Neurological Disorders

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

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

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

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

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

CIRM Tissue Collection for Neurodevelopmental Disabilities

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

Induced pluripotent stem cells from children with autism spectrum disorders

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06571
ICOC Funds Committed: 
$530 265
Disease Focus: 
Autism
Neurological Disorders
Pediatrics
oldStatus: 
Active
Public Abstract: 
Autism spectrum disorders (ASD) are a family of disabling disorders of the developing brain that affect about 1% of the population. Studying the biology of these conditions has been difficult as they have been challenging to represent in animal models. The core symptoms of ASD, including deficits in social communication, imagination and curiosity are intrinsically human and difficult to model in organisms commonly studied in the laboratory. Ideally, the mechanisms underlying ASDs need to be studied in human patients and in their cells. Since they maintain the genetic profile of an individual, studying neurons derived from human induced pluripotent stem cells (hiPSC) is attractive as a method for studying neurons from ASD patients. hiPSC based studies of ASDs hold promise to uncover deficits in cellular development and function, to evaluate susceptibility to environmental insults, and for screening of novel therapeutics. In this project our goal is to contribute blood and skin samples for hiPSC research from 200 children with an ASD and 100 control subjects to the CIRM repository. To maximize the value of the collected tissue, all subjects will have undergone comprehensive clinical evaluation of their ASD. The cells collected through this project will be made available to the wider research community and should result in a resource that will enable research on hiPSC-derived neurons on a scale and depth that is unmatched anywhere else in the world.
Statement of Benefit to California: 
The prevalence and impact of Autism Spectrum Disorders (ASD) in California is staggering. California has experienced 13% new ASD cases each year since 2002. ASD are a highly heritable family of complex neurodevelopmental conditions affecting the brain, with core symptoms of impaired social skills, language, behavior and intellectual abilities. The majority with an ASD experience lifelong disability that requires intensive parental, school, and social support. The result has been a 12-fold increase in the number of people receiving ASD services in California since 1987, with over 50,000 people with ASDs served by developmental and regional centers. Within the school system, the number of special education students with ASD in California has more than tripled between 2002 and 2010. The economic, social and psychological toll is enormous. It is critical to both prevent and develop effective treatments for ASD. While rare genetic mutations account for a minority of cases, our understanding of idiopathic ASD (>85% of cases) is extremely limited. Mechanisms underlying ASDs need to be studied in human patients and in cells that share the genetic background of these patients. Since they maintain the complete genetic background of an individual, hiPSCs represent a very practical and direct method for investigating neurons from ASD patients to uncover cellular deficits in their development and function, and for screening of novel therapeutics.

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.

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.

Developing a regeneration-based functional restoration treatment for spinal cord injury

Funding Type: 
Research Leadership 7
Grant Number: 
LA1_C7-05735
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.

Stem cell based small molecule therapy for Alzheimer's disease

Funding Type: 
Early Translational III
Grant Number: 
TR3-05669
ICOC Funds Committed: 
$1 673 757
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Over 6 million people in the US suffer from AD. There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate their replacement. Even if nerve cells could be replaced, the toxic environment of the brain will kill them unless they are protected by a drug. Therefore, drugs that stimulate the generation of new neurons (neurogenesis) alone will not be effective; a drug with both neurogenic and neuroprotective properties is required. With the ability to use cells derived from human embryonic stem cells (hESCs) as a screen for neurogenic compounds, it should now be possible to identify and tailor drugs for therapeutic use in AD. Our laboratory has developed a drug discovery scheme based upon using hESCs to screen drug candidates. We have recently identified a very potent drug that is exceptionally effective in rodent models of AD. However, this molecule needs to be optimized for human use. In this proposal, we will harness the power of hESCs to develop derivatives of J147 specifically tailored to stimulate neurogenesis and be neuroprotective in human cells. This work will optimize the chances for its true therapeutic potential in AD, and presents a unique opportunity to expand the use of hESCs for the development of a therapeutic for a disease for which there is no cure. This work could lead to a paradigm shift in the treatment of neurodegenerative disease.
Statement of Benefit to California: 
Over 6 million people in the US suffer from Alzheimer’s disease (AD). Unless a viable therapeutic is identified it is estimated that this number will increase to 16 million by 2050, with a cost of well over $1 trillion per year, overwhelming California and national health care systems. Among the top 10 causes of death, AD (6th) is the only one with no treatment available to prevent, cure or slow down the condition. An enormous additional burden to families is the emotional and physical stress of having to deal with a family member with a disease which is going to become much more frequent with our aging population. In this application we use new human stem cell technologies to develop an AD drug candidate based upon a strong lead compound that we have already made that stimulates the multiplication of nerve precursor cells derived from human embryonic stem cells. This approach presents a unique opportunity to expand the use of human embryonic stem cells for the development of a therapeutic for a disease for which there is no cure, and could lead to a paradigm shift in the treatment of neurodegenerative disease. Since our AD drug discovery approach is fundamentally different from the unsuccessful approaches used by the pharmaceutical industry, it could also stimulate new biotech. The work in this proposal addresses one of the most important medical problems of California as well as the rest of the world, and if successful would benefit all.
Progress Report: 
  • Introduction: Over 6 million people in the US suffer from AD. There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate their replacement. Even if nerve cells could be replaced, the toxic environment of the brain will kill them unless they are protected by a drug. Therefore, drugs that stimulate the generation of new neurons (neurogenesis) alone will not be effective; a drug with both neurogenic and neuroprotective properties is required. With the ability to use cells derived from human embryonic stem cells (hESCs) as a screen for neurogenic compounds, it should now be possible to identify and tailor drugs for therapeutic use in AD. This is the overall goal of this application.
  • Year One Progress: Using a novel drug discovery paradigm, we have made a very potent drug called J147 that is exceptionally effective in rodent models of AD and also stimulates neurogenesis in both young and very old mice. Very few, if any, drugs or drug candidates are both neuroprotective and neurogenic, particularly in old animals. In the first year of this application we harnessed the power of hESCs and medicinal chemistry to develop derivatives of J147 specifically tailored to stimulate neurogenesis and be neuroprotective in human cells. Using iterative chemistry, we synthesized over 200 new compounds, tested them for neurogenic properties in ES-derived neural precursor cells, assayed their ability to protect from the amyloid toxicity associated with AD, and determined their metabolic stability. All of the year one milestones we met and we now have the required minimum of six compounds to move into year two studies. In addition, we have made a good start on the work for year two in that some pharmacokinetics and safety studies has been completed.
  • This work will optimize the chances for its true therapeutic potential in AD, and presents a unique opportunity to expand the use of hESCs for the development of a therapeutic for a disease for which there is no cure. This work could lead to a paradigm shift in the treatment of neurodegenerative disease.

Human ES cell-derived MGE inhibitory interneuron transplantation for spinal cord injury

Funding Type: 
Early Translational III
Grant Number: 
TR3-05606
ICOC Funds Committed: 
$1 623 251
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Transplantation of neuronal precursors into the central nervous system offers great promise for the treatment of neurological disorders including spinal cord injury (SCI). Among the most significant consequences of SCI are bladder spasticity and neuropathic pain, both of which likely result from a reduction in those spinal inhibitory mechanisms that are essential for normal bladder and sensory functions. Our preliminary data show that embryonic inhibitory neuron precursor cells integrate in the adult nervous system and increase inhibitory network activity. Therefore inhibitory nerve cell transplants could be a powerful way to establish new inhibitory circuits in the injured spinal cord that will reduce bladder spasticity and attenuate central neuropathic pain. We already have proof-of-principle data that murine inhibitory nerve cells integrate in the adult spinal cord and improve symptoms in an animal model of chronic spinal cord injury. We have also recently developed methods to create human inhibitory interneurons from embryonic stem cells. This proposal will capitalize on these recent developments and determine whether our human embryonic stem cell-derived inhibitory cells can be successfully transplanted into the grey matter of the injured spinal cord and reduce neurogenic bladder dysfunction and neuropathic pain, two major causes of suffering in chronic SCI patients. If successful, our studies will lay the groundwork for a potential novel therapy for chronic SCI.
Statement of Benefit to California: 
There are an estimated 260,000 individuals in the United States who currently live with disability associated with chronic spinal cord injury (SCI). Symptoms of chronic SCI include bladder dyssynergia reflected by incontinence coincident with asynchronous contraction of internal and external sphincters, and central neuropathic pain, both of which severely impede activities of daily living, reduce quality of life, and contribute to the very high medical costs of caring for the Californians who suffer from chronic spinal cord injury. The Geron trial for SCI, as well as other cell-based approaches, aim to treat acute SCI. This proposal considers a different potentially complementary cell-transplantation strategy that is directed to more chronic SCI with the goal of improving bladder function and reducing pain. We propose to use cell grafts of inhibitory interneurons that we have derived from human stem cells in order to provide a novel treatment. If successful, we will have defined a therapeutic option that targets the most prevalent population of spinal cord injured patients. As the country's most populous state, California has the largest number of patients with chronic SCI, approximately 12,000. The estimated economic cost to California in lost productivity and medical expenses amounts to $400,000,000 annually. The potential savings in medical care costs, and improvement in quality of life will therfore have a disproportional benefit to the state of California.
Progress Report: 
  • From the past six months of work, we report considerable progress toward our aims of investigating the safety and efficacy of human inhibitory nerve precursor (MGE) cell transplantation for the treatment of spinal cord injury-induced bladder spasticity and neuropathic pain. Our first aim details the injection of human MGE cells into the uninjured rodent spinal cord and investigation of cell fate and potential adverse side effects from their transplantation. During the reporting period, we completed histological analyses for the two-month time point post-injection, and we found that the human MGE cells, derived from human embryonic stem cells (hESCs), appropriately matured into forebrain-type inhibitory interneurons in the rodent spinal cord. Also, we initiated histological examination of animals six months post-injection and detected robust human cell survival, dispersal into the spinal cord grey matter, and neuronal maturation, but no evidence of tumor formation. In addition, we completed behavioral analyses of animals injected with hESC-derived MGE cells at two and six months post-injection. Thus far, we have not observed any adverse side effects when human MGE cells are transplanted into the uninjured animal as determined by measures of body weight, locomotion, bladder function, and pain sensitivity.

Neural Stem Cell-Based Therapy For Parkinson’s Disease

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05431
ICOC Funds Committed: 
$99 976
Disease Focus: 
Parkinson's Disease
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
Ongoing degeneration of dopaminergic (DA) neurons in the midbrain is the hallmark of Parkinson’s disease (PD), a movement disorder that manifests with tremor, bradykinesia and rigidity. One million Americans live with PD and 60,000 are diagnosed with this disease each year. Although the cost is $25 billion per year in the United States alone, existing therapies for PD are only palliative and treat the symptoms but do not address the underlying cause. Levodopa, the gold standard pharmacological treatment to restore dopamine, is compromised over time by decreased efficacy and particularly increased side effects over time. Neural transplantation is a promising strategy for improving dopaminergic dysfunction in PD. The rationale behind neural transplantation is that grafting cells that produce DA into the denervated striatum will reestablish regulated neurotransmission and restore function. Indeed, over 20 years of research using fetal mesencephalic tissue as a source of DA neurons has demonstrated the therapeutic potential of cell transplantation therapy in animal model of PD and in human patients. However, there are limitations associated with primary human fetal tissue transplantation, including high tissue variability, lack of scalability, ethical concerns and inability to obtain an epidemiologically meaningful quantity of tissue. Thus, the control of the identity, purity and potency of these cells becomes exceedingly difficult and jeopardizes both the safety of the patient and the efficacy of the therapy. Thus the search of self-renewable sources of cells is a very worthwhile goal with societal importance and commercial application. Human neural stem cells are currently the only potential reliable and continuous source of homogenous and qualified populations of DA neurons for cell therapy for PD. Such cell source is ideal for developing a consistently safe and efficacious cellular product for treating large number of PD patients in California and throughout the world We have developed a human neural stem cell line with midbrain dopaminergic properties and the technology to make 75% of the neuronal population express dopamine. We have also shown that these cells are efficacious in the most authentic animal model of PD. We now propose to conduct the manufacturing of these cells in conjunction with the safety and efficacy testing to bring this much needed cellular product to PD patients and treat this devastating disease.
Statement of Benefit to California: 
In this grant application we propose to develop a unique technology to manufacture neurons that will be used to treat patients suffering from Parkinson’s disease. One million Americans live with PD and 60,000 are diagnosed with this disease each year. Although the cost is $25 billion per year in the United States alone, existing therapies for PD are only palliative and treat the symptoms but do not address the underlying cause. Levodopa, the gold standard pharmacological treatment to restore dopamine, is compromised over time by decreased efficacy and increased side effects. Human stem cells are currently the only potential reliable and continuous source of homogenous and qualified populations of DA neurons for cell therapy for PD. Such cell source is ideal for developing a consistently safe and efficacious cellular product for treating large number of PD patients in California and throughout the world We have developed a human neural stem cell line with midbrain dopaminergic properties and the technology to make 75% of the neuronal population express dopamine. We have also shown that these cells are efficacious in the most authentic animal model of PD. We now propose to conduct the manufacturing of these cells and safety and efficacy testing to bring this cell product to PD patients and treat this devastating disease. The CIRM grant will help us create further intellectual property pertaining to the optimization of the process of manufacturing of the cellular product we developed to treat PD. The grant will also create jobs at Californian institutions and contract companies we will work with to develop this product. Importantly, the intellectual property will be made available for licensing to biotechnology companies here in California to develop this product to treat the over 10 million people afflicted with PD world wide. Revenues from such a product will be beneficial to the California economy.
Progress Report: 
  • The planning award allowed the PI and members of the disease team to identify gaps in studies performed to date and strategically plan manufacturing and preclinical IND enabling studies to lead into a phase I clinical trial
  • The PI, Marcel Daadi, PhD assembled a team comprised of neurosurgeons, neurologists and scientists with expertise in Parkinson’s disease, a contract manufacturing organization (CMO) for cell production, a contract research organization (CRO) for the pharmacology and toxicology studies, and accomplished regulatory and project management consultants to work together on developing a cellular product for treating Parkinson’s disease.
  • Together with the members of the disease team, the PI established a detailed strategy to meet the overall goal of the project, to develop a human neural stem cell (NSC) line for transplantation into patients. The team put together a plan to manufacture the cells that included seven stages:
  • STAGE 1: Product manufacturing and process development in the PI laboratory, with CMO’s participation, in preparation for technology transfer including material sourcing, gap analysis of the current manufacturing and analytical process, development of product characterization profile, refinement of manufacturing and analytical procedures and development of requisite documentation.
  • STAGE 2: Technology transfer to CMO, comprised of training and establishing the necessary resources, perform the manufacturing process in house, demonstrate tech transfer and perform runs to manufacture GMP-like cell product suitable for non-GLP animal studies at the CRO facility.
  • STAGE 3: Manufacturing of GLP materials for use in the pre-clinical studies.
  • STAGE 4: Early pre-clinical non-GLP studies using materials that meet product release criteria. The preclinical studies will address critical issues such as delivery devise and approach, immuno-suppression regiment, dose-range finding study, imaging MRI/PET, micro-dialysis, immune response, behavioral outcome, dyskinesias, immunohistopathology and biochemical analysis.
  • STAGE 5: Formal GLP pre-clinical studies using the GMP materials manufactured at CMO with primary efficacy endpoint that is a significant change in the PD score without appearance of dyskinesias.
  • STAGE 6: Regulatory support activities, including pre-pre IND and pre-IND meetings, and compilation and filing of the IND.
  • STAGE 7: Full Process Qualification at the CMO, and manufacture of the GMP cell bank.
  • Among preclinical development studies proposed are a definitive single-dose toxicity and toxicokinetic study in rats with functional observation battery, a one year recovery period (GLP), tumorigenicity in NOD-SCID mice and study to determine dose-range for efficacy and safety in non-human primates.

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