Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Grant Type: 
Basic Biology IV
Grant Number: 
RB4-06079
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$1 506 420
Disease Focus: 
Huntington's Disease
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

A major medical problem in CA is the growing population of individuals with neurodegenerative diseases, including Parkinson’s (PD) and Huntington’s (HD) disease. These diseases affect millions of people, sometimes during the prime of their lives, and lead to total incapacitation and ultimately death. No treatment blocks the progression of neurodegeneration. We propose to conduct fundamental studies to understand the basic common disease mechanisms of neurodegenerative disorders to begin to develop effective treatments for these diseases. Our work will target human stem cells made from cells from patients with HD and PD that are developed into the very cells that degenerate in these diseases, striatal neurons and dopamine neurons, respectively. We will use a highly integrated approach with innovative molecular analysis of gene networks that change the states of proteins in these diseases and state-of-the-art imaging technology to visualize living neurons in a culture dish to assess cause and effect relationships between biochemical changes in the cells and their gradual death. Importantly, we will test whether drugs effective in animal model systems are also effective in blocking the disease mechanisms in the human HD and PD neurons. These human preclinical studies could rapidly lead to clinical testing, since some of the drugs have already been examined extensively in humans in the past for treating other disorders and are safe.

Statement of Benefit to California: 

Neurodegenerative diseases, such as Parkinson’s (PD) and Huntington’s disease (HD), are devastating to patients and families and place a major financial burden on California. No treatments effectively block progression of any neurodegenerative disease. A forward-thinking team effort will allow highly experienced investigators in neurodegenerative disease and stem cell research to investigate common basic mechanisms that cause these diseases. Most important is the translational impact of our studies. We will use neurons and astrocytes derived from patient induced pluripotent stem cells to identify novel targets and discover disease-modifying drugs to block the degenerative process. These can be quickly transitioned to testing in preclinical and clinical trials to treat HD and other neurodegenerative diseases. We are building on an existing strong team of California-based investigators to complete the studies. Future benefits to California citizens include: 1) discovery and development of new HD treatments with application to other diseases, such as PD, that affect thousands of Californians, 2) transfer of new technologies and intellectual property to the public realm with resulting IP revenues to the state with possible creation of new biotechnology spin-off companies, and 3) reductions in extensive care-giving and medical costs. We anticipate the return to the State in terms of revenue, health benefits for its Citizens and job creation will be significant.

Grant Type: 
Basic Biology IV
Grant Number: 
RB4-06093
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 264 248
Disease Focus: 
Neurological Disorders
Pediatrics
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

White matter is the infrastructure of the brain, providing conduits for communication between neural regions. White matter continues to mature from birth until early adulthood, particularly in regions of brain critical for higher cognitive functions. However, the precise timing of white matter maturation in the various neural circuits is not well described, and the mechanisms controlling white matter developmental/maturation are poorly understood. White matter is conceptually like wires and their insulating sheath is a substance called myelin. It is clear that neural stem and precursor cells contribute significantly to white matter maturation by forming the cells that generate myelin. In the proposed experiments, we will map the precise timing of myelination in the human brain and changes in the populations of neural precursor cells that generate myelin from birth to adulthood and define mechanisms that govern the process of white matter maturation. The resulting findings about how white matter develops may provide insights for white matter regeneration to aid in therapy for diseases such as cerebral palsy, multiple sclerosis and chemotherapy-induced cognitive dysfunction.

Statement of Benefit to California: 

Diseases of white matter account for significant neurological morbidity in both children and adults in California. Understanding the cellular and molecular mechanisms that govern white matter development the may unlock clues to the regenerative potential of endogeneous stem and precursor cells in the childhood and adult brain. Although the brain continues robust white matter development throughout childhood, adolescence and young adulthood, relatively little is known about the mechanisms that orchestrate proliferation, differentiation and functional maturation of neural stem and precursor cells to generate myelin-forming oligodendrocytes during postnatal brain development. In the present proposal, we will define how white matter precursor cell populations vary with age throughout the brain and determine if and how neuronal activity instructs neural stem and precursor cell contributions to human white matter myelin maturation.

Disruption of white matter myelination is implicated in a range of neurological diseases, including cerebral palsy, multiple sclerosis, cognitive dysfunction from chemotherapy exposure, attention deficit and hyperactivity disorder (ADHD) and even psychiatric diseases such as schizophrenia. The results of these studies have the potential to elucidate clues to white matter regeneration that may benefit hundreds of thousands of Californians.

Grant Type: 
Basic Biology IV
Grant Number: 
RB4-06045
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 393 200
Disease Focus: 
Amyotrophic Lateral Sclerosis
Dementia
Neurological Disorders
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Amyotrophic lateral sclerosis (ALS) is an idiopathic adult-onset degenerative disease characterized by progressive weakness from loss of upper and lower motor neurons. Onset is insidious, progression is essentially linear, and death occurs within 3-5 years in 90% of patients. In the US, 5,000 deaths occur per year and in the world, 100,000. In October, 2011, the causative gene defect in a long sought after locus on chromosome 9 for ALS, frontotemporal dementia (FTD) and overlap ALS-FTD was identified to be a expansion of a hexanucleotide repeat in the uncharacterized C9ORF72 gene. The goal of the proposed research is to generate human stem cell models from cells derived from ALS patients with the C9ORF72 expanded repeats and relevant control cells using genome-editing technology. We will also generate a stem cell model expressing the repeat independent of the C9ORF72 gene to study if the repeat alone is causing neural defects. Using advanced genome technologies, biochemical and cellular approaches, we will study the molecular pathways affected in motor neurons derived from these stem cell models. Finally, we will use innovative technologies to rescue the abnormal phenotypes that arise from the expanded repeat in human motor neurons. Completion of the proposed research is expected to transform our understanding of the regulatory and pathogenetic mechanisms underlying ALS and FTD, and establish therapeutic options for these debilitating diseases.

Statement of Benefit to California: 

Our research provides the foundation for decoding the mechanisms that underlie the single most frequent genetic mutation found to contribute to both ALS and FTD, debilitating neurological diseases that impact many Californians. In California, the expected prevalence of ALS (the number of total existing cases) is 2,200 to 3,000 cases at any one time, and the incidence is 750-1,100 new cases each year. The number of FTD cases is five times as many. Our research has and will continue to serve as a basis for understanding deviations from normal and disease patient neuronal cells, enabling us to make inroards to understanding neurological disease modeling using neurons differentiated from reprogammed patient-specific lines. Such disease modeling will have great potential for California health care patients, pharmaceutical and biotechnology industries in terms of improved human models for drug discovery and toxicology testing. Our improved knowledge base will support our efforts as well as other Californian researchers to study stem cell models of neurological disease and design new diagnostics and treatments, thereby maintaining California's position as a leader in clinical research.

Grant Type: 
iPSC Consortia Award
Grant Number: 
RP1-05741
Investigator: 
Type: 
PI
Type: 
Partner-PI
ICOC Funds Committed: 
$300 000
Disease Focus: 
Huntington's Disease
Neurological Disorders
Collaborative Funder: 
NIH
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Statement of Benefit to California: 
Grant Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05320
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$17 842 617
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human 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.

Grant Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05416
Investigator: 
Institution: 
Type: 
PI
Type: 
Co-PI
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 

Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the US, someone develops AD every 69 seconds and there are over 5 million individuals suffering from AD, including approximately 600,000 Californians. Current treatments do not alter the disease course. The absence of effective therapies coupled with the sheer number of affected patients renders AD a medical disorder of unprecedented need and a public health concern of significant magnitude. In 2010, the global economic impact of dementias was estimated at $604 billion, a figure far beyond the costs of cancer or heart disease. These numbers do not reflect the devastating social and emotional tolls that AD inflicts upon patients and their families. Efforts to discover novel and effective treatments for AD are ongoing, but unfortunately, the number of active clinical studies is low and many traditional approaches have failed in clinical testing. An urgent need to develop novel and innovative approaches to treat AD is clear.

We propose to evaluate the use of human neural stem cells as a potential innovative therapy for AD. AD results in neuronal death and loss of connections between surviving neurons. The hippocampus, the part of the brain responsible for learning and memory, is particularly affected in AD, and is thought to underlie the memory problems AD patients encounter. Evidence from animal studies shows that transplanting human neural stem cells into the hippocampus improves memory, possibly by providing growth factors that protect neurons from degeneration. Translating this approach to humans could markedly restore memory and thus, quality of life for patients.

The Disease Team has successfully initiated three clinical trials involving transplantation of human neural stem cells for neurological disorders. These trials have established that the cells proposed for this therapeutic approach are safe for transplantation into humans. The researchers in this Disease Team have shown that AD mice show a dramatic improvement in memory skills following both murine and human stem cell transplantation. With proof-of-concept established in these studies, the Disease Team intends to conduct the animal studies necessary to seek authorization by the FDA to start testing this therapeutic approach in human patients.

This project will be conducted as a partnership between a biotechnology company with unique experience in clinical trials involving neural stem cell transplantation and a leading California-based academic laboratory specializing in AD research. The Disease Team also includes expert clinicians and scientists throughout California that will help guide the research project to clinical trials. The combination of all these resources will accelerate the research, and lead to a successful FDA submission to permit human testing of a novel approach for the treatment of AD; one that could enhance memory and save lives.

Statement of Benefit to California: 

The number of AD patients in the US has surpassed 5.4 million, and the incidence may triple by 2050. Roughly 1 out of every 10 patients with AD, over 550,000, is a California resident, and alarmingly, because of the large number of baby-boomers that reside in this state, the incidence is expected to more than double by 2025. Besides the personal impact of the diagnosis on the patient, the rising incidence of disease, both in the US and California, imperils the federal and state economy.

The dementia induced by AD disconnects patients from their loved ones and communities by eroding memory and cognitive function. Patients gradually lose their ability to drive, work, cook, and carry out simple, everyday tasks, ultimately losing all independence. The quality of life for AD patients is hugely diminished and the burden on their families and caregivers is extremely costly to the state of California. Annual health care costs are estimated to exceed $172 billion, not including the additional costs resulting from the loss of income and physical and emotional stress experienced by caregivers of Alzheimer's patients. Given that California is the most populous state and the state with the highest number of baby-boomers, AD’s impact on California families and state finances is proportionally high and will only increase as the AD prevalence rises.

Currently, there is no cure for AD and no means of prevention. Most approved therapies address only symptomatic aspects of AD and no disease-modifying approaches are currently available. By enacting Proposition 71, California voters acknowledged and supported the need to investigate the potential of novel stem cell-based therapies to treat diseases with a significant unmet medical need such as AD.

In a disease like AD, any therapy that exerts even a modest impact on the patient's ability to carry out daily activities will have an exponential positive effect not only for the patients but also for their families, caregivers, and the entire health care system. We propose to evaluate the hypothesis that neural stem cell transplantation will delay the progression of AD by slowing or stabilizing loss of memory and related cognitive skills. A single, one-time intervention may be sufficient to delay progression of neuronal degeneration and preserve functional levels of memory and cognition; an approach that offers considerable cost-efficiency.

The potential economic impact of this type of therapeutic research in California could be significant, and well worth the investment of this disease team proposal. Such an approach would not only reduce the high cost of care and improve the quality of life for patients, it would also make California an international leader in a pioneering approach to AD, yielding significant downstream economic benefits for the state.

Grant Type: 
Early Translational III
Grant Number: 
TR3-05669
Investigator: 
ICOC Funds Committed: 
$1 673 757
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Human 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.

Grant Type: 
Early Translational III
Grant Number: 
TR3-05577
Investigator: 
ICOC Funds Committed: 
$1 857 600
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

We propose to discover new drug candidates for Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel candidates by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drugs by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.

Statement of Benefit to California: 

Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drugs to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches to drug discovery for AD.

Grant Type: 
Early Translational III
Grant Number: 
TR3-05476
Investigator: 
ICOC Funds Committed: 
$5 509 978
Disease Focus: 
Neurological Disorders
Pediatrics
Human Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

Children with inherited degenerative diseases of the brain will be among the first to benefit from novel approaches based on stem cell therapy (SCT). This assertion is based on a number of medical and experimental observations and precedents including:

1) These diseases currently lack effective therapies and can cause profound mental retardation or lead to death;
2) SCT has already been shown to work in the milder forms of similar diseases that do not affect the brain;
3) Experimental work and early clinical studies have clearly shown that stem cells delivered directly into the brain can be used to treat diseases affecting the brain; and
4) The clinical safety of stem cells delivered directly into the brain has already been established during recent Phase 1 clinical trials.

Our approach is designed to lead to a therapeutic development candidate, based on stem cells, by addressing two critical issues: (i) that early intervention is not only required but is indeed possible in this patient population and that, (ii) induction of immune tolerance is also required. We not only address these two important issues but also set the stage for efficient translation of our approach into clinical practice, by adapting transplant techniques that are standard in clinical practice or in clinical trials and using laboratory cell biology methods that are easily transferrable to the scale and processes of clinical cell manufacturing.

Statement of Benefit to California: 

We are focusing on a class of childhood brain diseases that causes a child's brain to degenerate and results in severe mental retardation or death, in addition to damage to many other organ systems. These diseases are not yet represented in CIRM’s portfolio. Recently blood stem cell transplantation has been applied to these diseases, showing that some of the organ systems can be rescued by stem cell therapy. Unfortunately, the brain component of the disease is not impacted by blood stem cell therapy. Our team proposes to take these important lessons to develop a therapy that treats all organ dysfunction, including brain. Because of the established stem cell success in the clinical treatment of non-brain organs and the experimental treatment of the brain, we propose a novel, combined stem cell therapy. Based on our own work and recent clinical experience, this dual stem cell therapy has a high probability of success for slowing or reversing disease, and importantly, will not require children to be treated with toxic immunosuppressive drugs. This therapy will thus benefit California by: 1) reducing disease burden in individuals and the State's burden for caring for these children; 2) providing a successful model of stem cell therapy of the brain that will both bolster public confidence in CIRM's mission to move complex stem cell therapies into the clinic; and 3) laying the groundwork for using this type of therapy with other brain diseases of children.

Grant Type: 
Early Translational III
Grant Number: 
TR3-05628
Investigator: 
ICOC Funds Committed: 
$4 699 569
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

We aim to develop a novel stem cell treatment for spinal cord injury (SCI) that is substantially more potent than previous stem cell treatments. By combining grafts of neural stem cells with scaffolds placed in injury sites, we have been able to optimize graft survival and filling of the injury site. Grafted cells extend long distance connections with the injured spinal cord above and below the lesion, while the host spinal cord also sends inputs to the neural stem cell implants. As a result, new functional relays are formed across the lesion site. These result in substantially greater functional improvement than previously reported in animal studies of stem cell treatment. Work proposed in this grant will identify the optimal human neural stem cells for preclinical development. Furthermore, in an unprecedented step in spinal cord injury research, we will test this treatment in appropriate preclinical models of SCI to provide the greatest degree of validation for human translation. Successful findings could lead to clinical trials of the most potent neural stem cell approach to date.

Statement of Benefit to California: 

Spinal cord injury (SCI) affects approximately 1.2 million people in the United States, and there are more than 11,000 new injuries per year. A large number of spinal cord injured individuals live in California, generating annual State costs in the billions of dollars. This research will examine a novel stem cell treatment for SCI that could result in functional improvement, greater independence and improved life styles for injured individuals. Results of animal testing of this approach to date demonstrate far greater functional benefits than previous stem cell therapies. We will generate neural stem cells from GMP-compatible human embryonic stem cells, then test them in the most clinically relevant animal models of SCI. These studies will be performed as a multi-center collaborative effort with several academic institutions throughout California. In addition, we will leverage expertise and resources currently in use for another CIRM-funded project for ALS, thereby conserving State resources. If successful, these studies will form the basis for clinical trials in a disease of great unmet medical need, spinal cord injury. Moreover, the development of this therapy would reduce costs for clinical care while bringing novel biomedical resources to the State.

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