Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06345
Investigator: 
ICOC Funds Committed: 
$1 360 450
Disease Focus: 
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
iPS 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.
  • 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. During the progress period, we have obtained considerable evidence that this hypothesis not only applies to mouse stem cells but also human embryonic stem cells. 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. During the progress period, we obtained both experimental and genome-wide data that this applies to human embryonic stem cells. 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 and characterizing induced-pluripotent stem (iPS) cells from intellectual disability patients with mutations in the UPF3B gene towards this goal.
Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06079
Investigator: 
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.
  • 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 reporting period we have made good progress in both developing new assays and novel autophagy compounds and identifying potential genetic targets that could lead to novel therapeutic strategies for patients with HD and PD. We have developed methods to measure the degradation rates of proteins involved in causing neurodegeneration and the decay rates of mitochondria that are disrupted during the progression of these diseases. We are now investigating if and how these degradation rates differ in cells from patients with HD. We have developed novel compounds that can activate the autophagy pathway which is critical for degrading the toxic proteins that cause neurodegeneration. We are now testing if these compounds can increase the survival of neurons derived from iPSCs from patients with HD. Using pathway analysis we have also identified specific genes within the proteostasis network that are modulated in HD. Specifically we have identified deubiquitinating enzymes as modulators of HD induced toxicity and autophagy modulation, potentially indicating that importance of the autophagy pathway in the disease progression. We are also using RNAseq analysis to investigate if neurons derived from iPSCs from PD patients exhibit differences in the genes expressed in the proteostasis network. If we identify key genes we will use our established human neuron model for PD to validate whether these genes modulate the disease phenotype via changes in proteostasis. Ultimately we hope to identify overlapping targets that could potentially rescue disease associated phenotypes in both HD and PD.
Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06277
Investigator: 
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.
  • 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 have been studying these AxD astrocytes to find out how their defects cause the disease and have identified a defective signaling pathway in these cells. 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.
Funding Type: 
iPSC Consortia Award
Grant Number: 
RP1-05741
Investigator: 
Type: 
PI
Type: 
Partner-PI
ICOC Funds Committed: 
$300 000
Disease Focus: 
Huntington's Disease
Neurological Disorders
Collaborative Funder: 
NIH
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.
Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05736
Investigator: 
Institution: 
Type: 
PI
Type: 
Co-PI
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.
Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05416
Investigator: 
Institution: 
Type: 
PI
Type: 
Co-PI
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.
  • Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the United States, 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. Efforts to discover 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 urgent.
  • StemCells Inc., 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. 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 September 2012, the CIRM awarded a loan to StemCells Inc. to partially fund a program to test human neural stem cells in two animal models used by some researchers to study AD and the study was initiated in July of 2013. The goal of this study was chiefly to try to replicate earlier successful experiments with human neural stem cells in these mice in support of an IND filing with the U.S. FDA within four years.
  • In the first year of the study, the Disease Team actively worked on 5 important scientific milestones in our effort to develop human neural stem cells as a potential therapy for AD. We also held a pre-IND meeting with the FDA in which we shared our plans for the preclinical and clinical studies in AD; the meeting provided helpful guidance and assurances regarding our IND enabling activities.
  • As of the second year of the study, all of the first 5 scientific milestones have been completed. Specifically, the team conducted three animal studies believed necessary 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.
  • Despite seeing a very exciting increase in the number of connections between key hippocampal neurons within the brains of mice treated with human neural stem cells, this did not appear to robustly and consistently improve memory in the animals. Without seeing a significant change in memory performance, the preclinical results of the study did not satisfy one or more of the specific “No/No Go” scientific milestones agreed to with the CIRM. Given this, the loan was subsequently terminated in December 2014 as a consequence of the unanticipated preclinical results.
  • This study was 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. Although disappointing, the results of this study do not negate the potential of neural stem cell transplantation in AD; rather, having reviewed and discussed the data with our collaborators, we believe the data highlight the challenge of obtaining reliable and consistent behavior readouts of memory improvement in animals. Finally, the observed increases in the connections between hippocampal neurons are very interesting and may justify further efforts to improve pre-clinical development for this complex disorder.
Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05320
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$17 842 617
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Stem Cell Use: 
Other
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.
  • The goal of this project is to produce a clinical grade of human neural progenitor cells that are modified to release the powerful growth factor GDNF that protects dying motor neurons in the spinal cord. In year 2 of this project, we have significantly advanced all aspects of the study and overcome a major hurdle related to the production of the clinical grade human neural progenitor cells (our product that is called CNS10-NPC-GDNF). The challenge was to scale up our laboratory methods (where we produce only a few vials of the cells for lab use) to a clinical grade set of over 1000 vials. Thanks to a major collaborative effort with the City of Hope, many weeks of trouble shooting, and the tenacity of our own scientists, and the CIRM funding, we are happy to report that we now have a clinical grade lot of cells (1,200 vials) for use in all of our animal testing studies and the clinical trial itself. In addition we have now completed all of our dose ranging studies and demonstrated that transplantation CNS10-NPC-GDNF in the lumbar spinal cord of an ALS rat model has a neuroprotective effect on motor neurons at all doses investigated. During this year we have completed more pilot studies in the pig using a novel delivery device (developed by Cedars-Sinai) that will now be used to deliver the cells to the spinal cord of the patients in the trial and is currently moving though the regulatory pathway. Our ALS clinic has expanded rapidly over the past year and implemented more extensive patient testing using the new CIRM funded ATLAS chair to assess overall body strength. Given the size of our clinic we are now confident of recruiting enough patients within southern California to alter the trial from multi sites to a single site within California – Cedars-Sinai. This will allow a more focused approach and development of this novel treatment locally – with subsequent expansion to more sites. We have recruited more members of the clinical team to allow for this. Finally we have continued to present our results at meetings around the world and publish our data in the spirit of communicating this important work to both the scientific community and public.
Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05415
Investigator: 
Type: 
PI
Name: 
Type: 
Co-PI
ICOC Funds Committed: 
$18 950 061
Disease Focus: 
Huntington's Disease
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
One in every ten thousand people in the USA has Huntington's disease, and it impacts many more. Multiple generations within a family can inherit the disease, resulting in escalating health care costs and draining family resources. This highly devastating and fatal disease touches all races and socioeconomic levels, and there are currently no cures. Screening for the mutant HD gene is available, but the at-risk children of an affected parent often do not wish to be tested since there are currently no early prevention strategies or effective treatments. We propose a novel therapy to treat HD; implantation of cells engineered to secrete Brain-Derived Neurotrophic factor (BDNF), a factor needed by neurons to remain alive and healthy, but which plummets to very low levels in HD patients due to interference by the mutant Huntingtin (htt) protein that is the hallmark of the disease. Intrastriatal implantation of mesenchymal stem cells (MSC) has significant neurorestorative effects and is safe in animal models. We have discovered that MSC are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into each damaged cell that they contact. Thus we are utilizing nature's own paramedic system, but we are arming them with enhanced neurotrophic factor secretion to enhance the health of at-risk neurons. Our novel animal models will allow the therapy to be carefully tested in preparation for a phase I clinical trial of MSC/BDNF infusion into the brain tissue of HD patients, with the goal of restoring the health of neurons that have been damaged by the mutant htt protein. Delivery of BDNF by MSC into the brains of HD mice is safe and has resulted in a significant reduction in their behavioral deficits, nearly back to normal levels. We are doing further work to ensure that the proposed therapy will be safe and effective, in preparation for the phase I clinical trial. The significance of our studies is very high because there are currently no treatments to diminish the unrelenting decline in the numbers of medium spiny neurons in the striata of patients affected by HD. Our biological delivery system for BDNF could also be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1), Alzheimer's Disease, and some forms of Parkinson's Disease, where neuroregeneration is needed. Development of novel stem cell therapies is extremely important for the community of HD and neurodegenerative disease researchers, patients, and families. Since HD patients unfortunately have few other options, the potential benefit to risk ratio for the planned trial is very high.
Statement of Benefit to California: 
It is estimated that one in 10,000 CA residents have Huntington’s disease (HD). While the financial burden of HD is estimated to be in the billions, the emotional cost to friends, families, and those with or at risk for HD is immeasurable. Health care costs are extremely high for HD patients due to the long progression of the disease, often for two decades. The lost ability of HD patients to remain in the CA workforce, to support their families, and to pay taxes causes additional financial strain on the state’s economy. HD is inherited as an autosomal dominant trait, which means that 50% of the children of an HD patient will inherit the disease and will in turn pass it on to 50% of their children. Individuals diagnosed through genetic testing are at risk of losing insurance coverage in spite of reforms, and can be discriminated against for jobs, school, loans, or other applications. Since there are currently no cures or successful clinical trials to treat HD, many who are at risk are very reluctant to be tested. We are designing trials to treat HD through rescuing neurons in the earlier phases of the disease, before lives are devastated. Mesenchymal stem cells (MSC) have been shown to have significant effects on restoring synaptic connections between damaged neurons, promoting neurite outgrowth, secreting anti-apoptotic factors in the brain, and regulating inflammation. In addition to many trials that have assessed the safety and efficacy of human MSC delivery to tissues via systemic IV infusion, MSC are also under consideration for treatment of disorders in the CNS, although few MSC clinical trials have started so far with direct delivery to brain or spinal cord tissue. Therefore we are conducting detailed studies in support of clinical trials that will feature MSC implantation into the brain, to deliver the neurotrophic factor BDNF that is lacking in HD. MSC can be transferred from one donor to the next without tissue matching because they shelter themselves from the immune system. We have demonstrated the safe and effective production of engineered molecules from human MSC for at least 18 months, in pre-clinical animal studies, and have shown with our collaborators that delivery of BDNF can have significant effects on reducing disease progression in HD rodent models. We are developing a therapeutic strategy to treat HD, since the need is so acute. HD patient advocates are admirably among the most vocal in California about their desire for CIRM-funded cures, attending almost every public meeting of the governing board of the California Institute for Regenerative Medicine (CIRM). We are working carefully and intensely toward the planned FDA-approved approved cellular therapy for HD patients, which could have a major impact on those affected in California. In addition, the methods, preclinical testing models, and clinical trial design that we are developing could have far-reaching impact on the treatment of other neurodegenerative disorders.
Progress Report: 
  • Huntington’s disease (HD) is a hereditary, fatal neuropsychiatric disease. HD occurs in one in every ten thousand people in the USA. The effects of the disease on patients, families, and care givers are devastating as it reaches from generation to generation. This fatal disease touches all races and socioeconomic levels, and current treatment is strictly palliative. Existing drugs can reduce the involuntary movements and psychiatric symptoms, but do nothing to slow the inexorable progression. There is currently no cure for HD. People at risk of inheriting HD can undergo a genetic counseling and testing to learn if they are destined to develop this dreadful disease. Many people from HD families fear the consequences of stigma and genetic discrimination. Those at-risk often do not choose to be tested since there are currently no early prevention strategies or effective treatments.
  • We propose a novel therapy to treat HD: implantation of cells engineered to secrete Brain-Derived
  • Neurotrophic Factor (BDNF), a factor that can promote addition of new neurons to the affected area of the brain. BDNF is reduced in HD patients due to interference by the mutant Huntingtin (htt) protein that is the hallmark of the disease. We have discovered that mesenchymal stem/stromal cells (MSC), a type of adult stem cell, are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into damaged cells they contact. In animal models of HD implantation of MSC into the brain has significant neurorestorative effects and is safe. We propose to use these MSCs as “nature's own paramedic system”, arming them with BDNF to enhance the health of at-risk neurons. Our HD animal models will allow the therapy to be carefully tested in preparation for a proposed Phase I clinical trial of MSC/BDNF implantation into the brain of HD patients (HD-CELL), with the goal of slowing disease progression.
  • Delivery of BDNF by MSC into the brains of HD mice is safe and has resulted in a significant reduction in their behavioral deficits, nearly back to normal levels. We are doing further efficacy and safety studies in preparation for the Phase I clinical trial. The significance of our studies is very high because there are currently no other options, there is no current treatment to delay the onset or slow the progression of the disease.. There are potential applications beyond Huntington’s disease. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer's disease, and some forms of Parkinson's disease. Since HD patients unfortunately have few other options, the potential benefit to risk ratio for the planned trial is very high.
  • In the first year of our grant we have successfully engineered human MSCs to produce BDNF, and are studying effects on disease progression in HD mice. We have developed methods to produce these cells in large quantities to be used for future human clinical studies. As we go forward in year 2 we plan to complete the animal studies that will allow us to apply for regulatory approval to go forward with the planned Phase I trial.
  • We have designed an observational study, PRE-CELL, to track disease progression and generate useful data in preparation for this future planned Phase I clinical trial. PRE-CELL has been approved by the institution’s ethics board and is currently enrolling subjects. PRE-CELL was designed to operate concurrently with the ongoing pre-clinical safety testing. For additional information go to: ClinicalTrials.gov Identifier: NCT01937923
  • Background: Huntington’s disease (HD) is a genetically inherited, fatal neuropsychiatric disorder which strikes 1/10,000 people. The cause is a repeat expansion in the Huntingtin gene which leads to progressive brain degeneration, ultimately resulting in death after 15-20 years. HD passes from generation to generation. Each child of a parent with HD has a 50% chance of inheriting the HD mutation. There is currently no treatment, therapy or medication that will delay the onset of the disease or slow its progression. All currently available treatments are palliative, which focus on symptom management alone. There is currently no cure for HD.
  • Proposed therapy: We propose a novel therapy for HD: implantation of mesenchymal stem cells engineered to secrete Brain-Derived Neurotrophic Factor (MSC/BDNF). BDNF levels are reduced in the brains of HD patients. BDNF has been shown in numerous transgenic HD mouse studies to prevent cell death and to stimulate the growth and migration of new neurons in the brain, and is thus a lead candidate for neuroprotection in HD. We are using MSCs as delivery vehicles to produce BDNF in the affected areas of the striatum. We are conducting detailed tests of MSC/BDNF in HD mouse models in preparation for a proposed Phase I clinical trial of MSC/BDNF implantation into the brain of HD patients (HD-CELL), with the goal of slowing disease progression.
  • Progress, Year 2 of grant: Based on recommendations from the CIRM Clinical Development Advisory Panel (CDAP), we altered our vector and added a second animal model. Following CDAP, we repeated all manufacturing and testing of MSC/BDNF using the new vector, produced using Standard Operating Procedures (SOPs) from our UC Davis Good Manufacturing Practices (GMP) Facility. We have shown that MSC/BDNF produces high levels of BDNF and that a multiplicity of infection of ten virus particles per cell generates a single unrearranged integrant per cell, on average. This is data critical to the Recombinant DNA Advisory Committee (RAC), for whom we have prepared an Appendix M application. RAC approval is needed prior to FDA approval because it is a proposed stem cell gene therapy trial. We are currently refining our application to the FDA and will seek CIRM approval for submission.
  • We are completing our double-blinded studies, now using the new vector, examining the effects on disease progression of implantation of MSC/BDNF in two strains of HD transgenic mice: YAC 128 and R6/2 (CAG 120). The R6/2 (CAG 120) model has the early onset of neurologic dysfunction and dies much earlier than wild-type of YAC 128 models. For this reason it is a more suitable model of juvenile HD. In the R6/2 model we have successfully demonstrated that implantation of MSC/BDNF causes an improvement in deficits in open field exploration, a behavioral assay. We have also shown that MSC/BDNF causes increased neurogenesis in the brain of treated mice, an important milestone.
  • The YAC 128 model develops slowly progressive behavior symptoms in mid-life and has loss of brain cells that mirrors changes seen in HD patients. In the YAC 128 model we have shown that implantation of our MSC/BDNF product decreases striatal atrophy between 8 and 12 months of age. Wild type mice have a typical lifespan of two years, so this age in the YAC 128 mouse roughly corresponds to the typical age at onset for early-stage HD patients that we are proposing to treat in our future planned Phase 1 study, HD-CELL.
  • Clinical Update: In tandem with the on-going preIND studies in the lab, the clinical team is conducting an observational study, PRE-CELL. The goal of PRE-CELL is to establish baseline characteristics and track disease progression in a group of early stage HD patients. PRE-CELL subjects undergo detailed neurological, psychiatric, cognitive, imaging and laboratory testing, including measurement of BDNF levels. PRE-CELL participants who have completed at least 1 year of follow-up and meet inclusion and exclusion criteria will be considered for the future planned cell therapy trial. PRE-CELL has been approved by the Institutional Review Board at UC Davis since July 2013 and is still enrolling. For additional information, please go to: ClinicalTrials.gov Identifier: NCT01937923.
  • Significance: Our progress to date supports the completion of our final pre-clinical studies and our plan to go forward toward regulatory approval. There are potential applications of our research beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer's disease, and some forms of Parkinson's disease. It also provides a platform for our future gene editing studies, since we will again use MSCs to deliver the needed molecules into the neurons.
Funding Type: 
Research Leadership 7
Grant Number: 
LA1_C7-05735
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$5 609 890
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
One of the most exciting and challenging frontiers in neuroscience and medicine is to repair traumatic injuries to the central nervous system (CNS). Most spinal cord and head injuries result in devastating paralyses, yet very limited clinical intervention is currently available to restore the lost abilities. Traumatic injuries of the spine cause fractures and compression of the vertebrae, which in turn crush and destroy the axons, long processes of nerve cells that carry signals up and down the spinal cord between the brain and the rest of the body. It follows that the best chance for promoting functional recovery is identifying strategies that enable lesioned axons to regenerate and reconnect the severed neural circuits. Even minor improvements in voluntary motor functions after spinal cord injury could be immensely helpful for increasing the quality of life, employability, and independence, especially for patients with injuries at the upper spinal level. Thus, our overall research program centers on axon regeneration in general, with a focus on regenerating descending axons from the brain that control voluntary motor and other functions. We recently made breakthrough discoveries in identifying key biological mechanisms stimulating the re-growth of injured axons in the adult nervous system, which led to unprecedented extents of axon regeneration in various CNS injury models. While our success was compelling, we found that many regenerated axons were stalled at the lesion sites by the injury-induced glial scars. Furthermore, it is unclear whether the regenerated axons can form functional synaptic connections when they grow into the denervated spinal cord. This proposed research program is aimed at solving these obstacles by using human stem cell technologies. In the first aim, we will use human neural stem cells to engineer “permissive cell bridges” that can guide the maximum number of regenerating axons to grow across injury sites. In the second aim, we will test the therapeutic potential of human stem cell-derived neurons in forming “functional relays” that could propagate the brain-derived signals carried by regenerating axons to the injured spinal cord. Together, our research program is expected to develop a set of therapeutic strategies that have immediate clinical implications for human SCI patients.
Statement of Benefit to California: 
Approximately 1.9% of the U.S. population, roughly 5,596,000 people, report some forms of paralysis; among whom, about 1,275,000 individuals are paralyzed due to spinal cord injuries (SCI). The disabilities and medical complications associated with SCI not only severely reduce the quality of life for the injured individuals, but also result in an estimated economical burden of $400,000,000 annually for the state of California in lost productivity and medical expenses. Traumatic injuries of the spine cause fractures and compression of the vertebrae, which in turn crush and destroy the axons, long processes of nerve cells that carry signals up and down the spinal cord between the brain and the rest of the body. Thus, identifying strategies that enable lesioned axons to regenerate and reconnect the severed neural circuits is crucial for promoting functional recovery after SCI. In recent years, we made breakthrough discoveries in identifying key biological mechanisms stimulating the re-growth of injured axons in the adult nervous system. This proposed research program is aimed at developing human neural stem cell based therapeutic strategies that enable regenerated axons to grow through tissue cavities at the injury site, and establish functionally relays between the regenerating cortical axons and the spinal circuits below the injury site, thereby restore the lost sensory/motor functions in SCI patients. Success of these proposed studies could lead to immediate therapeutic applications for SCI patients. The first stem cell-based clinical trial for human SCI is started in California in which stem cells are used to provide support and stimulate remyelination. Our stem cell based therapeutic strategies are aimed at re-building neural connections, which will compliment the existing strategy nicely. As a result, Californians will be the first beneficiaries of these therapies.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05628
Investigator: 
ICOC Funds Committed: 
$4 699 569
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
We aim to develop a novel stem cell treatment for spinal cord injury (SCI) that is substantially more potent than previous stem cell treatments. By combining grafts of neural stem cells with scaffolds placed in injury sites, we have been able to optimize graft survival and filling of the injury site. Grafted cells extend long distance connections with the injured spinal cord above and below the lesion, while the host spinal cord also sends inputs to the neural stem cell implants. As a result, new functional relays are formed across the lesion site. These result in substantially greater functional improvement than previously reported in animal studies of stem cell treatment. Work proposed in this grant will identify the optimal human neural stem cells for preclinical development. Furthermore, in an unprecedented step in spinal cord injury research, we will test this treatment in appropriate preclinical models of SCI to provide the greatest degree of validation for human translation. Successful findings could lead to clinical trials of the most potent neural stem cell approach to date.
Statement of Benefit to California: 
Spinal cord injury (SCI) affects approximately 1.2 million people in the United States, and there are more than 11,000 new injuries per year. A large number of spinal cord injured individuals live in California, generating annual State costs in the billions of dollars. This research will examine a novel stem cell treatment for SCI that could result in functional improvement, greater independence and improved life styles for injured individuals. Results of animal testing of this approach to date demonstrate far greater functional benefits than previous stem cell therapies. We will generate neural stem cells from GMP-compatible human embryonic stem cells, then test them in the most clinically relevant animal models of SCI. These studies will be performed as a multi-center collaborative effort with several academic institutions throughout California. In addition, we will leverage expertise and resources currently in use for another CIRM-funded project for ALS, thereby conserving State resources. If successful, these studies will form the basis for clinical trials in a disease of great unmet medical need, spinal cord injury. Moreover, the development of this therapy would reduce costs for clinical care while bringing novel biomedical resources to the State.
Progress Report: 
  • In the first 12 months of this project we have made important progress in the following areas:
  • 1) Identified the lead embryonic stem cell type for potential use in a translational clinical program.
  • 2) Replicated the finding that implants of ES-derived neural progenitor cells from this lead cell type extend axons out from the spinal cord lesion site in very high numbers and over very long distances.
  • 3) Begun efforts to scale this work to larger animal models of spinal cord injury.
  • Very good progress has been made in the last year on this project. We are attempting to address a great unmet medical need to develop effective therapies for human spinal cord injury (SCI). We aim to develop and optimize a pluripotent neural stem cell line for grafting to sites of spinal cord injury, and develop this line for clinical translation. Unlike other programs of stem cell therapy for SCI, we are transplanting neural stem cells directly into the injury site, in high numbers, and we observe very extensive growth of axons both into and out of the graft. The amount of axon growth in this model is substantially greater than that observed with other approaches to the injured spinal cord, including approaches currently in clinical trials. Accordingly, we believe that our approach provides a substantially greater opportunity to improve outcomes after SCI.
  • In the last year, we have identified a lead stem cell line for potential human translation, and validated its ability to engraft to the injured spinal cord. We have observed that human neural stem cells, grafted into mice and rats, exhibit a human time frame for maturation and growth: cells require at least one year to develop and mature. This knowledge is very important for planning human clinical trials.
  • Remaining work will characterize the long term safety and efficacy of these cells in rodent and large animal models of SCI.

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