Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
Investigator: 
ICOC Funds Committed: 
$9 999 834
Disease Focus: 
Developmental Disorders
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Critical to the long term success of the CIRM iPSC Initiative of generating and ensuring the availability of high quality disease-specific human IPSC lines is the establishment and successful operation of a biorepository with proven methods for quality control, safe storage and capabilities for worldwide distribution of high quality, highly-characterized iPSCs. Specifically the biorepository will be responsible for receipt, expansion, quality characterization, safe storage and distribution of human pluripotent stem cells generated by the CIRM stem cell initiative. This biobanking resource will ensure the availability of the highest quality hiPSC resources for researchers to use in disease modeling, target discovery and drug discovery and development for prevalent, genetically complex diseases.

Statement of Benefit to California: 

The generation of induced pluripotent stem cells (iPSCs) from patients and subsequently, the ability to differentiate these iPSCs into disease-relevant cell types holds great promise in facilitating the “disease-in-a-dish” approach for studying our understanding of the pathological mechanisms of human disease. iPSCs have already proven to be a useful model for several monogenic diseases such as Parkinson’s, Fragile X Syndrome, Schizophrenia, Spinal Muscular Atrophy, and inherited metabolic diseases such as 1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease. In addition, the differentiated cells obtained from iPSCs represent a renewable, disease-relevant cell model for high-throughput drug screening and toxicology/safety assessment which will ultimately lead to the successful development of new therapeutic agents. iPSCs also hold great hope for advancing the use of live cells as therapies for correcting the physiological manifestations caused by disease or injury.

Progress Report: 
  • The California Institute for Regenerative Medicine (CIRM) Human Pluripotent Stem Cell Biorepository is operated by the Coriell Institute for Medical Research and is a critical component of the CIRM Human Stem Cell Initiative. The overall goal of this initiative is to generate, for world-wide use by non-profit and for-profit entities, high quality, disease-specific induced pluripotent stem cells (iPSCs). These cells are derived from existing tissues such as blood or skin, and are genetically manipulated in the laboratory to change into cells that resemble embryonic stem cells. iPSCs can be grown indefinitely in the Petri dish and have the remarkable capability to be converted into most of the major cell types in the body including neurons, heart cells, and liver cells. This ability makes iPSCs an exceptional resource for disease modeling as well as for drug screening. The expectation is that these cells will be a major benefit to the process for understanding prevalent, genetically complex diseases and in developing innovative therapeutics.
  • The Coriell CIRM iPSC Biorepository, located at the Buck Institute for Research on Aging in Novato, CA, is funded through a competitive grant award to Coriell from CIRM and is managed by Mr. Matt Self under the supervision of the Program Director, Dr. Steven Madore, Director of Molecular Biology at Coriell. The Biorepository will receive biospecimens consisting of peripheral blood mononuclear cells (PBMCs) and skin biopsies obtained from donors recruited by seven Tissue Collector grant awardees. These biospecimens will serve as the starting material for iPSC derivation by Cellular Dynamics, Inc (CDI). Under a contractual agreement with Coriell, CDI will expand each iPSC line to generate sufficient aliquots of high quality cryopreserved cells for distribution via the Coriell on-line catalogue. Aliquots of frozen cell lines and iPSCs will be stored in liquid nitrogen vapor in storage units at the Buck Institute with back-up aliquots stored in a safe off-site location.
  • Renovation and construction of the Biorepository began at the Buck Institute in late January. The Biorepository Manger was hired March 1 and after installation of cryogenic storage vessels and alarm validation, the first biospecimens were received on April 30, 2014. Additionally, Coriell has developed a Clinical Information Management System (CIMS) for storing all clinical and demographic data associated with enrolled subjects. Tissue Collectors utilize CIMS via a web interface to upload and edit the subject demographic and clinical information that will ultimately be made available, along with the iPSCs, via Coriell’s on-line catalogue
  • As of November 1 specimens representing a total of 725 unique individuals have been received at the Biorepository. These samples include PBMCs obtained from 550 unique individuals, skin biopsies from 72 unique individuals, and 103 primary dermal fibroblast cultures previously prepared in the laboratories of the CIRM Tissue Collectors. A total of 280 biospecimen samples have been delivered to CDI for the purpose of iPSC derivation. The Biorepository is anticipating delivery of the first batches of iPSCs for distribution in early 2015. These lines, along with the associated clinical data, will become available to scientists via the on-line Coriell catalogue. The CIRM Coriell iPSC Biorepository will ensure safe long-term storage and distribution of high quality iPSCs.
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: 
Preclinical Development Awards
Grant Number: 
PC1-08117
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$4 951 623
Disease Focus: 
Huntington's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Huntington’s disease (HD) is a devastating degenerative brain disease with at least a 1 in 10,000 prevalence that inevitably leads to death. These numbers do not fully reflect the large societal and familial cost of HD, which requires extensive care-giving. HD has no effective treatment or cure and symptoms unstoppably progress for 15-20 years, with onset typically striking in midlife. Because HD is genetically dominant, the disease has a 50% chance of being inherited by the children of patients. Symptoms of the disease include uncontrolled movements, difficulties in carrying out daily tasks or continuing employment, and severe psychiatric manifestations including depression. Current treatments only address some symptoms and do not change the course of the disease, therefore a completely unmet medical need exists. Human embryonic stem cells (hESCs) and their derivatives offer a possible long-term treatment approach that could relieve the tremendous suffering experienced by patients and their families. HD is the 3rd most prevalent neurodegenerative disease, but because it is entirely genetic and the mutation known, a diagnosis can be made with certainty and clinical applications of hESCs may provide insights into treating brain diseases that are not caused by a single, known mutation. Trials in mice where protective factors were directly delivered to the brains of HD mice have been effective, suggesting that delivery of these factors by hESCs may help patients. Transplantation of tissue in HD patients suggests that replacing neurons that are lost may also be effective. The ability to differentiate hESCs into neural populations offers a powerful and sustainable alternative to provide neuroprotection to the brain with the possibility of cell replacement. We have assembled a multidisciplinary team of investigators and consultants with expertise in basic, translational and clinical development and have identified a lead developmental candidate, ESI-017 neural stem cells, that have disease modifying activity in HD mice with sufficient promise to perform systematic efficacy and safety studies in HD mice with cells generated for this project. We will utilize the collaborative research team, additional preclinical and clinical investigators, stem cell experts and FDA consultants to finalize work that will lead to a productive pre-IND meeting with the FDA and a path forward for clinical trials with the neural stem cell development candidate.

Statement of Benefit to California: 

The disability and loss of earning power and personal freedom resulting from Huntington's disease (HD) is devastating and creates a financial burden for California. Individuals are struck in the prime of life, at a point when they are their most productive and have their highest earning potential. As the disease progresses, individuals require institutional care at great financial cost. Therapies using human embryonic stem cells (hESCs) have the potential to change the lives of hundreds of individuals and their families, which brings the human cost into the thousands. For the potential of hESCs in HD to be realized, we have brought together a team of investigators highly experienced in HD basic science and preclinical development, stem cell research, HD clinical trials and FDA regulatory activities to evaluate a human stem cell derived neural stem cell line, ESI-107 NSC in HD mouse models. This selection of this development candidate is based on efficacy in behavioral and electrophysiology measurements in a rapidly progressing mouse model of HD. HD is the 3rd most prevalent neurodegenerative disease, but because it is entirely genetic and the mutation known, a diagnosis can be made with certainty and clinical applications of NSCs may provide insights into treating brain diseases that are not caused by a single, known mutation. We have assembled a strong team of California-based investigators to carry out proposed studies to move ESI-017 NSCs to the point of a productive pre-IND meeting with the FDA to ultimately move this clinical product into Investigative New Drug-enabling (IND) activities with the goal of performing clinical trials in HD subjects. Anticipated benefits to the citizens of California include: 1) development of new human stem cell-based treatments for HD with application to other neurodegenerative diseases such as Alzheimer's and Parkinson's diseases that affect thousands of individuals in California; 2) improved methods for following the course of the disease in order to treat HD as early as possible before symptoms are manifest; 3) transfer of new technologies and intellectual property to the public realm with resulting IP revenues coming into the state with possible creation of new biotechnology spin-off companies; and 4) reductions in extensive care-giving and medical costs. It is anticipated that the return to the State in terms of revenue, health benefits for its Citizens and job creation will be substantial.

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: 
RT2-01965
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$1 327 983
Disease Focus: 
Parkinson's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

The goal of this proposal is to establish a novel research tool to explore the molecular basis of Parkinson’s disease (PD) - a critical step toward the development of new therapy. To date, a small handful of specific genes and associated mutations have been causally linked to the development of PD. However, how these mutations provoke the degeneration of specific neurons in the brain remains poorly understood. Moreover, conducting such genotype-phenotype studies has been hampered by two significant experimental problems. First, we have historically lacked the ability to model the relevant human cell types carrying the appropriate gene mutation. Second, the genetic variation between individuals means that the comparison of a cell from a disease-carrier to a cell derived from a normal subject is confounded by the many thousands of genetic changes that normally differentiate two individuals from one another. Here we propose to combine two powerful techniques – one genetic and one cellular – to overcome these barriers and drive a detailed understanding of the molecular basis of PD. Specifically, we propose to use zinc finger nucleases (ZFNs) in patient-derived induced pluripotent stem cells (iPSC) to accelerate the generation of a panel of genetically identical cell lines differing only in the presence or absence of a single disease-linked gene mutation. iPSCs have the potential to differentiate into many cell types – including dopaminergic neurons that become defective in PD. Merging these two technologies will thus allow us to study activity of either the wild-type or the mutant gene product in cells derived from the same individual, which is critical for elucidating the function of these disease-related genes and mutations. We anticipate that the generation of these isogenic cells will accelerate our understanding of the molecular causes of PD, and that such cellular models could become important tools for developing novel therapies.

Statement of Benefit to California: 

Approx. 36,000-60,000 people in the State of California are affected with Parkinson’s disease (PD) – a number that is estimated to double by the year 2030. This debilitating neurodegenerative disease causes a high degree of disability and financial burden for our health care system.

Importantly, recent work has identified specific gene mutations that are directly linked to the development of PD. Here we propose to exploit the plasticity of human induced pluripotent stem cells (iPSC) to establish models of diseased and normal tissues relevant to PD. Specifically, we propose to take advantage of recent developments allowing the derivation of stem cells from PD patients carrying specific mutations. Our goal is to establish advanced stem cell models of the disease by literally “correcting” the mutated form of the gene in patient cells, therefore allowing for direct comparison of the mutant cells with its genetically “repaired” yet otherwise identical counterpart. These stem cells will be differentiated into dopaminergic neurons, the cells that degenerate in the brain of PD patients, permitting us to study the effect of correcting the genetic defect in the disease relevant cell type as well as provide a basis for the establishment of curative stem cells therapies.

This collaborative project provides substantial benefit to the state of California and its citizens by pioneering a new stem cell based approach for understanding the role of disease causing mutations via “gene repair” technology, which could ultimately lead to advanced stem cell therapies for Parkinson’s disease – an unmet medical need without cure or adequate long-term therapy.

Progress Report: 
  • The goal of this proposal was to establish a novel research tool to explore the molecular basis of Parkinson’s disease (PD) - a critical step toward the development of new therapy. To date, a small handful of specific genes and associated mutations have been causally linked to the development of PD. However, how these mutations provoke the degeneration of specific neurons in the brain remains poorly understood.
  • In the first year of the grant, we have successfully modified the LRRK2 G2019S mutation in patient-derived induced pluripotent stem cells (iPSC) using zinc-finger technology. We created several clonal lines with the gene correction and also with a knockdown of the LRRK2 gene.
  • We characterized these lines for pluripotency, karyotype, and differentiation potential and currently, we are testing the lines for functional differences in the next reporting period and will generate iPSCs with specific LRRK2 mutations introduced using zinc-finger technology.
  • Despite the growing number of diseases linked to single gene mutations, determining the molecular mechanisms by which such errors result in disease pathology has proven surprisingly difficult. The ability to correlate disease phenotypes with a specific mutation can be confounded by background of genetic and epigenomic differences between patient and control cells. To address this problem, we employed zinc finger nucleases-based genome editing in combination with a newly developed high-efficiency editing protocol to generate isogenic patient-derived induced pluripotent stem cells (iPSC) differing only at the most common mutation for Parkinson's disease (PD), LRRK2 p.G2019S. We show that correction of the LRRK2 p.G2019S mutation rescues a panel of neuronal cell phenotypes including reduced dopaminergic cell number, impaired neurite outgrowth and mitochondrial dysfunction. These data reveal that PD-relevant cellular pathophysiology can be reversed by genetic repair, thus confirming the causative role of this prevalent mutation – a result with potential translational implications.
  • The goal of this proposal has been to establish a novel research tool to explore the molecular basis of Parkinson’s disease (PD) - a critical step toward the development of new therapies. To date, a small handful of specific genes and associated mutations have been causally linked to the development of PD. However, how these mutations provoke the degeneration of specific neurons in the brain remains poorly understood.
  • Moreover, conducting such genotype-phenotype studies has been hampered by two significant experimental problems. First, we have historically lacked the ability to model the relevant human cell types carrying the appropriate gene mutation. Second, the genetic variation between individuals means that the comparison of a cell from a disease-carrier to a cell derived from a normal subject is confounded by the many thousands of genetic changes that normally differentiate two individuals from one another.
  • We proposed to use zinc finger nucleases (ZFNs) in patient-derived induced pluripotent stem cells (iPSC) to accelerate the generation of a panel of genetically identical cell lines differing only in the presence or absence of a single disease-linked gene mutation.
  • To this end, we have successfully generated a panel of LRRK2 isogenic cell lines that differ only in "one building block" in the genomic DNA of a cell which can cause PD, therefore we genetically 'cured' the cells in the culture dish. These lines are invaluable because they are a set of tools that allow to study the effect of this mutation in the context of neurodegeneration and cell death. We received interest from many outside academic laboratories and industry to distribute these novel tools and these cell lines will hopefully lead to the discovery of new drugs that can halt or even reverse PD.
  • Being afflicted with a chronic, progressive disease means that it never stops, it is there in the morning when you wake up and it is the last thing at night that you feel when you are falling asleep. Parkinson’s disease (PD) makes you slowly lose body functions that you once took for granted. Eating tasks become more challenging as well as chewing and swallowing, simple motor movements such as turning in bed or getting out of the car or a deep chair takes a lot of extra effort. You might also show signs of depression, anxiety, even hallucinations or just feeling indifferent towards hobbies/activities or being with loved ones. Autonomic functions are affected with lightheadedness, constipation, or urine control. You might lose your sense of smell, have changes in heart rate, and sleep problems. All these changes can occur at once or become apparent over time. Not everyone with PD is experiencing all of these symptoms. Every disease is different and the symptoms can be diverse. PD is a “designer disease” and needs a targeted approach clinically and scientifically.
  • In this CIRM project, we focused on the clinical and genetic variability and used gene editing technology to modify the genome at precise positions (“correct genetic mutations”) known to cause clinically and neuropathologically PD. The newly created patient-derived pluripotent stem cell lines only differ at the known positions and “off-target” modifications were excluded and we were able to experimentally show that the change in the genetic sequence is “rescuing” the cellular changes relevant for PD.
  • The advantage of these patient-specific cell lines are that specific genetic changes can be directly investigated without the experimental noise in control cell lines. This approach has been adopted by many laboratories in the field of disease modeling and will probably become the gold standard for stem cell modeling and drug discovery.
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.

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06693
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$2 278 080
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

ALS is a progressive neurodegenerative disease that primarily affects motor neurons (MNs). It results in paralysis and loss of control of vital functions, such as breathing, leading to premature death. Life expectancy of ALS patients averages 2–5 years from diagnosis. About 5,600 people in the U.S. are diagnosed with ALS each year, and about 30,000 Americans have the disease. There is a clear unmet need for novel ALS therapeutics because no drug blocks the progression of ALS. This may be due to the fact that multiple proteins work together to cause the disease and therapies targeting individual toxic proteins will not prevent neurodegeneration due to other factors involved in the ALS disease process. We propose to develop a novel ALS therapy involving small molecule drugs that stimulate a natural defense system in MNs, autophagy, which will remove all of the disease-causing proteins in MNs to reduce neurodegeneration. We previously reported on a class of neuronal autophagy inducers (NAIs) and in this grant will prioritize those drugs for blocking neurodegeneration of human iPSC derived MNs from patients with familial and sporadic ALS to identify leads that will then be tested for efficacy in vivo in animal models of ALS to select a clinical candidate. Since all of our NAIs are FDA approved for treating indications other than ALS, our clinical candidate could be rapidly transitioned to testing for efficacy and safety in treating ALS patients near the end of this grant.

Statement of Benefit to California: 

Neurodegenerative diseases such as ALS as well as Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s Disease (HD) are devastating to the patient and family and create a major financial burden to California (CA). These diseases are due to the buildup of toxic misfolded proteins in key neuronal populations that leads to neurodegeneration. This suggests that common mechanisms may be operating in these diseases. The drugs we are developing to treat ALS target this common mechanism, which we believe is an impairment of autophagy that prevents clearance of disease-causing proteins. Effective autophagy inducers we identify to treat ALS may turn out to be effective in treating other neurodegenerative diseases. This could have a major impact on the health care in CA. Most important in our studies is the translational impact of the use of patient iPSC-derived neurons and astrocytes to identify a new class of therapeutics to block neurodegeneration that can be quickly transitioned to testing in clinical trials for treating ALS and other CNS diseases. Future benefits to CA citizens include: 1) development of new treatments for ALS with application to other diseases such as AD, HD and PD that affect thousands of individuals in CA; 2) transfer of new technologies to the public realm with resulting IP revenues coming into the state with possible creation of new biotechnology spin-off companies and resulting job creation; and 3) reductions in extensive care-giving and medical costs.

Progress Report: 
  • ALS is a progressive neurodegenerative disease that primarily affects motor neurons (MNs). It results in paralysis and loss of control of vital functions, such as breathing, leading to premature death. Much scientific evidence indicates that ALS is due to the buildup of toxic misfolded proteins in key neuronal populations that leads to neurodegeneration. In this CIRM-funded project, we are developing drugs that can improve a cellular process called “autophagy” by which cells, including neurons, clear out built-up toxic misfolded proteins and increase their longevity. We had discovered that a series of FDA-approved drugs already on the market for other indications happen to induce autophagy in a manner that is independent of their original purpose. Our goal is to show that these FDA-approved drugs can induce autophagy and slow neurodegeneration in ALS patient-derived neurons, and to repurpose these drugs for ALS. In the last year, we have made significant progress towards testing these drugs on neurons that we derived from induced pluripotent stem cells engineered from skin cells taken from ALS patients. We have built robotic microscopes that can rapidly image ALS patient neurons that are treated with drugs in the lab and determine whether any of these “autophagy-inducing” FDA-approved drugs slowdown the rate of neurodegeneration. We have optimized large-scale methods to grow patient neurons, treat them with drugs, image them over many days, and analyze the images to measure neurodegeneration. In August 2014, we published a paper in the journal Nature Chemical Biology that showed two FDA-approved drugs can in fact induce autophagy and increase the clearing of an ALS-related protein called TDP43 in neurons. The drugs were also able to slow neurodegeneration in neurons and astrocytes derived from a familial ALS patient with an altered version of the TDP43 gene. We have now obtained stem cells from broader types of familial ALS as well as sporadic ALS patients, have made neurons from their stem cells, and have treated their stem cell-derived neurons with more than 10 autophagy-inducing drugs at varying concentrations to determine whether autophagy-inducers can slow neurodegeneration in neurons from broader forms of ALS. These neurons are currently being imaged using our robotic microscope. In addition, we have started to make astrocytes from patient stem cells and plan to test the drugs on astrocytes in the coming months.

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