Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07655
Investigator: 
Type: 
PI
Type: 
Partner-PI
ICOC Funds Committed: 
$1 784 052
Disease Focus: 
Neurological Disorders
Collaborative Funder: 
Germany
Public Abstract: 

Three years ago, with help from CIRM funding, we developed an assay. This is a genomics-base diagnostic assay, similar to those now used for diagnosing cancers; but in our case, it is designed to analyze human ES and iPS cells. The assay is very simple to use; researchers use microarrays to profile the genes that are active in their cells. They upload the microarray data to the website, and in a few minutes they find out whether or not their cells are pluripotent. Our assay is replacing the old method for proving pluripotency, which involves producing tumors in animals. Our assay has been extremely popular, with 9,386 samples analyzed by 581 research groups in 29 countries so far. In this proposal, we plan to take the same concept and apply it to translational stem cell applications. Our new assay will allow researchers to easily detect DNA damage in their stem cells, and will enable the detection of undifferentiated or other abnormal cells (which potentially could form a tumor) in populations used for cell replacement therapy. We are also designing specific assays for quality control of neuronal cells to be transplanted to Parkinson's disease patients and for other neurological therapies. Finally, with our European partners, we will develop an assay for ensuring reliability of drug screening assays using stem cells. Our tools will greatly simplify translation of hESCs and iPSCs to the clinic.

Statement of Benefit to California: 

California is at the leading edge of development of stem cell therapies to treat previously untreatable diseases. It is critical at this important stage, when treatments are being transferred from the lab to the clinic, that the cells used for therapy are carefully produced and qualified. Our project combines two of California's best scientific assets: genomics and stem cells. Our quality control assays for stem cell production are based on our long experience in genomic analysis of stem cells and development of genomics-based diagnostic tests. The assays will ensure that stem cells used for therapy are consistently of high quality. This will speed the development of stem cell therapies for Californians.

Funding Type: 
Early Translational III
Grant Number: 
TR3-05476
Investigator: 
ICOC Funds Committed: 
$5 509 978
Disease Focus: 
Neurological Disorders
Pediatrics
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.

Progress Report: 
  • The purpose of the ET3RA is to establish an experimental model of stem cell transplantation that accomplishes two equally important goals: 1) to devise a strategy of protection of the child's brain from the ravages of certain genetic diseases and 2) to devise a simultaneous strategy of transplantation that avoids immune system rejection. In our first year of work, we have shown that we can reliably produce the stem cells that we want to transplant into the brains of experimental animals (mice). We have also bred sufficient numbers of mice for the transplant experiments and have started the immune system-based strategy of transplantation. This puts us in the proper position to begin the brain stem cell transplantation in year 2. Thus, we are on course to accomplishing our goals for this ET3RA and for eventual development of this strategy for the initiation of clinical trials.
  • The purpose of the ET3RA is to establish an experimental model of stem cell transplantation that accomplishes two equally important goals: 1) to devise a strategy of protection of the child's brain from the ravages of certain genetic diseases and 2) to devise a simultaneous strategy of transplantation that avoids immune system rejection. In our first year of work, we have shown that we can reliably produce the stem cells that we want to transplant into the brains of experimental animals (mice). We have also bred sufficient numbers of mice for the transplant experiments and have started the immune system-based strategy of transplantation. During the second year, we successfully finished our first round of transplantation experiments, we fully characterized the stem cells for brain transplantation, we showed that the cells have the desired biological effects in the culture dish, and we completed installation of our Cell Production Facility. Thus, we are still on course to accomplishing our goals for this ET3RA and for eventual development of this strategy for the initiation of clinical trials.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05676
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 654 830
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Approximately 5,600 people in the U.S. are diagnosed with ALS each year. The incidence of ALS is two per 100,000 people, and it is estimated that as many as 30,000 Americans may have the disease at any given time. There are no effective therapies of ALS to-date. Recent genetic discoveries have pinpointed mutations that lead to the aberrant function of two proteins that bind to RNA transcripts in neurons. Misregulation of these RNA binding proteins is responsible for the aberrant levels and processing of hundreds of RNA representing genes that are important for neuronal survival and function. In this proposal, we will use neurons generated from patient cells that harbor the mutations in these RNA binding proteins to (1) prioritize a RNA “signature” unique to neurons suffering from the toxic function of these proteins and (2) as an abundant source of raw material to enable high-throughput screens of drug-like compounds that will bypass the mutations in the proteins and “correct” the RNA signature to resemble that of a healthy neuron. If successful, our unconventional approach that uses hundreds of parallel measurements of specific RNA events, will identify drugs that will treat ALS patients.

Statement of Benefit to California: 

Our research aims to develop drug-like compounds that are aimed to treat Amyotrophic Lateral Sclerosis (ALS), which may be applicable to other neurological diseases that heavily impact Californians, such as Frontotemporal Lobar Degeneration, Parkinson’s and Alzheimer’s. The cellular resources and genomic assays that we are developing in this research will have great potential for future research and can be applied to other disease areas. The cells, in particular will be beneficial to 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.

Progress Report: 
  • Our research aims to develop drug-like compounds that are aimed to treat Amyotrophic Lateral Sclerosis (ALS), which may be applicable to other neurological diseases that heavily impact Californians, such as Frontotemporal Lobar Degeneration, Parkinson’s and Alzheimer’s. In the first year, we have succeeded in improving the efficiency of motor neuron differentiation to generate high-quality motor neurons from induced pluripotent stem cells. We have generated RNA signatures from motor neurons differentiated from induced pluripotent stem cells from normal, healthy individuals whereby key proteins implicated in ALS are depleted using RNAi technology. We have also generated motor neurons from induced pluripotent stem cells that contained mutations in these key proteins and are in the process of applying genomic technologies to compare these cells to ones where we have depleted the proteins themselves. In parallel, we have started to optimize conditions for a small molecule screen to identify previously FDA-approved compounds that may alter aberrant and ALS-associated phenotypes in human cell lines.
  • In this reporting period, we have successfully generated lines that we have used to identify small molecules that alter the formation of aggregates in human neural progenitors and non-neuronal cell lines. These molecules will be tested for the reversal of aberrant RNA signatures in motor neurons from patients with ALS-associated mutations.
Funding Type: 
Early Translational IV
Grant Number: 
TR4-06847
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 333 795
Disease Focus: 
Huntington's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

The long-term objective of this project is to develop a drug to treat Huntington’s disease (HD), the most common inherited neurodegenerative disorder. Characterized by involuntary movements, personality changes and dementia, HD is a devastatingly progressive disease that results in death 10–20 years after disease onset and diagnosis. No therapy presently exists for HD; therefore, this project is highly innovative and ultimately aims to deliver something transformative for the HD patient population. The specific goal of the proposed research will be to achieve preclinical proof-of-concept with a novel small molecule that binds to and ameliorates the neurotoxicity of the mutant huntingtin (mHtt) protein that causes HD. Rationale for development of such compounds comes from previous research that found that mHtt assumes a shape that is selectively toxic to neurons, and that small molecules that disrupt this shape can reduce mHtt’s toxicity in primary neurons. Critical to the proposed studies will be assays that employ human striatal neurons derived from adult and juvenile HD patients and generated with induced pluripotent stem cell (iPSC) technology. These HD i-neurons display many characteristics that are also observed in striatal neurons of HD patients, including reduced survival times. They provide the most genetically precise preclinical system available to test for both drug efficacy and safety.

Statement of Benefit to California: 

The long-term objective of this project is to develop a first-in-class, disease-modifying drug to treat Huntington’s disease (HD), a devastatingly progressive genetic disorder that results in death 10–20 years after disease onset and diagnosis. No therapy presently exists for HD; therefore, this highly innovative project aims to deliver a medical breakthrough that will provide significant benefit for California’s estimated > 2000 HD patients and the family members, friends and medical system that care for them. The proposed research will be performed at a biotechnology startup, a leading academic research center and two contract research organizations, all of which are California-based. The work will over time involve more than 10 California scientists, thereby helping to employ tax-paying citizens and maintain the State’s advanced technical base. Finally, an effective, proprietary drug for the treatment of HD is expected to be highly valuable and to attract favorable financial terms upon out-licensing for development and commercialization. These revenues would flow to the California companies and institutions (including CIRM) that would have a stake in the proceeds.

Progress Report: 
  • The long-term objective for this project was to develop a first-in-class, disease-modifying drug to treat Huntington's disease (HD). This drug would comprise a small molecule that binds to and ameliorates the neurotoxicity of the mutant huntingtin protein (mHtt) that causes HD.
  • The goal of the research conducted under the CIRM Award was to demonstrate development candidate feasibility in vitro with a novel small molecule mHtt detoxifier early lead compound that is potent and efficacious in neurons from HD patients generated using stem cell technology (HD i-neurons) as well as suitable for use in mice as experimental models for HD.
  • The original project strategy was to 1) acquire or synthesize new samples of compounds identified as potential mHtt detoxifiers in the screening campaign conducted 7 years ago; 2) establish or re-establish the cell-free and cultured neuron biological assays needed to characterize potential small molecule mHtt detoxifiers (this work was carried out in the laboratory of our collaborator, Dr. Steven Finkbeiner of the J. David Gladstone Institutes); 3) acquire or synthesize new/novel analogs of the initial hits; 4) test new/novel compounds for activity in a cell-free assay for potential mHtt detoxifier activity; 5) test hits for efficacy in HD and non-HD i-neurons; and 6) profile the in vitro and in vivo pharmacokinetics and absorption, distribution, metabolism and elimination (PK/ADME) profiles of compounds that displayed selective neuroprotection toward HD i-neurons.
  • Specific achievements of the first year of the Project include:
  • • Acquiring 205 previously identified hits or analogs thereof from commercial sources;
  • • Synthesizing an additional 84 novel, designed analogs;
  • • Generating the reagents, re-establishing and implementing the screening assay;
  • • Testing all compounds acquired or synthesized in the screening assay;
  • • Establishing a counterscreen for false positives in the screening assay;
  • • Preliminary screening 48 previously reported hits in the counterscreen;
  • • Testing 14 previously or newly identified hits side-by-side in full concentration-response assays in both the screening and counterscreening assays;
  • • Profiling 11 diverse hits in in vitro PK/ADME assays;
  • • Testing 17 compounds for their ability to ameliorate neurotoxicity in a rodent primary neuron model; and
  • • Preliminary testing 2 previously identified hits in human HD i-neurons.
  • Unfortunately and surprisingly, we observed that all compounds displayed essentially identical profiles in full concentration-response studies in both the screening and counterscreening assays. We interpret this result to indicate that these compounds and structurally related compounds that we considered to be most promising and tested do not in fact bind to mHtt, i.e., they are all false positives. Since no valid starting points exist for continued work, the Project will be terminated after the first award period.
Funding Type: 
Preclinical Development Awards
Grant Number: 
PC1-08086
Investigator: 
ICOC Funds Committed: 
$1 737 271
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Cell Line Generation: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 

Over 6 million people in the US suffer from Alzheimer’s disease (AD). There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate nerve cell replacement in aged human brain. Importantly, even if nerve cells could be replaced, the toxic environment of the AD brain which caused the disease in the first place will likely kill any cells that are born into that environment unless they are resistant to those conditions or can be 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 neural precursor cells (hNPCs) derived from human embryonic stem cells (hESCs) as a screen for neurogenic compounds, we have shown that it is possible to identify and tailor drugs for therapeutic use in AD. With the support of CIRM, we have recently made a very potent AD drug candidate that is exceptionally effective in promoting the making of new nerve cells from human embryonic stem cells. It is both neurogenic and has therapeutic efficacy in a rodent model of AD. However, this molecule needs more preclinical development work before it can start the formal FDA pre clinical toxicity screening protocols. 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.

Statement of Benefit to California: 

Over 6 million people in the US suffer from AD, and unless a viable therapeutic is identified it is estimated that this number will increase to at least 16 million by 2050, with a cost of well over $1 trillion per year, likely overwhelming both the California and national health care systems. There is no treatment to prevent, cure or slow down this condition. In this application we have used the new human stem cell technologies to develop an AD drug candidate 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 stems 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.

Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07914
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$1 818 751
Disease Focus: 
Intestinal Disease
Pediatrics
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
Public Abstract: 

The intestine performs the essential function of absorbing food and water into the body. Without a functional intestine, children and adults cannot eat normal meals, and these patients depend on intravenous nutrition to sustain life. Many of these patients do not have a neural system that coordinates the function of the intestine. These patients have a poor quality of life, and the cost of medical care is over $200,000 per year for each patient. Stem cell therapies offer potential cures for these patients while avoiding the risks of invasive procedures and hazardous treatments. A novel approach to treat these patients is to use stem cells derived from the patient’s own skin to generate the neural system. This has been shown to be feasible in small animals, and the next step hinges on the demonstration of these results in a large animal model of intestinal dysfunction. We will develop a model in large animals that can be used to test the ability of skin-derived stem cells to form the neural system. Skin-derived stem cells will be isolated from large animal models and human skin to demonstrate their potential to generate a functional neural system. These cells will be transplanted into the animal model to determine the best way for these cells to make the intestine function properly. This research will gather critical information needed to begin a clinical trial using skin-derived cells to treat intestinal dysfunction.

Statement of Benefit to California: 

Gastrointestinal dysfunction destroys the lives of thousands of Californians. These Californians have frequent and prolonged hospitalizations and lost wages due to their chronic illness. It is estimated that the health care cost of Californians with gastrointestinal neuromuscular dysfunction is over 400 million dollars annually. Currently, most of these patients are covered by the state’s insurance agency. Stem cell therapies offer potential cures for these patients and reduce this economic burden. The proposed research will obtain critical information needed to begin a clinical trial using skin-derived cells to treat patients with intestinal dysfunction. The California economy will significantly benefit from this research through the reduced costs for health care and increased quality of life of the affected Californians. Additionally, this work will add to the state’s growing stem cell industry and will increase employment opportunities and revenue by the state of California. The educational benefit to Californians involved in this research project will also maintain California’s position in leading the stem cell effort in the future.

Funding Type: 
Tools and Technologies II
Grant Number: 
RT2-01881
Investigator: 
ICOC Funds Committed: 
$1 825 613
Disease Focus: 
Stroke
Neurological Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Stroke is the leading cause of adult disability. Most patients survive their initial stroke, but do not recover fully. Because of incomplete recovery, up to 1/3 of stroke patients are taken from independence to a nursing home or assisted living environment, and most are left with some disability in strength or control of the arms or legs. There is no treatment that promotes brain repair and recovery in this disease. Recent studies have shown that stem cell transplantation into the brain can promote repair and recovery in animal models of stroke. However, a stem cell therapy for stroke has not reached the clinic. There are at least three limitations to the development of a human stroke stem cell therapy: most of the transplanted cells die, most of the cells that survive do not interact with the surrounding brain, and the process of injecting stem cells into the brain may damage the normal brain tissue that is near the stroke site. The studies in this grant develop a novel investigative team and research approach to achieve a solution to these limits. Using the combined expertise of engineering, stem cell biology and stroke scientists the studies in this grant will develop tissue bioengineering systems for a stem cell therapy in stroke. The studies will develop a biopolymer hydrogel that provides a pro-growth and pro-survival environment for stem cells when injected with them into the brain. This approach has three unique aspects. First, the hydrogel system utilizes biological components that mimic the normal brain environment and releases specific growth factors that enhance transplanted stem cell survival. Second, these growth factors will also likely stimulate the normal brain to undergo repair and recovery, providing a dual mechanism for neural repair after stroke. Third, this approach allows targeting of the stroke cavity for a stem cell transplant, and not normal brain. The stroke cavity is an ideal target for a stroke stem cell therapy, as it is a cavity and can receive a stem cell transplant without displacing normal brain, and it lies adjacent to the site in the brain of most recovery in this disease—placing the stem cell transplant near the target brain region for repair in stroke.
The progress from stroke stem cell research has identified stem cell transplantation as a promising treatment for stroke. The research in this grant develops a next generation in stem cell therapies for the brain by combining new bioengineering techniques to develop an integrated hydrogel/stem cell system for transplantation, survival and neural repair in this disease.

Statement of Benefit to California: 

Advances in the early treatment of stroke have led to a decline in the death rate from this disease. At the same time, the overall incidence of stroke is projected to substantially increase because of the aging population. These two facts mean that stroke will not be lethal, but instead produce a greater number of disabled survivors. A 2006 estimate placed over half of the annual cost in stroke as committed to disabled stroke survivors, and exceeding $30 billion per year in the United States. The studies in this grant develop a novel stem cell therapy in stroke by focusing on one major bottleneck in this disease: the inability of most stem cell therapies to survive and repair the injured brain. With its large population California accounts for roughly 24% of all stroke hospital discharges in the Unites States. The development of a new stem cell therapy approach for this disease will lead to a direct benefit to the State of California.

Progress Report: 
  • This grant develops a tissue bioengineering approach to stem cell transplantation as a treatment for brain repair and recovery in stroke. Stem cell transplantation has shown promise as a therapy that promotes recovery in stroke. Stem cell transplantation in stroke has been limited by poor survival of the transplanted cells. The studies in this grant utilize a multidisciplinary team of bioengineers, neuroscientists/neurologists and stem cell biologists to develop an approach in which stem or progenitor cells can be transplanted into the site of the stroke within a biopolymer hydrogel that provides an environment which supports cell survival and treatment of the injured brain. These hydrogels need to contain naturally occurring brain molecules, so that they do not release foreign or toxic components when they degrade. Further, the hydrogels have to remain liquid so that the injection approach can be minimally invasive, and then gel within the brain. In the past year the fundamental properties of the hydrogels have been determined and the optimal physical characteristics, such as elasticity, identified. Hydrogels have been modified to contain molecules which stem or progenitor cells will recognize and support survival, and to contain growth factors that will both immediately release and, using a novel nanoparticle approach, more slowly release. These have been tested in culture systems and advanced to testing in rodent stroke models. This grant also tests the concept that the stem/progenitor cell that is more closely related to the area within the brain that receives the transplant will provide a greater degree of neural repair and recovery. Progress has been made in the past year in differentiating induced pluripotent stem cells along a lineage that more closely resembles the part of the brain injured in this stroke model, the cerebral cortex.
  • This grant determines the effect of a tissue bioengineering approach to stem cell survival and engraftment after stroke, as means of improving functional recovery in this disease. Stem cell transplantation in stroke has been limited by the poor survival of transplanted cells and their lack of differentiation in the brain. These studies use a biopolymer hydrogel, made of naturally occurring molecules, to provide a pro-survival matrix to the transplanted cells. The studies in the past year developed the chemical characteristics of the hydrogel that promote survival of the cells. These characteristics include the modification of the hydrogel so that it contains specific amounts of protein signals which resemble those seen in the normal stem cell environment. Systematic variation of the levels of these protein signals determined an optimal concentration to promote stem cell survival in vitro. Next, the studies identified the chemistry and release characteristics from the hydrogel of stem cell growth factors that normally promotes survival and differentiation of stem cells. Two growth factors have been tested, with the release characteristics more completely defined with one specific growth factor. The studies then progressed to determine which hydrogels supported stem cell survival in vivo in a mouse model of stroke. Tests of several hydrogels determined that some provide poor cell survival, but one that combines the protein signals, or “motifs”, that were studied in vitro provided improved survival in vivo. These hydrogels did not provoke any additional scarring or inflammation in surrounding tissue after stroke. Studies in the coming year will now determine if these stem cell/hydrogel matrices promote recovery of function after stroke, testing both the protein motif hydrogels and those that contain these motifs plus specific growth factors.
  • This grant determines the effect of a tissue bioengineering approach to stem cell survival and engraftment after stroke, as means of improving functional recovery in this disease. Stem cell transplantation in stroke has been limited by the poor survival of transplanted cells and their lack of differentiation in the brain. These studies use a biopolymer hydrogel, made of naturally occurring molecules, to provide a pro-survival matrix to the transplanted cells. The studies in past years developed the two chemical characteristics of hydrogels that contain recognition or signal elements for stem cells: “protein motifs” that resemble molecules in the normal stem cell environment and growth factors that normally communicate to stem cells in the brain. The hydrogels were engineered so that they contain these familiar stem cell protein motifs and growth factors and release the growth factors over a slow and sustained time course. In the past year on this grant, we tested the effects of hydrogels that had the combined characteristics of these protein motifs and growth factors, at varying concentrations, for their effect on induced pluripotent neural precursor cells (iPS-NPCs) in culture. We identified an optimum concentration for cell survival and for differentiation into immature neurons. We then initiated studies of the effects of this optimized hydrogel in vivo in a mouse model of stroke. These studies are ongoing. They will determine the cell biological effect of this hydrogel on adjacent tissue and on the transplanted cells—determining how the hydrogel enhances engraftment of the transplant. The behavioral studies, also under way, will determine if this optimized hydrogel/iPS-NPC transplant enhances recovery of movement, or motor, function after stroke.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05628
Investigator: 
ICOC Funds Committed: 
$4 699 569
Disease Focus: 
Spinal Cord Injury
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

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

Statement of Benefit to California: 

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

Progress Report: 
  • In the first 12 months of this project we have made important progress in the following areas:
  • 1) Identified the lead embryonic stem cell type for potential use in a translational clinical program.
  • 2) Replicated the finding that implants of ES-derived neural progenitor cells from this lead cell type extend axons out from the spinal cord lesion site in very high numbers and over very long distances.
  • 3) Begun efforts to scale this work to larger animal models of spinal cord injury.
  • Very good progress has been made in the last year on this project. We are attempting to address a great unmet medical need to develop effective therapies for human spinal cord injury (SCI). We aim to develop and optimize a pluripotent neural stem cell line for grafting to sites of spinal cord injury, and develop this line for clinical translation. Unlike other programs of stem cell therapy for SCI, we are transplanting neural stem cells directly into the injury site, in high numbers, and we observe very extensive growth of axons both into and out of the graft. The amount of axon growth in this model is substantially greater than that observed with other approaches to the injured spinal cord, including approaches currently in clinical trials. Accordingly, we believe that our approach provides a substantially greater opportunity to improve outcomes after SCI.
  • In the last year, we have identified a lead stem cell line for potential human translation, and validated its ability to engraft to the injured spinal cord. We have observed that human neural stem cells, grafted into mice and rats, exhibit a human time frame for maturation and growth: cells require at least one year to develop and mature. This knowledge is very important for planning human clinical trials.
  • Remaining work will characterize the long term safety and efficacy of these cells in rodent and large animal models of SCI.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05617
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$4 327 175
Disease Focus: 
Multiple Sclerosis
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

Multiple sclerosis (MS) is an autoimmune disease in which the myelin sheath that insulates neurons is destroyed, resulting in loss of proper neuronal function. Existing treatments for MS are based on strategies that suppress the immune response. While these drugs do provide benefit by reducing relapses and delaying progression (but have significant side effects), the disease invariably progresses. We are pursuing an alternative therapy aimed at regeneration of the myelin sheath through drugs that act on an endogenous stem cell population in the central nervous system termed oligodendrocyte precursor cells (OPCs). Remission in MS is largely dependent upon OPCs migrating to sites of injury and subsequently differentiating into oligodendrocytes – the cells that synthesize myelin and are capable of neuronal repair. Previous studies indicate that in progressive MS, OPCs are abundantly present at sites of damage but fail to differentiate to oligodendrocytes. As such, drug-like molecules capable of inducing OPC differentiation should have significant potential, used alone or in combination with existing immunomodulatory agents, for the treatment of MS. The objective of this project is to identify a development candidate (DC) for the treatment of multiple sclerosis (MS) that functions by directly stimulating the differentiation of the adult stem cells required for remyelination.

Statement of Benefit to California: 

Multiple Sclerosis (MS) is a painful, neurodegenerative disease that leads to an impairment of physical and cognitive abilities. Patients with MS are often forced to stop working because their condition becomes so limiting. MS can interfere with a patient's ability to even perform simple routine daily activities, resulting in a decreased quality of life. Existing treatments for MS delay disease progression and minimize symptoms, however, the disease invariably progresses to a state of chronic demyelination. The goal of this project is to identify novel promyelinating drugs, based on differentiation of an endogenous stem cell population. Such drugs would be used in combination with existing immunosuppressive drugs to prevent disease progression and restore proper neuronal activity. More effective MS treatment strategies represent a major unmet medical need that could impact the roughly 50,000 Californians suffering from this disease. Clearly the development of a promyelinating therapeutic would have a significant impact on the well-being of Californians and reduce the negative economic impact on the state resulting from this degenerative disease.

Progress Report: 
  • Multiple sclerosis (MS) is an autoimmune disease characterized by the destruction of the myelin sheath that insulates neurons, resulting in loss of proper neuronal function. Existing treatments for MS are based exclusively on strategies that suppress the immune response. We are pursuing an alternative stem cell-based therapeutic approach aimed at enhancing regeneration of the myelin sheath. Specifically, we are focused on the identification of drug-like molecules capable of inducing oligodendrocyte precursor cell (OPC) differentiation. To date, we have identified a series approved drugs that effectively induce OPC differentiation under tissue culture conditions. Additionally, we have demonstrated that several of these drug candidates reduce MS-like symptoms in relevant rodent models of the disease. We are currently conducting detailed pharmacology experiments to determine which of the identified molecules will serve as the best candidate for future clinical development.
  • The aim of this project is to identify and characterize molecules that induce the repair of lesions in multiple sclerosis. Molecules that induce the selective differentiation of oligodendrocyte precursor cells to oligodendrocytes and thereby lead to remyelination of axons are being characterized with respect to their in vitro activity and in vivo efficacy in relevant animal models, alone and in combination with immunosuppressive drugs. This work may lead to a new regenerative therapy for multiple sclerosis that is complementary to the current immune-focused therapies.
Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07800
Investigator: 
Type: 
PI
Type: 
Co-PI
ICOC Funds Committed: 
$1 380 557
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Vision Loss
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 

Cell replacement therapies (CRTs) have considerable promise for addressing unmet medical needs, including incurable neurodegerative diseases. However, several bottlenecks hinder CRTs, especially the needs for improved cell manufacturing processes and enhanced cell survival and integration after implantation. Engineering synthetic biomaterials that present biological signals to support cell expansion, differentiation, survival, and/or integration may help overcome these bottlenecks. Our prior work has successfully generated synthetic biomaterial platforms for the long-term expansion of human pluripotent stem cells (hPSCs) at large scale, efficient differentiation of hPSCs into dopaminergic progenitors and neurons for treating Parkinson’s Disease, and modulation of stem cell function to promote neuronal differentiation within the brain. We now propose to advance this work and engineer two synthetic biomaterial platforms to treat neurodegenerative disease, in particular Parkinson’s Disease and Retinitis Pigmentosa. Specifically, our central goals are to further engineer biomaterial systems for scalable hPSC differentiation into dopaminergic and photoreceptor neurons, and to engineer a second biomaterial system as a biocompatible delivery vehicle to enhance the survival and engraftment of dopaminergic and photoreceptor neurons in disease models. The resulting modular, tunable platforms will have broad implications for other cell replacement therapies to treat human disease.

Statement of Benefit to California: 

This proposal addresses critical translational bottlenecks to stem cell therapies that are identified in the RFA, including the development of fully defined, xenobiotic free cell manufacturing systems and the development of clinically relevant technologies to enhance the survival and integration of human stem cell therapies. The proposed platform technologies for expanding and differentiating pluripotent stem cells in a scaleable, reproducible, safe, and economical manner will initially be developed for treating two major neurodegenerative disorders - Parkinson’s Disease and Retinitis Pigmentosa - that affect the well-being of hundreds of thousands of Californians and Americans. In addition, the biomaterial platforms are designed to be modular, such that they can be re-tuned towards other target cells to even more broadly enable cell replacement therapies and enhance our healthcare. This work will thus strongly enhance the scientific, technological, and economic development of stem cell therapeutics in California.

Furthermore, the principal investigator has a strong record of translating basic science and engineering towards clinical development within industry, particularly within California. Finally, this collaborative project will focus research groups with many students on an important interdisciplinary project at the interface of science and engineering, thereby training future employees and contributing to the technological and economic development of California.

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