Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06093
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 264 248
Disease Focus: 
Neurological Disorders
Pediatrics
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
White matter is the infrastructure of the brain, providing conduits for communication between neural regions. White matter continues to mature from birth until early adulthood, particularly in regions of brain critical for higher cognitive functions. However, the precise timing of white matter maturation in the various neural circuits is not well described, and the mechanisms controlling white matter developmental/maturation are poorly understood. White matter is conceptually like wires and their insulating sheath is a substance called myelin. It is clear that neural stem and precursor cells contribute significantly to white matter maturation by forming the cells that generate myelin. In the proposed experiments, we will map the precise timing of myelination in the human brain and changes in the populations of neural precursor cells that generate myelin from birth to adulthood and define mechanisms that govern the process of white matter maturation. The resulting findings about how white matter develops may provide insights for white matter regeneration to aid in therapy for diseases such as cerebral palsy, multiple sclerosis and chemotherapy-induced cognitive dysfunction.
Statement of Benefit to California: 
Diseases of white matter account for significant neurological morbidity in both children and adults in California. Understanding the cellular and molecular mechanisms that govern white matter development the may unlock clues to the regenerative potential of endogeneous stem and precursor cells in the childhood and adult brain. Although the brain continues robust white matter development throughout childhood, adolescence and young adulthood, relatively little is known about the mechanisms that orchestrate proliferation, differentiation and functional maturation of neural stem and precursor cells to generate myelin-forming oligodendrocytes during postnatal brain development. In the present proposal, we will define how white matter precursor cell populations vary with age throughout the brain and determine if and how neuronal activity instructs neural stem and precursor cell contributions to human white matter myelin maturation. Disruption of white matter myelination is implicated in a range of neurological diseases, including cerebral palsy, multiple sclerosis, cognitive dysfunction from chemotherapy exposure, attention deficit and hyperactivity disorder (ADHD) and even psychiatric diseases such as schizophrenia. The results of these studies have the potential to elucidate clues to white matter regeneration that may benefit hundreds of thousands of Californians.
Progress Report: 
  • Formation of the insulated fiber infrastructure of the human brain (called "myelin") depends upon the function of a precursor cell type called "oligodendrocyte precursor cells (OPC)". The first Aim of this study seeks to determine how OPCs differ from each other in different regions of the brain, and over different ages. Understanding this heterogeneity is important as we explore the regenerative capacity of this class of precursor cells. We have, in the past year, isolated OPCs from various regions of the human brain from individuals at various ages and are studying the molecular characteristics of these precursor cells at the single cell level in order to define distinct OPC subpopulations. We have also begun to study the functional capabilities of OPCs isolated from different brain regions. The second Aim of this study seeks to understand how interactions between electrically active neurons and OPCs affect OPC function and myelin formation. We have found that when mouse motor cortex neurons "fire" signals in such a way as to elicit a complex motor behavior, much as would happen when one practices a motor task, OPCs within that circuit respond and myelination increases. This affects the function of that circuit in a lasting way. These results indicate that neurons and OPCs interact in important ways to modulate myelination and supports the hypothesis that OPC function may play a role in learning.
  • Sending neural impulses quickly down a long nerve fiber requires a specialized type of insulation called myelin, made by a cell called an oligodendrocyte that wraps itself around neuronal projections. Myelin-insulated nerve fibers make up the “white matter” of the brain, the vast tracts that connect one information-processing area of the brain to another. We have now shown that neuronal activity prompts oligodendrocyte precursor cell (OPC) proliferation and differentiation into myelin-forming oligodendrocytes. Neuronal activity also causes an increase in the thickness of the myelin sheaths within the active neural circuit, making signal transmission along the neural fiber more efficient. This was found to be true in both juvenile and in adult brains Metaphorically, it’s much like a system for improving traffic flow along roadways that are heavily used. And as with a transportation system, improving the routes that are most productive makes the whole system more efficient.
  • Interestingly, some parts of the neural circuit studied showed evidence of myelin-forming precursor cell response to neuronal activity, while other parts of the active circuit did not. In related work, we are making progress towards understanding how OPCs differ in various regions of the brain, examining the molecular heterogeneity of human OPCs at a single cell level.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05577
Investigator: 
ICOC Funds Committed: 
$1 857 600
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
We propose to discover new drug candidates for Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel candidates by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drugs by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.
Statement of Benefit to California: 
Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drugs to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches to drug discovery for AD.
Progress Report: 
  • We have made steady and significant progress in developing a way to use human reprogrammed stem cells to develop drugs for Alzheimer's disease. In the more recent project term we have further refined our key assay, and generated sufficient cells to enable screening of 50,000 different chemical candidates that might reveal potential drugs for this terrible disease. With a little bit of additional refinement, we will be able to begin our search in earnest in collaboration with the Sanford-Burnham Prebys Screening Center.
  • During the past year we completed screening of our Alzheimers “disease in a dish” cultured stem cell lines for response of a critical measure of Alzheimers disease in a dish to FDA approved drugs and other potentially promising drug like compounds. We found several reproducible and interesting categories of potential drugs some of which are already in common use in human patients and therefore might be readily available to the Alzheimer's disease population. We are conducting more careful analyses of these drugs for their mechanism and behavior in human neurons with different types of Alzheimer like behavior and we are beginning to test whether all human variants behave the same way as preparation for potential clinical trials. We are also initiating analysis of new chemical entities for possible modification to improve potency.
Funding Type: 
Basic Biology III
Grant Number: 
RB3-02221
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 482 822
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
The goal of this research is to utilize novel research tools to investigate the molecular mechanisms that cause Parkinson’s disease (PD). The proposed work builds on previous funding from CIRM that directed the developed patient derived models of PD. The majority of PD patients suffer from sporadic disease with no clear etiology. However some PD patients harbor specific inherited mutations have been shown to cause PD. The most frequently observed form of genetic parkinsonism is caused by the LRRK2 G2019S mutation it the most common. This mutation accounts for approximately 1.5-2% of patients with apparently sporadic PD, increasing to 4-6% of patients with a family history of PD, and even higher in isolated populations. Importantly, LRRK2 induced PD is clinically and pathologically largely indistinguishable from sporadic PD. This proposal focuses on studying the most frequent cause of familial PD and induces disease that is clinically and pathologically identical to sporadic PD cases. It is likely that LRRK2 regulates a pathway(s) that is important in the more common sporadic form of PD as well. Therefore by employing relevant models of PD, we hope to drive the biological understanding of LRRK2 in a direction that facilitates the development of disease therapeutics in the future. We ascertained patients harboring mutations in LRRK2 [heterozygous (+/G2019S) and homozygous (G2019S/G2019S)] as well as sporadic cases and age matched controls. We have successfully derived iPSCs from each genotype and differentiated these to DA neurons. We will use these as a model system to investigate these LRRK2 based models of PD. We will adapt current biochemical assays of LRRK2, which are source material intensive, to the small culture volumes required for the differentiation of iPSCs to DA neurons. This is a crucial necessity for development for utilizing iPSC derived DA neurons as tractable models of LRRK2 based PD. We will then probe the roles of LRRK2 in neuronal cell differentiation and survival. We will also ask whether the mutant LRRK2 induces changes in autophagy, as this has been postulated as a mechanism of LRRK2 induced pathogenesis. By studying wild-type and disease mutant LRRK2, in DA models of PD we hope to provide crucial understanding of the role mutant LRRK2 has in disease.
Statement of Benefit to California: 
It is estimated that by the year 2030, 75,000-120,000 Californians will be affected by Parkinson’s disease. Currently, there is no cure, early detection mechanism, preventative treatment, or effective way to slow disease progression. The increasing disability caused by the progression of disease burdens the patients, their caregivers as well as society in terms of healthcare costs. The majority of PD patients suffer from sporadic disease with no clear etiology, and a in a handful of these patients specific inherited mutations have been shown to cause PD. The most frequently mutated gene is called Leucine Rich Repeat Kinase 2 (LRRK2). Our goal is to study the mutated gene product in patient based models of Parkinson’s disease. In previous CIRM funding, we have developed patient derived induced pluripotent stem cells (iPSCs) from patients harboring mutations in LRRK2. We have been successful in differentiating populations these iPSCs into the neurons that are depleted in PD. The next step is to utilize these cells as models of mutation induced PD ‘in a dish’. We will employ these pertinent disease models to answer basic biology questions that remain about the function of LRRK2. This project brings together scientists previously funded by CIRM with scientists well versed in the study of LRRK2. This multidisciplinary approach to studying the causes of PD is a natural benefit to the State of California and its citizens. By bringing a better understanding of the role of LRRK2 in the cells that are lost in the progression of PD, we will bring more concrete knowledge of PD as a whole, bringing more hope for the development of a therapeutic for disease.
Progress Report: 
  • The overarching goal of this work is to utilize models of Parkinson's disease (PD) that originate from cells of PD affected patients harboring mutations within the LRRK2 gene so that we may discern the role of mutated LRRK2 in disease. Mutations in LRRK2 are the most common cause of familial PD. The disease presentation of patients with LRRK2 mutation is typically clinically indistinguishable from sporadic PD cases, making the onset of disease due to LRRK2 dysfunction clinically relevant. We have employed stem cells derived from these patients to generate neuronal cells in which we can determine the roles of LRRK2 in the PD mutated and the unmutated state. We have focused on a cellular process called autophagy that regulates the cell response to nutrient deprivation and plays a role in the selective degradation of proteins within the cell.
  • In the first year of funding we have analyzed the expression of the protein LRRK2 in induced pluripotent stem cells, neuronal precursor cells and have begun to differentiate the neuronal precursors to dopaminergic cells of the type lost in PD (a difficult task in itself). We have applied a novel method for detection of LRRK2 in situ by marrying the protein detection of antibodies and the sensitivity of nucleic acid amplification. We will continue to develop this methodology for maximum sensitivity to LRRK2. We have established assays to assess the effects of the LRRK2 mutant on autophagy that are relevant to PD and neurological diseases in general. We have met or made great progress on most of our anticipated milestones and are eager to proceed to the next phase of the project.
  • The overarching goal of this work is to utilize stem cell based models of Parkinson's disease (PD) derived from cells of PD affected patients that harbor mutations in the LRRK2 gene so that we may elucidate the deleterious role of mutated LRRK2 in disease. Mutations in LRRK2 are the most common cause of familial PD. The disease presentation for these patients with LRRK2 mutation is typically clinically similar to those with sporadic disease, making the onset of disease due to LRRK2 dysfunction clinically relevant. We have utilized stem cells harboring a mutation in LRRK2 and also daughter cells of that line in which genomic editing techniques have been applied to correct the PD mutation or disrupt the LRRK2 gene. We have generated the same kind of cells in culture that are lost during PD and hope that next, we can determine how these mutations that eventually cause disease disrupt normal neuronal function. We have made great progress in the understanding the expression of LRRK2 in early differentiation of stem cells to neurons and his will inform our future studies on mutation caused dysfunctions.
  • The overarching goal of this work is to utilize stem cell based models of Parkinson's disease (PD) derived from cells of PD affected patients that harbor mutations in the LRRK2 gene so that we may elucidate the deleterious role of mutated LRRK2 in disease. Mutations in LRRK2 are the most common cause of familial PD. The disease presentation for these patients with LRRK2 mutation is typically clinically similar to those with sporadic disease, making the onset of disease due to LRRK2 dysfunction clinically relevant. We have utilized stem cells harboring a mutation in LRRK2 and also daughter cells of that line in which genomic editing techniques have been applied to correct the PD mutation or disrupt the LRRK2 gene. We have generated the same kind of cells in culture that are lost during PD and hope that next, we can determine how these mutations that eventually cause disease disrupt normal neuronal function. We have made great progress in the understanding the expression of LRRK2 in early differentiation of stem cells to neurons and this will inform our future studies on mutation caused dysfunctions.
  • During our project we achieved several scientific goals. Our project was to utilize Parkinson’s disease patient derived stem cells to model their disease. The particular cells we used were derived from patients with mutations in the LRRK2 gene, which is the most common cause of inherited Parkinson’s disease. At the end of our funding we can report proficiency in induced pluripotent stem cell (iPSC) differentiation to dopaminergic cells protocols in a workflow that allows higher throughput analysis. Dopaminergic cells are types of cells lost in the brain in Parkinson’s disease and if we study cells from patients with this mutation it will likely yield insight into the processes of disease onset and progression. This funding enabled collaboration with the laboratory of Dr. Schuele here at the Parkinson’s Institute to use cells generated in other CIRM funding (ETI-0246 and RT2-019665). The cell lines we used were edited to “fix” the genetic mutation in the LRRK2 gene and also to delete (or knockout) the LRRK2 gene. We used these cells and determined that loss of LRRK2 imparts an increased propensity for dopaminergic differentiation potential for knockouts over mutant and wild-type cells. Also, we determined that LRRK2 inhibitors do not negatively impact the generation of dopaminergic cells in cell culture modeling. We will continue to unravel the roles of LRRK2 in Parkinson’s disease using these pertinent, patient centric models.
Funding Type: 
Basic Biology III
Grant Number: 
RB3-05232
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 341 064
Disease Focus: 
Neuropathy
Neurological Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Induced pluripotent stem cells (iPSCs) have tremendous potential for patient-specific cell therapies, which bypasses immune rejection issues and ethical concerns for embryonic stem cells (ESCs). However, to fully harness the therapeutic potential of iPSCs, many fundamental issues of cell transplantation remain to be addressed, e.g., how iPSC-derived cells participate in tissue regeneration, which type of cells should be derived for specific therapy, and what kind of matrix is more effective for cell therapies. The goal of this project is to use iPSC-derived neural crest stem cells (NCSCs) and nerve regeneration as a model to address these fundamental issues of stem cell therapies. NCSCs are multipotent and can differentiate into cell types in all three germ layers (including neural, vascular, osteogenic and chondrogenic cells), which makes NCSC a valuable model to study stem cell differentiation and tissue regeneration. Peripheral nerve injuries and demyelinating diseases (e.g., multiple sclerosis, familial dysautonomia) affect millions of people. Stem cell therapy is a promising approach to cure these diseases, which will have broad impact on healthcare. This project will advance our understanding of how extracellular microenvironment (native or engineered) regulates stem cell fate and behavior during tissue regeneration, and whether stem cells such as iPSC-NCSCs and differentiated cells such as iPSC-Schwann cells have different therapeutic effects. The results from this project will provide insights that will facilitate the translation of stem cell technologies into therapies for nerve injuries, demyelinating diseases and many other disorders that may be treated with iPSC-NCSCs.
Statement of Benefit to California: 
Induced pluripotent stem cells (iPSCs), especially iPSCs without the integration of reprogramming factors into the genome, are valuable to model disease and to generate autologous cells for therapies. Understanding the role and differentiation of iPSC-derived cells in tissue regeneration will facilitate the translation of stem cell technologies into clinical applications. iPSC-derived neural crest stem cells (NCSCs) can differentiate into a variety of cell types, and hold promise for the therapies of diseases such as nerve injuries, demyelinating diseases, spina bifida, vascular diseases, osteoporosis and arthritis. The isolation and characterization of iPSC-NCSCs will provide a basis for their broad applications in tissue regeneration and disease modeling. This project will use peripheral nerve regeneration as a model to address the fundamental issues of using iPSC-NCSCs for therapies. Peripheral nerve injuries (over 800,000 cases in the United States every year) are very common following traumatic injuries and major surgeries (e.g., removing tumor), which often require surgical repair. Stem cell therapies can accelerate nerve regeneration and avoid the degeneration of muscle and other tissues lack of innervation. Since iPSC-NCSCs can promote the myelination of axons, the therapies for nerve injuries could also be adopted to treat demyelinating diseases. In many cases of stem cell therapies, matrix and scaffold materials are needed to enhance cell survival and achieve local delivery. The studies on appropriate matrix for stem cell delivery will provide a rational basis for designing and optimizing materials for stem cell therapies. The fundamental issues addressed in this project, such as the differentiation and signaling of transplanted cells, the therapeutic effects of cells at the different stages of differentiation and the roles of delivery matrix/materials, will have implications for stem cell therapies in many other tissues. Overall, the results from this project will advance our knowledge on stem cell differentiation and function during tissue regeneration, help us translate the knowledge into clinical applications, and benefit the health care in California and our society.
Progress Report: 
  • Induced pluripotent stem cells (iPSCs) have tremendous potential for regenerative medicine applications. Here we use peripheral nerve regeneration as a model to address the fundamental issues of using iPSCs and their derivatives for therapies. Specifically, we used integration-free iPSCs for our studies because this type of iPSCs has potential for clinical applications. We derived and characterized neural crest stem cells (NCSCs) from integration-free iPSCs, and demonstrated that these NCSCs can differentiate into a variety of cell types, including Schwann cells. We delivered NCSCs into nerve conduits to treat peripheral nerve injuries, and performed functional studies, electrophysiology analysis and histological analysis. Ongoing studies suggest that the transplantation of iPSC-NCSCs accelerate nerve regeneration. To investigate the interactions of transplanted stem cells with endogenous neural progenitors, we isolated and characterized endogenous progenitors from injured nerves, which will be used for mechanistic studies. In addition, we engineered the chemical components and the structure of nerve conduits, and developed and characterized hydrogels that could be used to deliver neurotrophic factors and minimize scar formation. The roles of neurotrophic factors, transplanted/endogenous stem cells and matrix for stem cell delivery will be investigated.
  • We use peripheral nerve regeneration as a model to address the critical issues of using induced pluripotent stem cells (iPSCs) and their derivatives for tissue regeneration. In the past year, we have made progress in all three Specific Aims. We generated 5 new integration-free IPSC lines by using episomal reprogramming. We also tested the methods of using biomaterials and chemical compounds to reprogram cells, in the presence or absence of transcriptional factors. We have derived and characterized additional neural crest stem cell (NCSC) lines from these new iPSC lines, and demonstrated that these NCSCs are multipotent in their differentiation potential. To investigate the mechanisms of how NCSCs enhanced the functional recovery of transected sciatic nerves, we examined the effects of paracrine signaling, cell differentiation and matrix stiffness. In vivo experiments showed that transplanted cells secreted neurotrophic factors to promote axon regeneration. In addition, NCSCs differentiated into Schwann cells to enhance myelination. The stiffness of extracellular matrix (ECM) indeed has effect on NCSC differentiation.
  • Here we use peripheral nerve regeneration as a model to address the critical issues of using induced pluripotent stem cells (iPSCs) and their derivatives for tissue regeneration. In the past year, we have made progress in all three Specific Aims, as detailed below. In Specific Aim 1, we generated 5 new integration-free IPSC lines by using episomal reprogramming. We also optimized the protocol to derive neural crest stem cells (NCSCs) from integration-free human iPSCs, and fully characterized the derived cells. Transplantation of selected NCSC lines significantly improved the functional recovery of peripheral nerve following injury. In addition, transplanted NCSCs differentiated into Schwann cells around regenerated axons. Nerve growth factor (NGF) appeared to be a major neurotrophic factor expressed by NCSCs, which was involved in nerve regeneration. In Specific Aim 2, we derived and characterized Schwann cells from NCSCs. Transplantation of NCSCs or Schwann cells showed that NCSC transplantation had better functional recovery than Schwann cell transplantation, suggesting that the differentiation stage of transplanted cells is critical for stem cell therapies. In Specific Aim 3, we demonstrated that the soft matrix worked much better than stiffer matrix for NCSC delivery and the functional recovery of damaged nerve. A new direction for this Specific Aim is a ground-breaking finding that matrix stiffness regulates the direct reprograming of fibroblasts into neurons, which has applications in generating neurons for drug discovery and disease modeling. Overall, our findings underline the importance of stem cell differentiation stage and biomaterials property in stem cell therapies, and will have broad impact on using stem cells for nerve regeneration and many other regenerative medicine applications.
Funding Type: 
Strategic Partnership III Track A
Grant Number: 
SP3A-07552
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$14 323 318
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
The proposed project is designed to assess the safety and preliminary activity of escalating doses of human embryonic stem cell derived oligodendrocyte progenitor cells (OPCs) for the treatment of spinal cord injury. OPCs have two important functions: they produce factors which stimulate the survival and growth of nerve cells after injury, and they mature in the spinal cord to produce myelin, the insulation which enables electrical signals to be conducted within the spinal cord. Clinical testing of this product initiated in 2010 after extensive safety and efficacy testing in more than 20 nonclinical studies. Initial clinical safety testing was conducted in five subjects with neurologically complete thoracic injuries. No safety concerns have been observed after following these five subjects for more than two years. The current project proposes to extend testing to subjects with neurologically complete cervical injuries, the intended population for further clinical development, and the population considered most likely to benefit from the therapy. Initial safety testing will be performed in three subjects at a low dose level, with subsequent groups of five subjects at higher doses bracketing the range believed most likely to result in functional improvements. Subjects will be monitored both for evidence of safety issues and for signs of neurological improvement using a variety of neurological, imaging and laboratory assessments. By completion of the project, we expect to have accumulated sufficient safety and dosing data to support initiation of an expanded efficacy study of a single selected dose in the intended clinical target population.
Statement of Benefit to California: 
The proposed project has the potential to benefit the state of California by improving medical outcomes for California residents with spinal cord injuries (SCIs), building on California’s leadership position in the field of stem cell research, and creating high quality biotechnology jobs for Californians. Over 12,000 Americans suffer an SCI each year, and approximately 1.3 million people in the United States are estimated to be living with a spinal cord injury. Although specific estimates for the state of California are not available, the majority of SCI result from motor vehicle accidents, falls, acts of violence, and recreational sporting activities, all of which are common in California. Thus, the annual incidence of SCI in California is likely equal to or higher than the 1,400 cases predicted by a purely population-based distribution of the nationwide incidence. The medical, societal and economic burden of SCI is extraordinarily high. Traumatic SCI most commonly impacts individuals in their 20s and 30s, resulting in a high-level of permanent disability in young and previously healthy individuals. At one year post injury, only 11.8% of SCI patients are employed, and fewer than 35% are employed even at more than twenty years post-injury (NSCISC Spinal Cord Injury Facts and Figures 2013). Life expectancies of SCI patients are significantly below those of similar aged patients with no SCI. Additionally, many patients require help with activities of daily living such as feeding and bathing. As a result, the lifetime cost of care for SCI patients are enormous; a recent paper (Cao et al 2009) estimated lifetime costs of care for a patient obtaining a cervical SCI (the population to be enrolled in this study) at age 25 at $4.2 million. Even partial correction of any of the debilitating consequences of SCI could enhance activities of daily living, increase employment, and decrease reliance on attendant and medical care, resulting in substantial improvements in both quality of life and cost of care for SCI patients. California has a history of leadership both in biotechnology and in stem cell research. The product described in this application was invented in California, and has already undergone safety testing in five patients in a clinical study initiated by a California corporation. The applicant, who has licensed this product from its original developer and recruited many of the employees responsible for its previous development, currently employs 17 full-time employees at its California headquarters, with plans to significantly increase in size over the coming years. The successful performance of the proposed project would enable significant additional jobs creation in preparation for pivotal trials and product registration.
Funding Type: 
Basic Biology V
Grant Number: 
RB5-07011
Investigator: 
ICOC Funds Committed: 
$1 161 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 
We propose to elucidate pathways of genes that lead from early causes to later defects in Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel genetic pathways by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drug targets by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.
Statement of Benefit to California: 
Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drug targets to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches.
Funding Type: 
Basic Biology V
Grant Number: 
RB5-07320
Investigator: 
ICOC Funds Committed: 
$598 367
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Our goal is to use the mechanisms that generate neuronal networks to create neurons from stem cells, to either replace diseased and damaged tissue or as a source of material to study disease mechanisms. A key focus of such regenerative studies is to restore function to the spinal cord, which is particularly vulnerable to damage. However, although considerable progress has been made in understanding how to direct stem cells towards motor neurons that control coordinated movement, little progress has been made so far directing stem cells to form the sensory neurons that allow us to experience the environment around us. Our proposed research will use insights from the mechanisms known to generate the sensory neurons during the development of the spinal cord, to derive these neurons from stem cells. We will initially use mouse embryonic stem cells in these studies, to accelerate the experimental progress. We will then apply our findings to human embryonic stem cells, and assess whether these cells are competent to repopulate the spinal cord. These studies will significantly advance our understanding of how to generate the full repertoire of neural subtypes necessary to repair the spinal cord after injury, specifically permitting patients to recover sensations such as pain and temperature. Moreover, they also represent a source of therapeutically beneficial cells for modeling debilitating diseases, such as the chronic insensitivity to pain.
Statement of Benefit to California: 
Millions of Californians live with compromised nervous systems, damaged by either traumatic injury or disease. These conditions can be devastating, stripping patients of their ability to move, feel and think, and currently have no cure. As well as being debilitating for patients, living with these diseases is also extremely expensive, costing both Californians and the state of California many billions of dollars. For example, the estimated lifetime cost for a single individual managing spinal paralysis is estimated to be up to $3 million. Stem cell technology offers tremendous hope for reversing or ameliorating both disease and injury states. Stem cells can be used to replenish any tissue damaged by injury or disease, including the spinal cord, which is particularly vulnerable to physical damage. Our proposed studies will develop the means to produce the spinal sensory neurons that permit us to perceive the environment. We will also determine whether these in vitro derived sensory neurons are suitable for transplantation back into the spinal cord. The generation of these neurons will constitute an important step towards reversing or ameliorating spinal injuries, and thereby improve the productivity and quality of life of many Californians. Moreover, progress in this field will solidify the leadership role of California in stem cell research and stimulate the future growth of the biotechnology and pharmaceutical industries within the state.
Progress Report: 
  • A promising strategy to treat neurodegenerative diseases is to use embryonic stem cell (ESC)-derived neurons to replace damaged or diseased populations of neurons. In our CIRM-funded studies, we proposed to establish a protocol that will derive spinal sensory interneurons (INs) from ESCs. These INs are required to reestablish the sensory connections that would allow an injured patient to perceive external stimuli, such as pain and temperature. The existence of in vitro derived spinal sensory INs would also accelerate studies examining the basis of debilitating spinal dysfunctions, such as congenital pain insensitivity.
  • We have made significant progress towards this goal in year 1. We have identified that specific members of the Bone Morphogenetic Protein (BMP) family can direct mouse ESCs towards specific classes of spinal INs. These signals appear to be evolutionally conserved: our preliminary results suggest that BMPs have the same activity directing human ESCs towards spinal sensory IN fates. We are thus well poised to initiate our proposed studies in year 2: assessing whether stem cell derived INs can integrate in the spinal cord.
Funding Type: 
Basic Biology V
Grant Number: 
RB5-07254
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 003 590
Disease Focus: 
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 
Stem cells generate mature, functional cells after proteins on the cell surface interact with cues from the environment encountered during development or after transplantation. Thus, these cell surface proteins are critical for directing transplanted stem cells to form appropriate cells to treat injury or disease. A key modification regulating cell surface proteins is glycosylation, which is the addition of sugars onto proteins and has not been well studied in neural stem cells. We focus on a major unsolved problem in the neural stem cell field: do different proteins coated with sugars on the surfaces of cells in this lineage (neuron precursors, NPs and astrocyte precursors, APs) determine what types of mature cells will form? We hypothesize key players directing cellular decisions are glycosylated proteins controlling how precursors respond to extracellular cues. We will address this hypothesis with aims investigating whether (1) glycosylation pathways predicted to affect cell surface proteins differ between NPs and APs, (2) glycosylated proteins on the surface of NPs and APs serve as instructive cues governing fate or merely mark their fate potential, and (3) glycosylation pathways regulate cell surface proteins likely to affect fate choice. By answering these questions we will better understand the formation of NPs and APs, which will improve the use of these cells to treat brain and spinal cord diseases and injuries.
Statement of Benefit to California: 
The goal of this project is to determine how cell surface proteins differ between cells in the neural lineage that form two types of final, mature cells (neurons and astrocytes) in the brain and spinal cord. In the course of these studies, we will uncover specific properties of human stem cells that are used to treat neurological diseases and injuries. We expect this knowledge will improve the use of these cells in transplants by enabling more control over what type of mature cell will be formed from transplanted cells. Also, cells that specifically generate either neurons or astrocytes can be used for drug testing, which will help to predict the effects of compounds on cells in the human brain. We hope our research will greatly improve identification, isolation, and utility of specific types of human neural stem cells for treatment of human conditions. Furthermore, this project will generate new jobs for high-skilled workers and, hopefully, intellectual property that will contribute to the economic growth of California.
Progress Report: 
  • Overall, our biggest breakthrough this year has been the identification of a link among the sugars on the cell surface, a label free electrical measure reflecting the type of mature cell the stem cells will become (membrane capacitance), and stem cell fate potential, or the ability of the cell to form a particular type of mature cell. Stem cells generate mature, functional cells after proteins on the cell surface interact with cues from the environment encountered during development or after transplantation. Thus, these cell surface proteins are critical for directing transplanted stem cells to form the appropriate types of cells to treat injury or disease. A key modification regulating cell surface proteins is glycosylation, which is the addition of sugars onto proteins and has not been well studied in neural stem cells. Our project focuses on a major unsolved problem in the neural stem cell field: do different proteins coated with sugars on the surfaces of cells in this lineage (neuron precursors, NPs and astrocyte precursors, APs) determine what types of mature cells will form? We hypothesize key players directing cellular decisions are glycosylated proteins controlling how precursors respond to extracellular cues. This year on the project, we found a particular glycosylation pathway that adds highly branched sugars regulates cell surface properties and controls the decision to form either a neuron or an astrocyte. In the next year of the project, we will explore this pathway further and perform experiments to identify the proteins on the cell surface important for determining the formation of either mature neurons or astrocytes. By answering these questions, we will better understand the regulation of NPs and APs, which will improve the use of these cells to treat brain and spinal cord diseases and injuries.
Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06571
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$530 265
Disease Focus: 
Autism
Neurological Disorders
Pediatrics
oldStatus: 
Active
Public Abstract: 
Autism spectrum disorders (ASD) are a family of disabling disorders of the developing brain that affect about 1% of the population. Studying the biology of these conditions has been difficult as they have been challenging to represent in animal models. The core symptoms of ASD, including deficits in social communication, imagination and curiosity are intrinsically human and difficult to model in organisms commonly studied in the laboratory. Ideally, the mechanisms underlying ASDs need to be studied in human patients and in their cells. Since they maintain the genetic profile of an individual, studying neurons derived from human induced pluripotent stem cells (hiPSC) is attractive as a method for studying neurons from ASD patients. hiPSC based studies of ASDs hold promise to uncover deficits in cellular development and function, to evaluate susceptibility to environmental insults, and for screening of novel therapeutics. In this project our goal is to contribute blood and skin samples for hiPSC research from 200 children with an ASD and 100 control subjects to the CIRM repository. To maximize the value of the collected tissue, all subjects will have undergone comprehensive clinical evaluation of their ASD. The cells collected through this project will be made available to the wider research community and should result in a resource that will enable research on hiPSC-derived neurons on a scale and depth that is unmatched anywhere else in the world.
Statement of Benefit to California: 
The prevalence and impact of Autism Spectrum Disorders (ASD) in California is staggering. California has experienced 13% new ASD cases each year since 2002. ASD are a highly heritable family of complex neurodevelopmental conditions affecting the brain, with core symptoms of impaired social skills, language, behavior and intellectual abilities. The majority with an ASD experience lifelong disability that requires intensive parental, school, and social support. The result has been a 12-fold increase in the number of people receiving ASD services in California since 1987, with over 50,000 people with ASDs served by developmental and regional centers. Within the school system, the number of special education students with ASD in California has more than tripled between 2002 and 2010. The economic, social and psychological toll is enormous. It is critical to both prevent and develop effective treatments for ASD. While rare genetic mutations account for a minority of cases, our understanding of idiopathic ASD (>85% of cases) is extremely limited. Mechanisms underlying ASDs need to be studied in human patients and in cells that share the genetic background of these patients. Since they maintain the complete genetic background of an individual, hiPSCs represent a very practical and direct method for investigating neurons from ASD patients to uncover cellular deficits in their development and function, and for screening of novel therapeutics.
Progress Report: 
  • Autism Spectrum Disorders (ASD) have a worldwide prevalence of 1% (>1.5 million in the US) and a lifetime cost per affected individual of $3.2M. ASDs are amongst the most heritable of psychiatric disorders. Genome Wide Association studies utilizing samples in the thousands provide only weak evidence for common allele risk effects; positive findings rarely replicate, and genetic effects sizes are small (odds ratios of ~1.1). In contrast, evidence to date for risk or causation conferred by rare variation, particularly rare copy number variants, is very strong. Pathway analyses of the rare mutations implicated and genome-wide transcriptome analysis of brain and blood tissue provide converging evidence that neural-related pathways are central to the development of autism. Core impairments of ASDs, such as imagination and curiosity about the environment, cannot be modeled well in other organisms. The mechanisms underlying ASDs need to be studied in humans and cells that share the genetic background of the patients, such as neurons from patients derived from induced pluripotent cell lines (iPSC).
  • Our goal was to provide the CIRM repository with samples from 200 well characterized individuals with an ASD and 100 demographically matched controls. To date we have enrolled 63 participants.
Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06530
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$3 031 737
Disease Focus: 
Neuropathy
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
The applicant is an MD/PhD trained physician scientist, whose clinical expertise is neuromuscular disorders including peripheral nerve disease. The proposal is aimed at providing a research proposal and career development plan that will allow the applicant to develop an independent research program, which attempts to bring stem cell based therapies to patients with peripheral nerve diseases. The proposal will use “adult stem cells” derived from patients with an inherited nerve disease, correct the genetic abnormality in those cells, and determine the feasibility of transplanting the genetically engineered cells back into peripheral nerve to slow disease progression.
Statement of Benefit to California: 
The proposed research will benefit the State of California as it will support the career development of a uniquely trained physician scientist to establish an innovative translational stem cell research program aimed toward direct clinical application to patients. The cutting edge technologies proposed are directly in line with the fundamental purpose of the California Initiative for Regenerative Medicine. If successful, both scientific and patient advocate organizations would recognize that these advances came directly from the unique efforts of CIRM and the State of California to lead the world in stem cell research. Finally, as a result of funding of this award, further financial investments from private and public funding organizations would directly benefit the State in the years to come.
Progress Report: 
  • During this award period we have made significant progress. We have established induced pluripotent stem cell (iPSC) lines from four patients with Charcot-Marie-Tooth disease type 1A (CMT1A) due to the PMP22 duplication. We have validated our strategy to genetically engineer induced pluripotent stem cells from patients with inherited neuropathy, and have genetically engineered several patient lines. We further have begun to differentiate these iPSCs into Schwann cell precursors, to begin to investigate cell type specific defects that cause peripheral neurodegeneration in patients with CMT1A. Finally we have imported and characterized a transgenic rat model of CMT1A in order to begin to investigate the ability to inject iPSC derived Schwann cell precursors into rodent nerves as a possible neuroprotective strategy.
  • During this reporting period we developed genetically corrected induced pluripotent stem cell lines from patients with CMT1A. We improved and validated a novel method for differentiating Schwann cells from iPSCs, and used this to generate human Schwann cells from patients and controls. Finally we have initiated pilot studies injecting human iPSC derived Schwann cells into the peripheral nerves of rats with myelin diseases to determine whether cell replacement therapy is a viable strategy in these disorders.

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