Neurological Disorders

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

Programming Human ESC-derived Neural Stem Cells with MEF2C for Transplantation in Stroke

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06788
ICOC Funds Committed: 
$2 124 000
Disease Focus: 
Stroke
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
The goal of this project is to produce a stem cell-based therapy for stroke (also known as an ischemic cerebral infarct). Stroke is the third leading cause of death in the USA, and a leading cause of disability among adults. Currently, there are no effective treatments once a stroke has occurred (termed completed stroke). In this proposal, we aim to develop human stem cells for therapeutic transplantation to treat stroke. Potential benefits will outweigh risks because only patients with severe strokes that have compromised activities of daily living to an extreme degree will initially be treated. Using a novel approach, we will generate stem cells that do not form tumors, but instead only make new nerve cells. We will give drugs to avoid rejection of the transplanted cells. Thus, the treatment should be safe. We will first test the cells in stroke models in rodents (mice and rats) in preparation for a human clinical trial. We will collect comprehensive data on the mice and rats to determine if the stem cells indeed become new nerve cells to replace the damaged tissue and to assess if the behavior of the mice and rats has improved. If successfully developed and commercialized, this approach has the potential for revolutionizing stroke therapy.
Statement of Benefit to California: 
The goal of this project is to produce a stem cell-based therapy for stroke (also known as an ischemic cerebral infarct). Stroke is the third leading cause of death in the State of California, and a leading cause of disability among adults. Currently, there are no effective treatments once a stroke has occurred (termed completed stroke), and the quality of life is severely compromised in those that survive the malady. In this proposal, we aim to develop human stem cells for therapeutic transplantation to treat stroke. Using a novel approach, we will generate stem cells that do not form tumors, but instead only make new nerve cells. If successfully developed and commercialized, this approach could provide a therapeutic candidate for the unmet medical need, which would have a tremendous impact on the quality of life for the patient, his or her family, and for the economic and emotional burden on the State of California and its citizens.

Stem Cell Pathologies in Parkinson’s disease as a key to Regenerative Strategies

Funding Type: 
Research Leadership 10
Grant Number: 
LA1_C10-06535
ICOC Funds Committed: 
$6 718 471
Disease Focus: 
Parkinson's Disease
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
Protection and cell repair strategies for neurodegenerative diseases such as Parkinson’s Disease (“PD”) depend on well-characterized candidate human stem cells that are robust and show promise for generating the neurons of interest following stimulation of inherent brain stem cells or after cell transplantation. These stem cells must also be expandable in the culture dish without unwanted growth and differentiation into cancer cells, they must survive the transplantation process or, if endogenous brain stem cells are stimulated, they should insinuate themselves in established brain networks and hopefully ameliorate the disease course. The studies proposed for the CIRM Research Leadership Award have three major components that will help better understand the importance and uses of stem cells for the treatment of PD, and at the same time get a better insight into their role in disease repair and causation. First, we will characterize adult human neural stem cells from control and PD brain specimens to distinguish their genetic signatures and physiological properties of these cells. This will allow us to determine if there are stem cells that are pathological and fail in their supportive role in repairing the nervous system. Next, we will investigate a completely novel disease initiation and propagation mechanism, based on the concept that secreted vesicles from cells (also known as “exosomes”) containing a PD-associated protein, alpha-synuclein, propagate from cell-to cell. Our hypothesis is that these exosomes carry toxic forms of alpha-synuclein from cell to cell in the brain, thereby accounting disease spread. They may do the same with cells transplanted in patients with PD, thereby causing these newly transplanted cells designed to cure the disease, to be affected by the same process that causes the disease itself. This is a bottleneck that needs to be overcome for neurotransplantation to take its place as a standard treatment for PD. Our studies will address disease-associated toxicity of exosomal transmission of aggregated proteins in human neural precursor stem cells. Importantly, exosomes in spinal fluid or other peripheral tissues such as blood might represent a potentially early and reliable disease biomarker as well as a new target for molecular therapies aimed at blocking transcellular transmission of PD-associated molecules. Finally, we have chosen pre-clinical models with α-synucleinopathies to test human neural precursor stem cells as cell replacement donors for PD as well as interrogate, for the first time, their potential susceptibility to PD and contribution to disease transmission. These studies will provide a new standard of analysis of human neural precursor cells at risk for and contributing to pathology (so-called “stem cell pathologies”) in PD and other neurodegenerative diseases via transmission of altered or toxic proteins from one cell to another.
Statement of Benefit to California: 
According to the National Institute of Health, Parkinson’s disease (PD) is the second most common neurodegenerative disease in California and the United States (one in 100 people over 60 is affected) second only to Alzheimer’s Disease. Millions of Americans are challenged by PD, and according to the Parkinson’s Action Network, every 9 minutes a new case of PD is diagnosed. The cause of the majority of idiopathic PD is unknown. Identified genetic factors are responsible for less than 5% of cases and environmental factors such as pesticides and industrial toxins have been repeatedly linked to the disease. However, the vast majority of PD is thought to be etiologically multi-factorial, resulting from both genetic and environmental risk factors. Important events leading to PD probably occur in early or mid adult life. According to the Michael J. Fox Foundation, “…there is no objective test, or reliable biomarker for PD, so rate of misdiagnosis is high, and there is a seriously pressing need to develop better early detection approaches to be able to attempt disease-halting protocols at a non-symptomatic, so-called prodromal stage.” The proposed innovative and transformative research program will have a major direct impact for patients who live in California and suffer from PD and other related neurodegenerative diseases. If these high-risk high-pay-off studies are deemed successful, this new program will have tackled major culprits in the PD field. They could lead to a better understanding of the role of stem cells in health and disease. Furthermore they could greatly advance our knowledge of how the disease spreads throughout the brain which in turn could lead to entire new strategies to halt disease progression. In a similar manner these studies could lead to ways to prevent the disease from spreading to cells that have been transplanted to the brain of Parkinson’s patients in an attempt to cure their disease. This is critical for neurotransplantation to thrive as a therapeutic approach to treating PD. In addition, if we extend the cell-to-cell transmissible disease hypothesis to other neurodegenerative diseases, and cancer, the studies proposed here represent a new diagnostic approach and therapeutic targets for many diseases affecting Californians and humankind in general. This CIRM Research Leadership Award will not only have an enormous impact on understanding the cause of PD and developing new therapeutic strategies using stem cells and its technologies, this award will also be the foundation of creating a new Center for Translational Stem Cell Research within California. This could lead to further growth at the academic level and for the biotechnology industry, particularly in the area regenerative medicine.

Collection of skin biopsies to prepare fibroblasts from patients with Alzheimer's disease and cognitively healthy elderly controls

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06589
ICOC Funds Committed: 
$643 693
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
oldStatus: 
Active
Public Abstract: 
Alzheimer's Disease (AD), the most common form of dementia in the elderly, affects over 5 million Americans. There are no treatments to slow progression or prevent AD. This reflects limitations in knowledge of mechanisms underlying AD, and in tools and models for early development and testing of treatment. Genetic breakthroughs related to early onset AD led to initial treatment targets related to a protein called amyloid, but clinical trials have been negative. Extensive research links genetic risk to AD, even when the age at onset is after the age of 65. AD affects the brain alone, therefore studying authentic nerve cells in the laboratory should provide the clearest insights into mechanisms and targets for treatment. This has recently become feasible due to advances in programming skin cells into stem cells and then growing (differentiating) them into nerve cells. In this project we will obtain skin biopsies from a total of 220 people with AD and 120 controls, who are extensively studied at the [REDACTED] AD Research Center. These studies include detailed genetic (DNA) analysis, which will allow genetic risks to be mapped onto reprogrammed cells. These derived cells that preserve the genetic background of the person who donated the skin biopsy will be made available to the research community, and have the promise to accelerate studies of mechanisms of disease, understanding genetic risk, new treatment targets, and screening of new treatments for this devastating brain disorder.
Statement of Benefit to California: 
The proposed project will provide a unique and valuable research resource, which will be stored and managed in California. This resource will consist of skin cells or similar biological samples, suitable for reprogramming, obtained from well-characterized patients with Alzheimer's Disease and cognitively healthy elderly controls. Its immediate impact will be to benefit CIRM-funded researchers as well as the greater research community, by providing them access to critical tools to study, namely nerve cells that can be grown in a dish (cultured) that retain the genetic background of the skin cell donors. This technology to develop and reprogram cells into nerve cells or other cell types results from breakthroughs in stem cell research, many of which were developed using CIRM funding. Alzheimer's Disease affects over 600,000 Californians, and lacks effective treatment. Research into mechanisms of disease, identifying treatment targets, and screening novel drugs will be greatly improved and accelerated through the availability of the resources developed by this project, which could have a major impact on the heath of Californians. California is home to world class academic and private research institutes, Biotechnology and Pharmaceutical Companies, many of whom are already engaged in AD research. This project could provide them with tools to make research breakthroughs and pioneer the development of novel treatments for AD.

CIRM Tissue Collection for Neurodevelopmental Disabilities

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06611
ICOC Funds Committed: 
$874 135
Disease Focus: 
Neurological Disorders
Pediatrics
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Most children who go to the clinic with brain disorders have symptoms combining autism, cerebral palsy and epilepsy, suggesting underlying and shared mechanisms of brain dysfunction in these conditions. Such disorders affect 4-6% of the population with life-long disease, and account for about 10% of health care expenditures in the US. Genetic studies have pointed to frequent low-penetrant or low-frequency genetic alterations, but there is no clear way to use this information to make gene-specific diagnosis, to predict short- or long-term prognosis or to develop disease-specific therapy. We propose to recruit about 500 patients with these disorders mostly from our Children’s Hospital, through a dedicated on-site collaborative approach. Extracting from existing medical records, taking advantage of years of experience in recruitment and stem cell generation, and already existing or planned whole exome or genome sequencing on most patients, we propose a safe, anonymous database linked to meaningful biological, medical, radiographic and genetic data. Because team members will be at the hospital, we can adjust future disease-specific recruitment goals depending upon scientific priorities, and re-contact patients if necessary. The clinical data, coupled with the proposed hiPSC lines, represents a platform for cell-based disease investigation and therapeutic discovery, with benefits to the children of California.
Statement of Benefit to California: 
This project can benefit Californians both in financial and non-financial terms. NeuroDevelopmental Disabilities (NDDs) affect 4-6% of Californians, create a huge disease burden estimated to account for 10% of California health care costs, and have no definitive treatments. Because we cannot study brain tissue directly, it is extraordinarily difficult to arrive at a specific diagnosis for affected children, so doctors are left ordering costly and low-yield tests, which limit prognostic information, counseling, prevention strategies, quality of life, and impede initiation of potentially beneficial therapies. Easily obtainable skin cells from Californians will be the basis of this project, so the study results will have maximal relevance to our own population. By combining “disease in a dish” platforms with cutting edge genomics, we can improve diagnosis and treatments for Californians and their families suffering from neurodevelopmental disorders. Additionally, this project, more than others, will help Californians financially because: 1] The ongoing evaluations of this group of patients utilizes medical diagnostics and genetic sequencing tools developed and manufactured in California, increasing our state revenues. 2] The strategy to develop “disease in a dish” projects centered on Neurodevelopmental Disabilities supports opportunities for ongoing efforts of California-based pharmaceutical and life sciences companies to leverage these discoveries for future therapies.

Induced pluripotent stem cells from children with autism spectrum disorders

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06571
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.

Stem Cell Mechanisms Governing Discrete Waves of Gliogenesis in the Childhood Brain

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06093
ICOC Funds Committed: 
$1 264 248
Disease Focus: 
Neurological Disorders
Pediatrics
Stem Cell Use: 
Adult 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.

Modeling disease in human embryonic stem cells using new genetic tools

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05855
ICOC Funds Committed: 
$1 387 800
Disease Focus: 
Neuropathy
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
The use of stem cells or stem cell-derived cells to treat disease is one important goal of stem cell research. A second, important use for stem cells is the creation of cellular models of human development and disease, critical for uncovering the molecular roots of illness and testing new drugs. However, a major limitation in achieving these goals is the difficulty in manipulating human stem cells. Existing means of generating genetically modified stem cells are not ideal, as they do not preserve the normal gene regulation, are inefficient, and do not permit removal of foreign genes. We have developed a method of genetically modifying mouse embryonic stem cells that is more efficient than traditional methods. We are adapting this approach for use with human embryonic stem cells, so that these cells can be better understood and harnessed for modeling, or even treating, human diseases. We will use this approach to create a human stem cell model of Charcot-Marie-Tooth (CMT) disease, an inherited neuropathy. How gene dysfunction leads to nerve defects in CMT is not clear, and there is no cure or specific therapy for this neurological disease. Thus, we will use our genetic tools to investigate how gene function is disrupted to cause CMT. By developing these tools and using them to gain understanding of CMT, we will illustrate how this system can be used to gain insight into other important diseases.
Statement of Benefit to California: 
Although human stem cells hold the potential to generate new understanding about human biology and new approaches to important diseases, the inability to efficiently and specifically modify stem cells currently limits the pace of research. Also, there is presently no safe means of changing genes compatible with the use of the stem cells in therapies. We are developing new genetic tools to allow for the tractable manipulation of human stem cells. By accelerating diverse other stem cell research projects, these tools will enhance the scientific and economic development of California. We will use these tools to create cellular models of Charcot-Marie-Tooth (CMT), a neurological disease with no cure that affects about 15,000 Californians. This model will facilitate understanding of the etiology of CMT, and may lead to insights that can be used to develop specific therapies. Beyond gaining insight into CMT, the ability to engineer specific genetic changes in human stem cells will be useful for many applications, including the creation of replacement cells for personalized therapies, reporter lines for stem cell-based drug screens, and models of other diseases. Thus, our research will assist the endeavors of the stem cell community in both the public and private arenas, contributing to economic growth and new product development. This project will also train students and postdoctoral scholars in human stem cell biology, who will contribute to the economic capacity of California.
Progress Report: 
  • An important use for stem cells is the creation of cellular models of human development and disease, critical for uncovering the molecular roots of illness and testing new drugs. However, a major limitation in achieving these goals is the difficulty in manipulating human stem cells. We have developed a method of genetically modifying mouse embryonic stem cells that is more efficient than traditional methods. During the first year of this project, we adapted this approach for use with human embryonic stem cells. We have also created gene trap mutations in a diversity of human embryonic stem cell genes that can be used to better harness human embryonic stem cells for modeling, or even treating, human diseases.

Mechanism and Utility of Direct Neuronal Conversion with a MicroRNA-Chromatin Switch

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05886
ICOC Funds Committed: 
$1 392 426
Disease Focus: 
Neurological Disorders
Stem Cell Use: 
Directly Reprogrammed Cell
oldStatus: 
Active
Public Abstract: 
Many human diseases and injuries that affect the brain and nervous system could potentially be treated by either introducing healthy neurons or persuading the cells that normally provide supporting functions to become functioning neurons. A number of barriers must be traversed to bring these goals to practical therapies. Recently our laboratory and others have found ways of converting different human cell types to functioning neurons. Surprisingly, two routes for the production of neurons have been discovered. Our preliminary evidence indicates that these two routes are likely to work together and therefore more effective ways of producing neurons can likely be provided by understanding these two routes, which is one aim of this application. Another barrier to effective treatment of human neurologic diseases has been the inability to develop good models of human neurologic disease due to inability to sample tissues from patients with these diseases. Hence we will understand ways of making neurons from blood cells and other cells, which can be easily obtained from patients with little or no risk. Our third goal will be to understand how different types of neurons can be produced from patient cells. We would also like to understand the barriers and check points that keep one type of cell from becoming another another type of cell. Understanding these mysterious processes could help provide new sources of human cells for replacement therapies and disease models.
Statement of Benefit to California: 
The state of California and its citizens are likely to benefit from the work described in this proposal by the development of more accurate models for the testing of drugs and new means of treatment of human neurologic diseases. Presently these diseases are among the most common afflicting Californians, as well as others and will become more common in an aging population. Common and devastating diseases such as Alzheimer’s, Schizophrenia, Parkinson's Disease, and others lack facile cell culture models that allow one to probe the basis of the disease and to test therapies safely and without risk to the patient. Our work is already providing these models, but we hope to make even better ones by understanding the fundamental processes that allow one cell type (such as a skin cell or blood cell) to be converted to human neurons, where the disease process can be investigated. In the past the inability to make neurons from patients with specific diseases has been a major roadblock to treatment. In the future the studies described here might be able to provide healthy neurons to replace ones loss through disease or injury.
Progress Report: 
  • During the past year, our laboratory has investigated the way that human skin cells can be changed to neurons. To do this, we have used a natural switch that occurs as embryonic cells decide to become neurons. We have found that this process proceeds in a highly ordered series of stages that involve first a resetting of fundamental cell biologic processes characteristic of neurons. This is followed by activation of genes encoding proteins that allow different types of neurons to interact and develop communication between one another. This finding surprised us since we expected to find changes in transcription factors, which instruct the formation of neurons. Instead, we find that the natural switching mechanism in neurons first regulates cell-to-cell communication.

Role of the NMD RNA Decay Pathway in Maintaining the Stem-Like State

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06345
ICOC Funds Committed: 
$1 360 450
Disease Focus: 
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
A subset of intellectual disability cases in humans are caused by mutations in an X-linked gene essential for a quality control mechanism called nonsense-mediated RNA decay (NMD). Patients with mutations in this gene—UPF3B—commonly have not only ID, but also schizophrenia, autism, and attention-deficit/hyperactivity disorder. Thus, the study of UPF3B and NMD may provide insight into a wide spectrum of cognitive and psychological disorders. To examine how mutations in UPF3B can cause mental defects, we will generate and characterize induced-pluripotent stem cells from intellectual disability patients with mutations in the UPF3B gene. In addition to having a role in neural development, our recent evidence suggests that NMD is important for maintaining the identity of ES cells and progenitor cells. How does NMD do this? While NMD is a quality control mechanism, it is also a well characterized biochemical pathway that serves to rapidly degrade specific subsets of normal messenger ribonucleic acids (mRNAs), the transiently produced copies of our genetic material: deoxyribonucleic acid (DNA). We have obtained evidence that NMD preferentially degrades mRNAs that interfere with the stem cell program (i.e., NMD promotes the decay mRNAs encoding proteins that promote differentiation and inhibit cell proliferation). In this proposal, we will identify the target mRNAs of NMD in stem and progenitor cells and directly address the role of NMD in maintaining the stem-like state.
Statement of Benefit to California: 
iPS cells provide a means to elucidate the mechanisms underlying diseases that afflict a growing number of Californians. Our proposed project concerns making and testing iPS cells from patients with mutations in the UPF3B gene, all of whom have intellectual disabilities. In addition, many of these patients have autism, attention-deficit disorders, and schizophrenia. By using iPS cells to identify the cellular and molecular defects in these patients, we have the potential to ultimately ameliorate the symptoms of many of these patients. This is important, as over 1.6 million people in California have serious mental illness. Moreover, a large proportion of patients with UPF3B mutations have autism, a disorder that has undergone an alarming 12-fold increase in California between 1987 and 2007. The public mental health facilities in California are inadequate to meet the needs of people with mental health disorders. Furthermore, what is provided is expensive: $4.4 billion was spent on public mental health agency services in California in 2006. Mental health problems also exert a heavy burden on California’s criminal justice system. In 2006, over 11,000 children and 40,000 adults with mental health disorders were incarcerated in California’s juvenile justice system. Our research is also directed towards understanding fundamental mechanisms by which all stem cells are maintained, which has the potential to also impact non-psychiatric disorders suffered by Californians.
Progress Report: 
  • A key quality of stem cells is their ability to switch from a proliferative cell state in which they reproduce themselves to a differentiated cell state that ultimately allows them to carry out the functions of a fully mature cell. Most research on the nature of this switch has focused on the role of proteins that determine whether the genetic material—DNA—generates a copy of it itself in the form of messenger RNA, a process called transcription. In stem cells, such proteins—which are called transcription factors—activate the production of messenger RNAs encoding proteins that promote the proliferative and undifferentiated cell state. They also increase the production of messenger mRNAs that encode inhibitors of differentiation and cell proliferation. The level and profile of such transcription factors are altered in response to signals that trigger stem cells to differentiate. For example, transcription factors that promote the undifferentiated cell state are decreased in level and transcription factors that drive differentiation down a particular lineage are increased in level. While this transcription factor-centric view of stem cells explains some aspects of stem cell biology, it is, in of itself, insufficient to explain many of their behaviors, including both their ability to maintain the stem-like state and to differentiate. We hypothesize that a molecular pathway that complements transcription-base mechanisms in controlling stem cell maintenance vs. differentiation decisions is an RNA decay pathway called nonsense-mediated RNA decay (NMD). Messenger RNA decay is as important as transcription in determining the level of messenger RNA. Signals that trigger increased decay of a given messenger RNA leads to decreased levels of its encoded protein, while signals that trigger the opposite response increase the level of the encoded protein. Our project revolves around two main ideas. First, that NMD promotes the stem-like state by preferentially degrading messenger RNAs that encode differentiation-promoting proteins and proliferation inhibitor proteins. Second, that NMD must be downregulated in magnitude to allow stem cells to differentiate. During the progress period, we obtained substantial evidence for both of these hypotheses. With regard to the first hypothesis, we have used genome-wide approaches to identify hundreds of messenger RNAs that are regulated by NMD in both in vivo (in mice) and in vitro (in cell lines). To determine which of these messenger mRNAs are directly degraded by NMD, we have used a variety of approaches. This work has revealed that NMD preferentially degrades messenger RNAs encoding neural differentiation inhibitors and proliferation inhibitors in neural stem cells. In contrast, very few messenger RNAs encoding pro-stem cell proteins or pro-proliferation proteins are degraded by NMD. Together this provides support for our hypothesis that NMD promotes the stem-like state by shifting the proportion of messenger RNAs in a cell towards promoting an undifferentiated, proliferative cell state. With regard to the second hypothesis, we have found that many proteins that are directly involved in the NMD pathway are downregulated upon differentiation of stem and progenitor cells. Not only are NMD proteins reduced in level, but we find that the magnitude of NMD itself is reduced. We have used a variety of molecular techniques to determine whether this NMD downregulatory response has a role in neural differentiation and found that NMD downreglation is both necessary and sufficient for this event. Such experiments have also revealed particular messenger mRNAs degraded by NMD that are crucial for the NMD downregulatory response to promote neural differentiation. Our research has implications for intellectual disability cases in humans caused by mutations in an X-linked gene essential for NMD. Patients with mutations in this gene—UPF3B—not only have intellectual disability, but also schizophrenia, autism, and attention-deficit/hyperactivity disorder. Thus, the study of NMD may provide insight into a wide spectrum of cognitive and psychological disorders. We are currently in the process of generating induced-pluripotent stem (iPS) cells from intellectual disability patients with mutations in the UPF3B gene towards this goal.

Common molecular mechanisms in neurodegenerative diseases using patient based iPSC neurons

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06079
ICOC Funds Committed: 
$1 506 420
Disease Focus: 
Huntington's Disease
Neurological Disorders
Parkinson's Disease
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
A major medical problem in CA is the growing population of individuals with neurodegenerative diseases, including Parkinson’s (PD) and Huntington’s (HD) disease. These diseases affect millions of people, sometimes during the prime of their lives, and lead to total incapacitation and ultimately death. No treatment blocks the progression of neurodegeneration. We propose to conduct fundamental studies to understand the basic common disease mechanisms of neurodegenerative disorders to begin to develop effective treatments for these diseases. Our work will target human stem cells made from cells from patients with HD and PD that are developed into the very cells that degenerate in these diseases, striatal neurons and dopamine neurons, respectively. We will use a highly integrated approach with innovative molecular analysis of gene networks that change the states of proteins in these diseases and state-of-the-art imaging technology to visualize living neurons in a culture dish to assess cause and effect relationships between biochemical changes in the cells and their gradual death. Importantly, we will test whether drugs effective in animal model systems are also effective in blocking the disease mechanisms in the human HD and PD neurons. These human preclinical studies could rapidly lead to clinical testing, since some of the drugs have already been examined extensively in humans in the past for treating other disorders and are safe.
Statement of Benefit to California: 
Neurodegenerative diseases, such as Parkinson’s (PD) and Huntington’s disease (HD), are devastating to patients and families and place a major financial burden on California. No treatments effectively block progression of any neurodegenerative disease. A forward-thinking team effort will allow highly experienced investigators in neurodegenerative disease and stem cell research to investigate common basic mechanisms that cause these diseases. Most important is the translational impact of our studies. We will use neurons and astrocytes derived from patient induced pluripotent stem cells to identify novel targets and discover disease-modifying drugs to block the degenerative process. These can be quickly transitioned to testing in preclinical and clinical trials to treat HD and other neurodegenerative diseases. We are building on an existing strong team of California-based investigators to complete the studies. Future benefits to California citizens include: 1) discovery and development of new HD treatments with application to other diseases, such as PD, that affect thousands of Californians, 2) transfer of new technologies and intellectual property to the public realm with resulting IP revenues to the state with possible creation of new biotechnology spin-off companies, and 3) reductions in extensive care-giving and medical costs. We anticipate the return to the State in terms of revenue, health benefits for its Citizens and job creation will be significant.
Progress Report: 
  • The goal of our study is to identify common mechanisms that cause the degeneration of neurons and lead to most neurodegenerative disorders. Our work focuses on the protein homeostasis pathways that are disrupted in many forms of neurodegeneration, including Huntington’s disease (HD) and Parkinson’s disease (PD). In this first reporting period we have made great progress in developing novel methods to probe the autophagy pathway in single cells. This pathway is involved in the turnover of misfolded proteins and dysfunction organelles. Using our novel autophagy assays, we have preliminary data that indicate that the autophagy pathway in neurons from HD patients is modulated compared to healthy controls. We have also begun validating small molecules that activate the autophagy pathway and we are now moving these inducers into human neurons from HD patients to see if they reduce toxicity or other disease related phenotypes. Using pathway analysis we have also identified specific genes within the proteostasis network that are modulated in HD. We are now testing whether modulating these genes in human neurons from HD patients can lead to a reduction in neurodegeneration. In the final part of this study we are investigating whether neurodegenerative diseases, such as HD and PD, share changes in similar genes or pathways, specifically those involved in protein homeostasis. We have now established a human neuron model for PD and have used it to identify potential targets that modulate the disease phenotype via changes in proteostasis. Using the assays, autophagy drugs and pathway analysis described above, we hope to identify overlapping targets that could potentially rescue disease associated phenotypes in both HD and PD.

Pages

Subscribe to RSS - Neurological Disorders

© 2013 California Institute for Regenerative Medicine