Neurological Disorders

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

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.

Stem cell models to analyze the role of mutated C9ORF72 in neurodegeneration

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06045
ICOC Funds Committed: 
$1 393 200
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Dementia
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Amyotrophic lateral sclerosis (ALS) is an idiopathic adult-onset degenerative disease characterized by progressive weakness from loss of upper and lower motor neurons. Onset is insidious, progression is essentially linear, and death occurs within 3-5 years in 90% of patients. In the US, 5,000 deaths occur per year and in the world, 100,000. In October, 2011, the causative gene defect in a long sought after locus on chromosome 9 for ALS, frontotemporal dementia (FTD) and overlap ALS-FTD was identified to be a expansion of a hexanucleotide repeat in the uncharacterized C9ORF72 gene. The goal of the proposed research is to generate human stem cell models from cells derived from ALS patients with the C9ORF72 expanded repeats and relevant control cells using genome-editing technology. We will also generate a stem cell model expressing the repeat independent of the C9ORF72 gene to study if the repeat alone is causing neural defects. Using advanced genome technologies, biochemical and cellular approaches, we will study the molecular pathways affected in motor neurons derived from these stem cell models. Finally, we will use innovative technologies to rescue the abnormal phenotypes that arise from the expanded repeat in human motor neurons. Completion of the proposed research is expected to transform our understanding of the regulatory and pathogenetic mechanisms underlying ALS and FTD, and establish therapeutic options for these debilitating diseases.
Statement of Benefit to California: 
Our research provides the foundation for decoding the mechanisms that underlie the single most frequent genetic mutation found to contribute to both ALS and FTD, debilitating neurological diseases that impact many Californians. In California, the expected prevalence of ALS (the number of total existing cases) is 2,200 to 3,000 cases at any one time, and the incidence is 750-1,100 new cases each year. The number of FTD cases is five times as many. Our research has and will continue to serve as a basis for understanding deviations from normal and disease patient neuronal cells, enabling us to make inroards to understanding neurological disease modeling using neurons differentiated from reprogammed patient-specific lines. Such disease modeling will have great potential for California health care patients, pharmaceutical and biotechnology industries in terms of improved human models for drug discovery and toxicology testing. Our improved knowledge base will support our efforts as well as other Californian researchers to study stem cell models of neurological disease and design new diagnostics and treatments, thereby maintaining California's position as a leader in clinical research.
Progress Report: 
  • Expanded hexanucleotide repeats in the C9ORF72 gene were identified in Oct 2011 as a cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), thus identifying the single most frequent genetic cause of each and connecting them to repeat expansion disease. We are developing stem cell disease models to enable key hypotheses of pathogenesis and new interventions to be tested. We have successfully engineered stem cell models to analyze the effects of C9ORF72 mutations, and have differentiated these stem cell models into motor neurons which enabled us to conduct transcriptomic and biochemical studies. In addition, we have utilized antisense-oligonucleotides (ASOs) from ISIS Pharmaceuticals to deplete mutant C9ORF72 in motor neurons. We expect our efforts to provide mechanistic insights and a potential therapy in human cells.

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.

Modeling Alexander disease using patient-specific induced pluripotent stem cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06277
ICOC Funds Committed: 
$1 367 172
Disease Focus: 
Neurological Disorders
Pediatrics
oldStatus: 
Active
Public Abstract: 
Alexander disease (AxD) is a devastating childhood disease that affects neural development and causes mental retardation, seizures and spasticity. The most common form of AxD occurs during the first two years of life and AxD children show delayed mental and physical development, and die by the age of six. AxD occurs in diverse ethnic, racial, and geographic groups and there is no cure; the available treatment only temporally relieves symptoms, but not targets the cause of the disease. Previous studies have shown that specific nervous system cells called astrocytes are abnormal in AxD patients. Astrocytes support both nerve cell growth and function, so the defects in AxD astrocytes are thought to lead to the nervous system defects. We want to generate special cells, called induced pluripotent stem cells (iPSCs) from the skin or blood cells of AxD patients to create an unprecedented, new platform for the study and treatment of AxD. We can grow large quantities of iPSCs in the laboratory and then, using novel methods that we have already established, coax them to develop into AxD astrocytes. We will study these AxD astrocytes to find out how their defects cause the disease, and then use them to validate potential drug targets. In the future, these cells can also be used to screen for new drugs and to test novel treatments. In addition to benefiting AxD children, we expect that our approach and results will benefit the study of other, similar childhood nervous system diseases.
Statement of Benefit to California: 
It is estimated that California has approximately 12% of all US cases of AxD, a devastating childhood neurological disorder that leads to mental retardation and early death. At present, there is no cure or standard treatment available for AxD. Current treatment is symptomatic only. In addition to the tremendous emotional and physical pain that this disease inflicts on Californian families, it adds a medical and fiscal burden larger than that of any other states. Therefore, there is a real need to understand the underlying mechanisms of this disease in order to develop an effective treatment strategy. Stem cells provide great hope for the treatment of a variety of human diseases. Our proposal to establish a stem cell-based cellular model for AxD could lead to the development of new therapies that will represent great potential not only for Californian health care patients, but also for the Californian pharmaceutical and biotechnology industries. In addition to benefiting the treatment of AxD patients, we expect that our approach and results will benefit the study of other related neurological diseases that occur in California and the US.
Progress Report: 
  • Alexander disease (AxD) is a devastating childhood disease that affects neural development and causes mental retardation, seizures and spasticity. AxD children usually die by the age of six. AxD occurs in diverse ethnic, racial, and geographic groups and there is no cure; the available treatment only temporally relieves symptoms, but not targets the cause of the disease. Previous studies have shown that specific nervous system cells called astrocytes are abnormal in AxD patients. We generated special cells, called induced pluripotent stem cells (iPSCs) from the skin cells of AxD patients, and coaxed them to develop into AxD astrocytes. We will study these AxD astrocytes to find out how their defects cause the disease, and then use them to validate potential drug targets. In the future, these cells can also be used to screen for new drugs and to test novel treatments. In addition to benefiting AxD children, we expect that our approach and results will benefit the study of other, similar childhood nervous system diseases.

The HD iPSC Consortium: Repeat Length Dependent Phenotypes for Assay Development

Funding Type: 
iPSC Consortia Award
Grant Number: 
RP1-05741
ICOC Funds Committed: 
$300 000
Disease Focus: 
Huntington's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 
  • Huntington’s disease (HD) is a significant neurodegenerative disease with unique genetic features. A CAG expansion in Huntington gene is correlated with severity and onset of sub-clinical and overt clinical symptoms, make it particularly suited to therapeutic development . The single genetic cause offers the opportunity to understand the pathological process triggered in all individuals with a CAG expansion, as emerging evidence suggests effects of the mutation in all cell types, though striatal neurons are most vulnerable to degeneration. Moreover, by virtue of a molecular test for the mutation, a unique opportunity exists to intervene/treat before the onset of overt clinical symptoms utilizing sub-clinical phenotypes emerging in pre-manifest individuals. Since human induced pluripotent stem cells (iPSCs) have the power to make any cell type in the human body, we are utilizing the technology to make patients iPSCs and study the effects of different number of CAG repeats on the neurons we generate from the patient iPS cells. Preliminary studies indicate that CAG length–dependent phenotypes occur at all stages of differentiation, from iPSC through to mature neurons and are likely to occur in non-neuronal cells as well, which can also be investigated using the iPSC that we are creating. The non-integrating technology (avoids integration of potentially deleterious reprogramming factors in the cell DNA) for producing iPSC lines is crucial to obtaining reproducible disease traits from patient cells.
  • The Cedars-Sinai RMI iPSC Core is part of the Huntington’s Disease (HD) consortium. In the past year the iPSC Core has made many new non-integrating induced pluripotent stem (iPSC) cell lines from HD patients with different numbers of CAG repeat expansions. The grant application proposed generation of 18 HD and Control iPSC lines. Instead we are generating 20 iPSC lines. So far we have already generated 17 iPSC lines from individuals with Huntington’s disease and controls (10 HD patients and 7 controls). In order to have the disease trait reproducible across multiple groups, three clonal iPSC lines were generated from each subject. Some of these lines have (or are in process) of expansion for distribution to consortium members. We are now in the process of making the last 3 lines as part of this grant application to generate a HD iPSC repository with total of 20 patient/control lines from subjects with multitude of CAG repeat numbers. Most of these lines have undergone rigorous battery of characterization for pluripotency determination, while some other lines are currently being validated through more characterization tests. Neural stem cell aggregates (EZ spheres) have been generated from few of the patient lines in the Svendsen lab (not supported by this grant). We have also submitted 6 patient iPSC lines to Coriell Cell Repository for larger banking and distribution of these important and resourceful lines to other academic investigators and industry. We strongly believe that this iPSC repository will enormously speed up the process of understanding the disease causing mechanisms in HD patient brain cells as well as discovering novel therapeutics or drugs that may one day be able to treat HD patients.
  • Huntington’s disease (HD) is a fatal neurodegenerative condition with no current treatment. This significant neurodegenerative disease, whose relatively simple and unique known genetic cause, a CAG expansion in the HD gene correlated with severity and onset of clinical symptoms, makes it particularly suited to therapeutic development. The Huntington’s disease (HD) iPS cell consortium, funded with NIH and CIRM support, brings together leading groups in stem cell and HD research to establish whether newly created iPS cell lines show HD related (i.e., CAG length-dependent) phenotypes. Human iPSC technology can be used to generate specific neuronal and glial cell types, permitting investigation of the effects of the genetic lesion in the susceptible human cell types in the context of HD. The monogenic nature of HD and the existence of allelic series of iPSCs with a range of CAG repeat lengths confer tremendous power to model HD. Through CIRM support this consortium has capitalized on new technologies to use non-integrating approaches for reprogramming and promising phenotypes in current HD iPS lines to develop robust and validated assays for drug development for HD.
  • Significant progress has been made through CIRM-funded support of this proposal. Notably, the Cedars-Sinai Medical Center’s Board of iPSC core housed in the Board of Governors Regenerative Medicine Institute has taken skin cells from HD patients with a wide range of CAG repeats (43 to 180), and unaffected healthy controls (21 to 33) and reprogrammed then to pluripotency using the latest non-integrating iPS cell technology. So far 18 well-characterized patient-specific iPSC lines have been generated. These new iPSC lines have been rigorously characterized by our iPSC core and available to HD research community throughout California and the world. The Svendsen lab and the other HD iPSC Consortium laboratories have already used these lines and differentiated into relevant neuronal cell types to study the disease mechanisms as well develop new treatment.
  • These cell lines will be an essential resource for academic groups and pharmaceutical companies for studying pathogenesis and for testing experimental therapeutics for HD. The ultimate goal is to develop and validate methods and assays using >96 well format for CAG repeat length-dependent phenotypes that are amenable to high content/throughput screening methods. Assays developed using these patient-specific iPSC lines and their neuronal derivatives will allow academic groups and pharmaceutical companies to study pathogenesis and test experimental therapeutics for HD, which will significantly advance both our understanding of HD and potential treatments for this devastating and currently untreatable disease.

Neural stem cell transplantation for chronic cervical spinal cord injury

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05736
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 
1.3 million Americans suffer chronically from spinal cord injuries (SCI); each year ~15,000 individuals sustain a new injury. For California, this means nearly 147,000 individuals are living with a SCI which can leave otherwise healthy individuals with severe deficits in movement, sensation, and autonomic function. Recovery after SCI is often limited, even after aggressive emergency treatment with steroids and surgery, followed by rehabilitation. The need to develop new treatments for SCI is pressing. We believe that stem cell therapies could provide significant functional recovery, improve quality of life, and reduce the cost of care for SCI patients. The goal of this Disease Team is to evaluate a novel cell therapy approach to SCI involving transplantation of human neural stem cells. In 2005, the FDA authorized the world’s first clinical testing of human neural stem cell transplantation into the CNS. Since then, our research team has successfully generated clinical grade human neural stem cells for use in three clinical trials, established a favorable safety profile that now approaches five years in some subjects and includes evidence of long-term donor-cell survival. Relevant to this Disease Team, the most recent study began testing human neural stem cells in thoracic spinal cord injury. The initial group of three patients with complete injury has been successfully transplanted. The Disease Team seeks to extend the research into cervical SCI. Neural cell transplantation holds tremendous promise for achieving spinal cord repair. In preliminary experiments, the investigators on this Disease Team showed that transplantation of both murine and human neural stem cells into animal models of SCI restore motor function. The human neural stem cells migrate extensively within the spinal cord from the injection site, promoting new myelin and synapse formation that lead to axonal repair and synaptic integrity. Given these promising proof-of-concept studies, we propose to manufacture clinical-grade human neural stem cells and execute the preclinical studies required to submit an IND application to the FDA that will support the first-in-human neural stem cell transplantation trial for cervical SCI. Our unmatched history of three successful regulatory submissions, extensive experience in manufacturing, preclinical and clinical studies of human neural stem cells for neurologic disorders, combined with an outstanding team of basic and clinical investigators with expertise in SCI, stem cell biology, and familiarity with all the steps of clinical translation, make us an extremely competitive applicant for CIRM’s Disease Team awards. This award could ultimately lead to a successful FDA submission that will permit human testing of a new treatment approach for SCI; one that could potentially reverse paralysis and improve the patient’s quality of life.
Statement of Benefit to California: 
Spinal cord injuries affect more than 147,000 Californians; the majority are injuries to the cervical level (neck region) of the spinal cord. SCI exacts a devastating toll not only on patients and families, but also results in a heavy economic impact on the state: the lifetime medical costs for an individual with a SCI can exceed $3.3 million, not including the loss of wages and productivity. In California this translates to roughly $86 billion in healthcare costs. Currently there are no approved therapies for chronic thoracic or cervical SCI. We hope to advance our innovative cell therapy approach to treat patients who suffer cervical SCI. For the past 9 years, the assembled team (encompassing academic experts in pre-clinical SCI models, complications due to SCI, rehabilitation and industry experts in manufacturing and delivery of purified neural stem cells), has developed the appropriate SCI models and assays to elucidate the therapeutic potential of human neural stem cells for SCI repair. Human neural stem cell transplantation holds the promise of creating a new treatment paradigm. These cells restored motor function in spinal cord injured animal models. Our therapeutic approach is based on the hypothesis that transplanted human neural stem cells mature into oligodendrocytes to remyelinate demyelinated axons, and/or form neurons to repair local spinal circuitry. Any therapy that can partially reverse some of the sequelae of SCI could substantially change the quality-of-life for patients by altering their dependence on assisted living, medical care and possibly restoring productive employment. Through CIRM, California has emerged as a worldwide leader in stem cell research and development. If successful, this project would further CIRM’s mission and increase California’s prominence while providing SCI therapy to injured Californians. This Team already has an established track record in stem cell clinical translation. The success of this Disease Team application would also facilitate new job creation in highly specialized areas including cell manufacturing making California a unique training ground. In summary, the potential benefit to the state of California brought by a cervical spinal cord Disease Team project would be myriad. First, a novel therapy could improve the quality of life for SCI patients, restore some function, or reverse paralysis, providing an unmet medical need to SCI patients and reducing the high cost of health care. Moreover, this Disease Team would maintain California’s prominence in the stem cell field and in clinical translation of stem cell therapies, and finally, would create new jobs in stem cell technology and manufacturing areas to complement the state’s prominence in the biotech field.

Restoration of memory in Alzheimer’s disease: a new paradigm using neural stem cell therapy

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05416
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the US, someone develops AD every 69 seconds and there are over 5 million individuals suffering from AD, including approximately 600,000 Californians. Current treatments do not alter the disease course. The absence of effective therapies coupled with the sheer number of affected patients renders AD a medical disorder of unprecedented need and a public health concern of significant magnitude. In 2010, the global economic impact of dementias was estimated at $604 billion, a figure far beyond the costs of cancer or heart disease. These numbers do not reflect the devastating social and emotional tolls that AD inflicts upon patients and their families. Efforts to discover novel and effective treatments for AD are ongoing, but unfortunately, the number of active clinical studies is low and many traditional approaches have failed in clinical testing. An urgent need to develop novel and innovative approaches to treat AD is clear. We propose to evaluate the use of human neural stem cells as a potential innovative therapy for AD. AD results in neuronal death and loss of connections between surviving neurons. The hippocampus, the part of the brain responsible for learning and memory, is particularly affected in AD, and is thought to underlie the memory problems AD patients encounter. Evidence from animal studies shows that transplanting human neural stem cells into the hippocampus improves memory, possibly by providing growth factors that protect neurons from degeneration. Translating this approach to humans could markedly restore memory and thus, quality of life for patients. The Disease Team has successfully initiated three clinical trials involving transplantation of human neural stem cells for neurological disorders. These trials have established that the cells proposed for this therapeutic approach are safe for transplantation into humans. The researchers in this Disease Team have shown that AD mice show a dramatic improvement in memory skills following both murine and human stem cell transplantation. With proof-of-concept established in these studies, the Disease Team intends to conduct the animal studies necessary to seek authorization by the FDA to start testing this therapeutic approach in human patients. This project will be conducted as a partnership between a biotechnology company with unique experience in clinical trials involving neural stem cell transplantation and a leading California-based academic laboratory specializing in AD research. The Disease Team also includes expert clinicians and scientists throughout California that will help guide the research project to clinical trials. The combination of all these resources will accelerate the research, and lead to a successful FDA submission to permit human testing of a novel approach for the treatment of AD; one that could enhance memory and save lives.
Statement of Benefit to California: 
The number of AD patients in the US has surpassed 5.4 million, and the incidence may triple by 2050. Roughly 1 out of every 10 patients with AD, over 550,000, is a California resident, and alarmingly, because of the large number of baby-boomers that reside in this state, the incidence is expected to more than double by 2025. Besides the personal impact of the diagnosis on the patient, the rising incidence of disease, both in the US and California, imperils the federal and state economy. The dementia induced by AD disconnects patients from their loved ones and communities by eroding memory and cognitive function. Patients gradually lose their ability to drive, work, cook, and carry out simple, everyday tasks, ultimately losing all independence. The quality of life for AD patients is hugely diminished and the burden on their families and caregivers is extremely costly to the state of California. Annual health care costs are estimated to exceed $172 billion, not including the additional costs resulting from the loss of income and physical and emotional stress experienced by caregivers of Alzheimer's patients. Given that California is the most populous state and the state with the highest number of baby-boomers, AD’s impact on California families and state finances is proportionally high and will only increase as the AD prevalence rises. Currently, there is no cure for AD and no means of prevention. Most approved therapies address only symptomatic aspects of AD and no disease-modifying approaches are currently available. By enacting Proposition 71, California voters acknowledged and supported the need to investigate the potential of novel stem cell-based therapies to treat diseases with a significant unmet medical need such as AD. In a disease like AD, any therapy that exerts even a modest impact on the patient's ability to carry out daily activities will have an exponential positive effect not only for the patients but also for their families, caregivers, and the entire health care system. We propose to evaluate the hypothesis that neural stem cell transplantation will delay the progression of AD by slowing or stabilizing loss of memory and related cognitive skills. A single, one-time intervention may be sufficient to delay progression of neuronal degeneration and preserve functional levels of memory and cognition; an approach that offers considerable cost-efficiency. The potential economic impact of this type of therapeutic research in California could be significant, and well worth the investment of this disease team proposal. Such an approach would not only reduce the high cost of care and improve the quality of life for patients, it would also make California an international leader in a pioneering approach to AD, yielding significant downstream economic benefits for the state.
Progress Report: 
  • Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the US, someone develops AD every 69 seconds and there are over 5 million individuals suffering from AD, including approximately 600,000 Californians. Current treatments do not alter the disease course. The absence of effective therapies coupled with the sheer number of affected patients renders AD a medical disorder of unprecedented need and a public health concern of significant magnitude. In 2010, the global economic impact of dementias was estimated at $604 billion, a figure far beyond the costs of cancer or heart disease. These numbers do not reflect the devastating social and emotional tolls that AD inflicts upon patients and their families. Efforts to discover novel and effective treatments for AD are ongoing, but unfortunately, the number of active clinical studies is low and many traditional approaches have failed in clinical testing. An urgent need to develop novel and innovative approaches to treat AD is clear.
  • We have proposed to evaluate the use of human neural stem cells as a potential innovative therapy for AD. AD results in neuronal death and loss of connections between surviving neurons. The hippocampus, the part of the brain responsible for learning and memory, is particularly affected in AD, and is thought to underlie the memory problems AD patients encounter. Evidence from previous animal studies shows that transplanting human neural stem cells into the hippocampus improves memory, possibly by providing growth factors that protect neurons from degeneration. Translating this approach to humans could markedly restore memory and thus, quality of life for patients.
  • In the first year of the loan, the Disease Team actively worked on 5 important milestones in our effort to develop the use of human neural stem cells for AD. Of those, 2 milestones have been completed and 3 are ongoing. Specifically, the team has initiated three animal studies believed necessary to seek authorization by the FDA to start testing this therapeutic approach in human patients; these studies were designed to confirm that transplantation of the neural stem cells leads to improved memory in animal models relevant for AD. We are currently collecting and analyzing the data generated in these mouse studies. We have also identified the neural stem cell line that will be used in patients and have made considerable progress in its manufacturing and banking. Finally, we have held a pre-IND meeting with the FDA in which we shared our plans for the preclinical and clinical studies; the meeting provided helpful guidance and assurances regarding our IND enabling activities.
  • This project is a partnership between a biotechnology company with unique experience in clinical trials involving neural stem cell transplantation and a leading California-based academic laboratory specializing in AD research. Together with expert clinicians and scientists throughout California, we continue to work towards a successful IND submission to permit human testing of a novel and unique approach for the treatment of AD.

Progenitor Cells Secreting GDNF for the Treatment of ALS

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05320
ICOC Funds Committed: 
$17 842 617
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
This project aims to use a powerful combined neural progenitor cell and growth factor approach to treat patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease). ALS is a devastating disease for which there is no treatment or cure. Progression from early muscle twitches to complete paralysis and death usually happens within 4 years. Every 90 minutes someone is diagnosed with ALS in the USA, and every 90 minutes someone dies from ALS. In California the death rate is one person every one and a half days. Human neural progenitor cells found early in brain development can be isolated and expanded in culture to large banks of billions of cell. When transplanted into animal models of ALS they have been shown to mature into support cells for dying motor neurons called astrocytes. In other studies, growth factors such as glial cell line-derived growth factor (or GDNF) have been shown to protect motor neurons from damage in a number of different animal models including ALS. However, delivering GDNF to the spinal cord has been almost impossible as it does not cross from the blood to the tissue of the spinal cord. The idea behind the current proposal is to modify human neural progenitor cells to produce GDNF and then transplant these cells into patients. There they act as “Trojan horses”, arriving at sick motor neurons and delivering the drug exactly where it is needed. A number of advances in human neural progenitor cell biology along with new surgical approaches have allowed us to create this disease team approach. The focus of the proposal will be to perform essential preclinical studies in relevant preclinical animal models that will establish optimal doses and safe procedures for translating this progenitor cell and growth factor therapy into human patients. The Phase 1/2a clinical study will inject the cells into one side of the lumbar spinal cord (that supplies the legs with neural impulses) of 12 ALS patients from the state of California. The progression in the treated leg vs. the non treated leg will be compared to see if the cells slow down progression of the disease. This is the first time a combined progenitor cell and growth factor treatment has been explored for patients with ALS.
Statement of Benefit to California: 
ALS is a devastating disease, and also puts a large burden on state resources through the need of full time care givers and hospital equipment. It is estimated that the cost of caring for an ALS patient in the late stage of disease while on a respiration is $200,000-300,000 per year. While primarily a humanitarian effort to avoid suffering, this project will also ease the cost of caring for ALS patients in California if ultimately successful. As the first trial in the world to combine progenitor cell and gene transfer of a growth factor, it will make California a center of excellence for these types of studies. This in turn will attract scientists, clinicians, and companies interested in this area of medicine to the state of California thus increasing state revenue and state prestige in the rapidly growing field of Regenerative Medicine.
Progress Report: 
  • ALS is a devastating disease for which there is no treatment or cure. Death of motor neurons in the spinal cord responsible for muscle function, results in complete paralysis and death usually within 2-4 years following diagnosis. This project will transplant stem cells secreting the powerful growth factor GDNF into the spinal cord of patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease) do delay motor neuron death and thus treat the disease. In the first year we have (i) put together an outstanding team that have been able to begin the process of all pre clinical studies required to reach a new investigational drug (IND) filing within two years, (ii) generated a bank of research grade neural stem cells producing GDNF and developed manufacturing protocols at clinical grad level to produce the final lot of cells for the trial, (iii) performed complete dose ranging studies in a rat model of ALS to generate the first set of data showing safety and optimal doses for the cell product, (iv) optimized parameters to perform small and large animal safety studies required to take this work to the clinic and (v) assembled an outstanding team of clinicians and developed a world leading ALS clinic that is now preparing for patients to enter this trial. In the next year, we hope to complete the clinical grade lot of stem cells producing GDNF, to complete the remaining safety studies in rodent and pigs that will allow us to submit the IND application enabling a Phase 1/2a clinical study in 18 ALS patients from the state of California.

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