Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Grant Type: 
Basic Biology II
Grant Number: 
RB2-01496
Investigator: 
Type: 
PI
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$1 284 921
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Collaborative Funder: 
Japan
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

Multipotent Neural Stem Cells (NSC) can be derived from adult central nervous system (CNS) tissue, embryonic stem cells (ESC), or iPSC and provide a partially committed cell population that has not exhibited evidence of tumorigenesis after long term CNS transplantation. Transplantation of NSC from these different sources has been shown by multiple investigators in different CNS injury and disease paradigms to promote recovery or ameliorate disease. Additionally, both {REDACTED} groups have shown that human NSCs transplanted in the subacute period after spinal cord injury promote functional recovery. While the role of the host immune response has been considered in the context of immune-rejection, predominantly regarding the T-cell response, the consequence of an ongoing inflammatory response within the context of the tissue microenvironment for cell fate, migration, and integration/efficacy has been largely overlooked. Critically, the tumorigeneis, fate, migration, and integration/repair potential of a stem cell is driven by: 1) the intrinsic properties of cell programming, e.g., the type and source of cell / means used to derive the cell, and maintenance/differentiation of the cell in vitro; and 2) the extrinsic factors the cell encounters. Variations in the intrinsic properties of the cell may affect the potential of that cell for uncontrolled proliferation or the response of the cell to extrinsic factors that it later encounters, defining its fate, migration, and integration/repair potential. The {REDACTED} group has demonstrated that iPS-derived neurospheres (iPS-NS) exhibit a surprisingly large degree of variation in tumorigenesis potential after CNS transplantation, which is correlated with tissue source as well as differentiation and NS forming capacity. Moreover, the intrinsic properties of hNSC populations derived from different cell sources have not been broadly characterized; in fact, {REDACTED} has published the first data in the field demonstrating the differences in fate and integration/repair potential between primary and secondary neurospheres generated via in vitro differentiation of mouse or human ESC and iPSC. In parallel, {REDACTED} has shown profound differences in the response of NSC derived from human tissue versus hESC to extrinsic signals. Together, these data suggest that both characterization of the intrinsic properties of NSCs derived from different sources is essential for our understanding of the basic biology of these cells. Investigation of molecules and signaling pathways directing hNSC fate choices in the injured CNS microenvironment will yield new insight into the mechanisms of fate and migration decisions in these cell populations.

Statement of Benefit to California: 

Multipotent Neural Stem Cells (NSC) can be derived from adult central nervous system (CNS) tissue, embryonic stem cells (ESC), or induced pluripotent cells (iPSC) and provide a partially committed cell population that has not exhibited evidence of tumorigenesis after long term CNS transplantation. Transplantation of NSC from these different sources has been shown by multiple investigators in different CNS injury and disease paradigms to promote recovery or ameliorate disease. Accordingly, stem cell based therapeutics such as these have the potential to treat a variety of traumatic, congenital, and acquired human conditions. However, while much progress has been made, translational research with human stem cell populations will remain limited by the progress of the fundamental understanding of the basic biology of these cells. The {REDACTED} group has pioneered understanding the critical role of timing in considering cell transplantation therapies. More recently, this group has focused on the neural induction of mouse- and human-derived iPSC and tested the potential of these cell populations for spinal cord injury treatment in animal models. {REDACTED} has established the NOD-scid mouse as a model for experimental neurotransplantation for xenograft studies, characterizing the relationship between transplant timing, engraftment outcome, cell fate, host remyelination, and functional recovery. Recently, this group has focused on how the innate inflammatory response influences cell fate and migration. In this collaborative proposal, researchers from California and Japan propose to combine their expertise to characterize and investigate some of the most fundamental aspects of the intrinsic properties of, and extrinsic factors influencing, human induced pluripotent (hiPSC) and human embryonic (hESC) stem cells, pooling knowledge and expertise in stem cell and animal model paradigms. The experiments proposed investigate the basic cellular and molecular mechanisms underlying the role of the host environment in stem cell fate regulation, and the relationship between reprogramming and tumorigenic/fate potential of hiPS-NSC in vitro and after transplantation, and key to this collaborative effort, the interface of these two aspects of basic stem cell biology. Critically, this international collaboration combines the expertise of two of the most advanced laboratories in translational stem cell biology to address several key unresolved questions in the control of cell fate, and will promote sharing of resources, data, and techniques between these labs to advance the field. Ultimately, the collaborative work proposed may permit the development of strategies to refine cellular reprogramming techniques, alter in vitro differentiation strategies, or manipulate the microenvironment to maximize the window for potential stem cell-based neurotherapeutics.

Grant Type: 
Disease Team Research I
Grant Number: 
DR1-01480
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Neurological Disorders
Stroke
Collaborative Funder: 
Germany
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

A stroke kills brain cells by interrupting blood flow. The most common “ischemic stroke” is due to blockage in blood flow from a clot or narrowing in an artery. Brain cells deprived of oxygen can die within minutes. The loss of physical and mental functions after stroke is often permanent and includes loss of movement, or motor, control. Stroke is the number one cause of disability, the second leading cause of dementia, and the third leading cause of death in adults. Lack of movement or motor control leads to job loss and withdrawal from pre-stroke community interactions in most patients and institutionalization in up to one-third of stroke victims. The most effective treatment for stroke, thrombolytics or “clot-busters”, can be administered only within 4.5 hours of the onset of stroke. This narrow time window severely limits the number of stroke victims that may benefit from this treatment. This proposal develops a new therapy for stroke based on embryonic stem cells. Because our (and others’) laboratory research has shown that stem cells can augment the brain’s natural repair processes after stroke, these cells widen the stroke treatment opportunity by targeting the restorative or recovery phase (weeks or months after stroke instead of several hours).

Embryonic stem cells can grow in a culture dish, but have the ability to produce any tissue in the body. We have developed a technique that allows us to restrict the potential of embryonic stem cells to producing cell types that are found in the brain, making them “neural stem cells”. These are more appropriate for treating stroke and may have lower potential for forming tumors. When these neural stem cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs. Based on these findings, we propose in this grant to further develop these neural stem cells into a clinical development program for stroke in humans at the end of this grant period.

This proposal develops a multidisciplinary team that will rigorously test the effectiveness of stem cell delivery in several models of stroke, while simultaneously developing processes for the precise manufacture, testing and regulatory approval of a stem cell therapy intended for human use. Each step in this process consists of definite milestones that must be achieved, and provides measurable assessment of progress toward therapy development. To accomplish this task, the team consists of stroke physician/scientists, pharmacologists, toxicologists, experts in FDA regulatory approval and key collaborations with biotechnology firms active in this area. This California-based team has a track record of close interactions and brings prior stroke clinical trial and basic science experience to the proposed translation of a stem cell therapy for stroke.

Statement of Benefit to California: 

The State of California has made a historic investment in harnessing the potential of stem cells for regenerative therapy. While initially focused on developing new stem cell technologies, CIRM has recognized that translational progress from laboratory to clinic must also be fostered, for this is ultimately how Californians will benefit from their investment. Our focus on developing a neuro-restorative therapy for treatment of motor sequelae following sub-cortical stroke contains several benefits to California. The foremost benefit will be the development of a novel form of therapy for a major medical burden: The estimated economic burden for stroke exceeds $56.8 billion per year in the US, with 55% of this amount supporting chronic care of stroke survivors (1). While the stroke incidence markedly increases in the next half-century, death rates from stroke have declined. These statistics translate into an expected large increase in disabled stroke survivors (1) that will have a significant impact on many aspects of life for the average Californian. Stroke is the third greatest cause of death, and a leading cause of disability, among Californians. Compared to the nation, California has slightly above average rates for stroke (2). Treatments that improve repair and recovery in stroke will reduce this clinical burden.

The team that has been recruited for this grant is made of uniquely qualified members, some of whom were involved in the development, manufacturing and regulatory aspects of the first clinical trial for safety of neural stem cells for stroke. Thus not only is the proposed work addressing a need that affects most Californians, it will result in the ability to initiate clinical studies of stem cells for stroke recovery from a consortium of academic and biotechnology groups in California.

1. Carmichael, ST. (2008) Themes and strategies for studying the biology of stroke recovery in the poststroke epoch. Stroke 39(4):1380-8.

2. Reynen DJ, Kamigaki AS, Pheatt N, Chaput LA. The Burden of Cardiovascular Disease in California: A Report of the California Heart Disease and Stroke Prevention Program. Sacramento, CA: California Department of Public Health, 2007.

Grant Type: 
Disease Team Research I
Grant Number: 
DR1-01471
Investigator: 
ICOC Funds Committed: 
$5 694 308
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Amyotrophic lateral sclerosis (ALS), a lethal disease lacking effective treatments, is characterized by the loss of upper and lower motor neurons. 5-10% of ALS is familial, but the majority of ALS cases are sporadic with unknown causes. The lifetime risk is approximately 1 in 2000. This corresponds to ~30,000 affected individuals in the United States and ~5000 in the Collaborative Funding Partner country. There is currently only one FDA-approved compound, Rilutek, that extends lifespan by a maximum of three months. Although the causes of ALS are unknown and the presentation of the disease highly variable, common to all forms of ALS is the significant loss of motor neurons leading to muscle weakness, paralysis, respiratory failure and ultimately death. It is likely that many pathways are affected in the disease and focusing on a single pathway may have limited impact on survival. In addition, as ALS is diagnosed at a time that significant cell loss has occurred, an attempt to spare further cell loss would have significant impact on survival.
Several findings support the approach of glial (cells surrounding the motor neurons) transplants. Despite the relative selectivity of motor neuron cell death in ALS, published studies demonstrate that glial transporters critical for the appropriate balance of glutamate surrounding the motor neurons are affected both in animal models and in tissue from sporadic and familial ALS. The significance of non-neuronal cells in the disease process has been well characterized using SOD1 mouse models representing many of the key aspects of the human disease. In addition, transplantation using glial-restricted precursors (GRPs) that differentiate into astrocytes in SOD1 mutant rats has been shown to increase survival. Motor neurons have a process, the axon, up to a meter in length which connects the cell body to its target, the muscle. The ability to appropriately rewire and ensure functional connections after motor neuron replacement remains a daunting task with no evidence to date that this will be possible in humans. Therefore, we will focus on the development of an ALS therapy based on hES-derived astrocyte precursor cell transplants to prevent the progression of ALS.
Our proposed project will develop clinical grade stem-cell derived astrocyte precursor transplants for therapy in a prospective Phase I clinical trial. We will: 1) generate astrocyte precursors from three different sources of human embryonic stem cell (hESC) lines; 2) identify the hESC line and glial progenitor combination that has the best characteristics of minimal toxicity, best efficiency in generating astrocytes, and reducing disease phenotypes in vivo in a rat model of ALS; 3) manufacture the appropriate cells in a GMP facility required by the FDA; 4) work with our established clinical team to design a Phase I safety trial; and 5) submit an application for an invesitgational new drug (IND) within the next four years.

Statement of Benefit to California: 

Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's Disease) is a common and devastating adult motor neuron disease that afflicts many Californians. In the absence of a cure, or an effective treatment, the cost of caring for patients with ALS is substantial, and the consequences on friends and family members similarly takes a devastating toll. Our goal is to develop a safe and effective cell transplant therapy for ALS by starting with human embryonic stem cells. If successful, this advance will hopefully diminish the cost of caring for the many Californians with ALS, extend their useful lives, and improve their quality of life. In addition, the development of this type of therapeutic approach in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop these types of therapies in California with consequent economic benefit.

Grant Type: 
Basic Biology I
Grant Number: 
RB1-01358
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 407 076
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Parkinson’s disease (PD) is a neurodegenerative movement disorder that affects 1 in 100 people over the age of 60, one million people in the US and six million worldwide. Patients show a resting tremor, slowness of movement (bradykinesia), postural instability and rigidity. Parkinson's disease results primarily from the loss of neurons deep in the middle part of the brain (the midbrain), in particular neurons that produce dopamine (referred to as “dopaminergic”). There are actually two groups of midbrain dopaminergic (DA) neurons, and only one, those in the substantia nigra (SN) are highly susceptible to degeneration in Parkinson’s patients. There is a relative sparing of the second group and these are called ventral tegmental area (VTA) dopaminergic neurons. These two groups of neurons reside in different regions of the adult ventral midbrain and importantly, they deliver dopamine to their downstream neuronal targets in different ways. SN neurons deliver dopamine in small rapid squirts, like a sprinkler, whereas VTA neurons have a tap that provides a continuous stream of dopamine.

A major therapeutic strategy for Parkinsons’ patients is to produce DA neurons from human embryonic stem cells for use in transplantation therapy. However early human trials were disappointing, since a number of patients with grafts of human fetal neurons developed additional, highly undesirable motor dyskinesias. Why this occurred is not known, but one possibility is that the transplant mixture, which contained both SN and VTA DA neurons, provided too much or unregulated amounts of DA (from the VTA neurons), overloading or confusing the target region in the brain that usually receives dopamine from SN neurons in small, regular quantities. Future human trials will likely utilize DA neurons that have been made from human embryonic stem cells (hES). Since stem cells have the potential to develop into any type of cell in the body, these considerations suggest that we should devise a way to specifically produce SN neurons and not VTA neurons from stem cells for use in transplantation. However, although we can produce dopaminergic neurons from hES cells, to date the scientific community cannot distinguish SN from VTA neurons outside of their normal brain environment and therefore has no ability to produce one selectively and not the other. We do know, however, that these two populations of neurons normally form connections with different regions in the brain, and we propose to use this fact to identify molecular markers that distinguish SN from VTA neurons and to determine optimal conditions for the differentiation of hES to SN DA neurons, at the expense of VTA DA neurons. Our studies have the potential to significantly impact transplantation therapy by enabling the production of SN over VTA neurons from hES cells, and to generate hypotheses about molecules that might be useful for coaxing SN DA neurons to form appropriate connections within the transplanted brain.

Statement of Benefit to California: 

The goal of our work is to further optimize our ability to turn undifferentiated human stem cells into differentiated neurons that the brain can use as replacement for neurons damaged by disease. We focus on Parkinson’s disease, a neurodegenerative disease that afflicts 4-6 million people worldwide in all geographical locations, but which is more common in rural farm communities compared to urban areas, a criteria important for California's large farming population. In Parkinson’s patients, a small, well-defined subset of neurons, the midbrain dopaminergic neurons have died, and one therapeutic strategy is to transplant healthy replacement neurons to the patient. Our work will further our understanding of the biology of these neurons in normal animals. This will allow us to refine the process of turning human embryonic stem cells onto biologically active dopaminergic neurons that can be used in transplantation therapy. Our work will be of benefit to all Parkinson's patients including afflicted Californians. Further, this project will utilize California goods and services whenever possible.

Grant Type: 
Basic Biology I
Grant Number: 
RB1-01367
Investigator: 
ICOC Funds Committed: 
$1 363 262
Disease Focus: 
Amyotrophic Lateral Sclerosis
Genetic Disorder
Neurological Disorders
Pediatrics
Spinal Cord Injury
Spinal Muscular Atrophy
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 

One of the main objectives of stem cell biology is to create physiologically relevant cell types that can be used to either facilitate the study of or directly treat human disease. Tremendous progress towards these goals has been made in the area of motor neuron disease and spinal cord injury through the findings that motor neurons can be generated from human embryonic stem cells and induced pluripotent stem cells. These advances have made possible the creation of motor neurons from patients afflicted with neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy that can be studied in the laboratory to determine the root causes of these diseases. In addition, stem cell-derived motor neurons could potentially serve as replacement cells that could be introduced into the spinal cord to recover motor functions in these patients, as well as those suffering from spinal cord injuries. A major assumption, however, is that human embryonic and induced pluripotent cell-derived motor neurons are identical to their normal counterparts. Despite its relevance, few studies of human motor neuron development have been carried out, and little information on the genetic and functional similarities between stem cell- and embryo-derived motor neurons has been obtained. The proposed research will provide important new insights into the profile of human motor neurons that must be recapitulated by stem cell studies. This approach is critical given that most of our knowledge on human motor neuron development is based on animal models. In addition, work with mouse embryonic stem cell-derived motor neurons has revealed limitations in the motor neuron subtypes that can be generated in culture, something others and we have also observed in human embryonic and induced pluripotent stem cell-derived motor neurons. The differences between embryo and stem cell-derived motor neurons are currently unknown, though our preliminary studies suggest that this deficiency may result from the inability of stem cell-derived motor neurons to express key regulators of motor neuron development. We will directly test this hypothesis by examining whether artificially expressing some of these important motor neuron fate determinants can alter the classes of motor neurons formed in culture and thereby broaden their innervation potential. Since most motor neuron diseases tend to affect certain motor neuron populations more than others, and that the pattern of motor innervation is highly specific to the type of cells formed, these studies will significantly advance our understanding of how the full repertoire of motor neuron subtypes may be created from stem cells to build disease models and generate therapeutically beneficial cells.

Statement of Benefit to California: 

Neurological diseases are among the most debilitating medical conditions that affect millions of Californians each year, and many more worldwide. Few effective treatments for these diseases currently exist, in part because we know very little about the mechanisms underlying these conditions. Through the use of human embryonic stem cell and induced pluripotent stem cell technologies, it is now possible to create neurons from patients suffering from a variety of neurological disorders that can serve as the basis for cell culture-based models to study disease pathologies in an experimentally accessible setting. Our proposed research seeks to develop the means to form different classes of neurons, confirm their physiological identities, and establish a system for studying their neurological activity in a cell culture setting. The generation of these models will constitute an important step towards understanding the basis of neurological illnesses and developing a platform for the discovery of drugs that can alter disease progression and improve the productivity and quality of life for many Californians. Moreover, progress in this field will help solidify the leadership role of California in bringing stem cell research to the clinic, and stimulate the future growth of the biotechnology and pharmaceutical industries within the state.

Grant Type: 
Progression Award - Discovery Stage Research Projects
Grant Number: 
DISC2P-12212
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$180 000
Disease Focus: 
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Statement of Benefit to California: 
Grant Type: 
Progression Award - Discovery Stage Research Projects
Grant Number: 
DISC2P-12150
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$202 667
Disease Focus: 
Neurological Disorders
Traumatic Brain Injury
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Statement of Benefit to California: 
Grant Type: 
Progression Award - Discovery Stage Research Projects
Grant Number: 
DISC2P-11700
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$202 500
Disease Focus: 
Epilepsy
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 
Statement of Benefit to California: 
Grant Type: 
Progression Award - Discovery Stage Research Projects
Grant Number: 
DISC2P-11595
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$201 150
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Human Stem Cell Use: 
iPS Cell
Public Abstract: 
Statement of Benefit to California: 
Grant Type: 
Therapeutic Translational Research Projects
Grant Number: 
TRAN1-11628
Investigator: 
ICOC Funds Committed: 
$4 963 684
Disease Focus: 
Brain Injury, hypoxic, ischemic
Neurological Disorders
Pediatrics
Human Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

Translational Candidate

An established stable human neural stem cell line unmanipulated genetically & propagated under defined conditions

Area of Impact

Perinatal asphyxia (also called hypoxic-ischemic injury), a major untreatable cause of cerebral palsy & cognitive disability

Mechanism of Action

hNSCs rescue the penumbra, the part of the brain lesion following perinatal asphyxia that still has viable though endangered cells. Such rescue includes preserving tissue; host neuron growth; revascularization; inhibiting inflammation & scarring. Anatomic & behavioral improvement results. If strategically administered, hNSCs can supply their neuroprotective molecules in a manner that synergizes with standard-of-care, hypothermia, which is only marginally effective but must be offered to babies.

Unmet Medical Need

Perinatal hypoxic-ischemic brain injury is an untreatable common cause of CP & disability. Hypothermia (HT) is standard-of-care for this condition although it is only marginally-effective. Any new trial must include HT. We will coordinate hNSC administration to synergize with HT & improve outcome.

Project Objective

Pre-IND meeting, ultimately a Phase 1b/2a trial

Major Proposed Activities

  • Ascertain the proper timing of hNSC administration in relation to hypothermia to achieve synergy
  • Determine the manufacturing specifications & biodistribution of the hNSCs in anticipation of IND-enabling studies
  • Preparation of a pre-IND package
Statement of Benefit to California: 

Perinatal asphyxia occurs in 2-4/1000 births. Despite hyperthermia (which is only marginally effective), 80% of asphyxiated infants develop neurologic signs with 10-20% remaining significantly impaired (e.g., CP; disability; epilepsy). The cost to California economy is $1M/child in terms of lifelong medical & rehabilitative care; the impact on family dynamics is 2-5-fold greater than that. We believe stem cell-based interventions can improve these outcomes.

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