Neurological Disorders

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

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

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

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

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

CIRM Tissue Collection for Neurodevelopmental Disabilities

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

Induced pluripotent stem cells from children with autism spectrum disorders

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

White matter neuroregeneration after chemotherapy: stem cell therapy for “chemobrain”

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06510
ICOC Funds Committed: 
$2 975 536
Disease Focus: 
Neurological Disorders
Brain Cancer
Cancer
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Chemotherapy for cancer is often life saving, but it also causes a debilitating syndrome of impaired cognition characterized by deficits in attention, concentration, information processing speed, multitasking and memory. As a result, many cancer survivors find themselves unable to return to work or function in their lives as they had before their cancer therapy. These cognitive deficits, colloquially known as "chemobrain" or "chemofog," are long-lasting and sometimes irreversible. For example, breast cancer survivors treated with chemotherapy suffer from cognitive disability even 20 years later. These cognitive problems occur because chemotherapy damages the neural stem and precursor cells necessary for the health of the brain's infrastructure, called white matter. We have discovered a powerful way to recruit the stem/precursor cells required for white matter repair that depends on an interaction between the electrical cells of the brain, neurons, and these white matter stem/precursor cells. In this project, we will determine the key molecules responsible for the regenerative influence of neurons on these white matter stem cells and will develop that molecule (or molecules) into a drug to treat chemotherapy-induced cognitive dysfunction. If successful, this will result in the first effective treatment for a disease that affects at least a million cancer survivors in California.
Statement of Benefit to California: 
Approximately 100,000 Californians are diagnosed with cancer each year, and the majority of these people require chemotherapy. While cancer chemotherapy is often life saving, it also causes a debilitating neurocognitive syndrome characterized by impaired attention, concentration, information processing speed, multitasking and memory. As a result, many cancer survivors find themselves unable to return to work or function in their lives as they had before their cancer therapy. These cognitive deficits, colloquially known as "chemobrain" or "chemofog" are long-lasting; for example, cognitive deficits have been demonstrated in breast cancer survivors treated with chemotherapy even 20 years later. With increasing cancer survival rates, the number of people living with cognitive disability from chemotherapy is growing and includes well over a million Californians. Presently, there is no known therapy for chemotherapy-induced cognitive decline, and physicians can only offer symptomatic treatment with medications such as psychostimulants. The underlying cause of "chemobrain" is damage to neural stem and precursor cell populations. The proposed project may result in an effective regenerative strategy to restore damaged neural precursor cell populations and ameliorate or cure the cognitive syndrome caused by chemotherapy. The benefit to California in terms of improved quality of life for cancer survivors and restored occupational productivity would be immeasurable.

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.

Progenitor Cells Secreting GDNF for the Treatment of ALS

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

MSC engineered to produce BDNF for the treatment of Huntington's disease

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05415
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

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.

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