hES cells to perform a high-throughput screen of over 7300 genes to identify multiple novel drug targets that may critically regulate the development of this disease. Taken together these studies aim to establish novel AD-specific hES cell lines that can be utilized by multiple Californian researchers to identify promising new therapeutic targets for this devastating disease.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00225
Investigator: 
ICOC Funds Committed: 
$759 000
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Stroke
Trauma
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

This proposal describes a sharply-focused, timely, and rigorous effort to develop new therapies for the treatment of injuries of the Central Nervous System (CNS). The underlying hypothesis for this proposal is that chemokines and their receptors (particularly those involved in inflammatory cascades) actually play important roles in mediating the directed migration of human neural stem cells (hNSCs) to, as well as engagement and interaction with, sites of CNS injury, and that understanding and manipulating the molecular mechanism of chemokine-mediated stem cell homing and engagement will lead to new, better targeted, more specific, and more efficacious chemokine-mediated stem cell-based repair strategies for CNS injury. In recent preliminary studies, we have discovered and demonstrated the important role of chemokine SDF-1-alpha and its receptor CXCR4 in mediating the directed migration of hNSCs to sites of CNS injury. To manipulate this SDF-1-alpha/CXCR4 pathway in stem cell migration, we have developed Synthetically and Modularly Modified Chemokines (SMM-chemokines) as highly potent and specific therapeutic leads. Here in this renewal application we propose to extend our research into a new area of stem cell biology and medicine involving chemokine receptors such as CXCR4 and its ligand SDF-1. Specifically, we will design more potent and specific analogs of SDF-1-alpha to direct the migration of beneficial stem cells toward the injury sites for the repair process.

Statement of Benefit to California: 

This proposal describes a sharply-focused, timely, and rigorous effort to develop new therapies for the treatment of injuries of the Central Nervous System (CNS). CNS injuries and related disorders such as stroke, traumatic brain injury and spinal cord injury are significant health issues in the nation including the state of California. The new stem cell-based therapies to be developed from this application will have important clinical application in patients with these diseases in California.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00271
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$633 170
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

A promising approach to alleviating the symptoms of Parkinson’s disease is to transplant healthy dopaminergic neurons into the brains of these patients. Due to the large number of transplant neurons required for each patient and the difficulty in obtaining these neurons from human tissue, the most viable transplantation strategy will utilize not fetal dopaminergic neurons but dopaminergic neurons derived from human stem cell lines. While transplantation has been promising, it has had limited success, in part due to the ability of the new neurons to find their correct targets in the brain. This incorrect targeting may be due to the lack of appropriate growth and guidance cues as well as to inflammation in the brain that occurs in response to transplantation, or to a combination of the two. Cytokines released upon inflammation can affect the ability of the new neurons to connect, and thus ultimately will affect their biological function. In out laboratory we have had ongoing efforts to determine the which guidance molecules are required for proper targeting of dopaminergic neurons during normal development and we have identified necessary cues. We now plan to extend these studies to determine how these critical guidance cues affect human stem cell derived dopaminergic neurons, the cells that will be used in transplantation. In addition, we will examine how these guidance cues affect both normal and stem cell derived dopaminergic neurons under conditions that are similar to the diseased and transplanted brain, specifically when the brain is inflamed. Ultimately, an understanding of how the environment of the transplanted brain influences the ability of the healthy new neurons to connect to their correct targets will lead to genetic, and/or drug-based strategies for optimizing transplantation therapy.

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 onParkinson’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 (Van Den Eeden et al., 2003), 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 ES 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. In addition to the direct benefit in improving PD therapies, discoveries from this work are also likely to generate substantial intellectual property and further boost clinical and biotechnical development efforts in California.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00205
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$612 075
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

The goal of this proposal is to generate forebrain neurons from human embryonic stem cells. Our general strategy is to sequentially expose ES cells to signals that lead to differentiation along a neuronal lineage, and to select for cells that display characteristics of forebrain neurons. These cells would then be used in transplantation experiments to determine if they are able to make synaptic connections with host neurons. If successful these experiments would provide a therapeutic strategy for the treatment of Alzheimer’s disease and other disorders that are characterized by loss of forebrain neurons. Currently there is no effective treatments for Alzheimer’s disease, and with an aging baby-boomer population, the incidence of this disease is likely to increase sharply. One of the few promising avenues to treat Alzheimer’s is the possibility of cell replacement therapy in which the neurons lost could be replaced by transplanted neurons. Embryonic stem cells, which have the ability to differentiate into various cells of the body, could be a key component of such a therapy if we can successfully differentiate them into forebrain neurons.

Statement of Benefit to California: 

Alzheimer’s disease is a devastating sporadic neurological disorder that places all of us at risk. As the California population ages, there will be a significant increase in the incidence of Alzheimer’s disease, and the medical and financial cost on the state will be severe. There are currently no effective treatments for this disorder, and one of the few promises is the possibility of transplantation therapy to replace the neurons that are lost in the disease. Being able to generate forebrain neurons from human embryonic stem cells would provide a key tool in the fight against this disease. Needless to say, the development of an effective cell replacement therapy would not only be of immense medical significance as we care for our senior population, it will also greatly relieve the financial burden associated with the care of Alzheimer’s patients, which is often borne by the state.

Grant Type: 
SEED Grant
Grant Number: 
RS1-00413
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$625 617
Disease Focus: 
Cancer
Neurological Disorders
Skeletal/Smooth Muscle disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

A variety of stem cells exist in humans throughout life and maintain their ability to divide and change into multiple cell types. Different types of adult derived stem cells occur throughout the body, and reside within specific tissues that serve as a reserve pool of cells that can replenish other cells lost due to aging, disease, trauma, chemotherapy or exposure to ionizing radiation. When conditions occur that lead to the depletion of these adult derived stem cells the recovery of normal tissue is impaired and a variety of complications result. For example, we have demonstrated that when neural stem cells are depleted after whole brain irradiation a subsequent deficit in cognition occurs, and that when muscle stem cells are depleted after leg irradiation an accelerated loss of muscle mass occurs. While an increase in stem cell numbers after depletion has been shown to lead to some functional recovery in the irradiated tissue, such recovery is usually very prolonged and generally suboptimal.Ionizing radiation is a physical agent that is effective at reducing the number of adult stem cells in nearly all tissues. Normally people are not exposed to doses of radiation that are cause for concern, however, many people are subjected to significant radiation exposures during the course of clinical radiotherapy. While radiotherapy is a front line treatment for many types of cancer, there are often unavoidable side effects associated with the irradiation of normal tissue that can be linked to the depletion of critical stem cell pools. In addition, many of these side effects pose particular threats to pediatric patients undergoing radiotherapy, since children contain more stem cells and suffer higher absolute losses of these cells after irradiation.Based on the foregoing, we will explore the potential utility and risks associated with using human embryonic stem cells (hESC) in the treatment of certain adverse effects associated with radiation-induced stem cell depletion. Our experiments will directly address whether hESCs can be used to replenish specific populations of stem cells in the brain and muscle depleted after irradiation in efforts to prevent subsequent declines in cognition and muscle mass respectively. In addition to using hESC to hasten the functional recovery of tissue after irradiation, we will also test whether implantation of such unique cells holds unforeseen risks for the development of cancer. Evidence suggests that certain types of stem cells may be prone to cancer, and since little is known regarding this issue with respect to hESC, we feel this critical issue must be addressed. Thus, we will investigate whether hESC implanted into animals develop into tumors over time. The studies proposed here comprise a first step in determining how useful hESCs will be in the treatment of humans exposed to ionizing radiation, as well as many other diseases where adult stem cell depletion might be a concern.

Statement of Benefit to California: 

Radiotherapy is a front line treatment used in California for many types of cancer, including brain, breast, prostate, bone and other cancer types presenting surgical complications. Treatment of these cancers through the use of radiation is however, often associated with side effects caused by the depletion of critical stem cell pools contained within non-cancerous normal tissue. While radiotherapy is clearly beneficial overall, many of these side effects have no viable treatment options. If we can demonstrate that human embryonic stem cells (hESC) hold promise as a safe therapeutic agent for the treatment of radiation-induced stem cell depletion, then cancer patients may have a new treatment for countering many of the debilitating side effects associated with radiotherapy. Once developed this new technology could position California to attract cancer patients throughout the United States, and the state would clearly benefit from the increased economic activity associated with a rise in patient numbers.

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