Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
Grant Type: 
Early Translational II
Grant Number: 
TR2-01832
Investigator: 
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$1 835 983
Disease Focus: 
Genetic Disorder
Neurological Disorders
Pediatrics
Collaborative Funder: 
Germany
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Canavan disease is a devastating disease of infants which affects their neural development and leads to mental retardation and early death. It occurs in 1 in 6,400 persons in the U.S. and there is no treatment so far. We propose to generate genetically-repaired and patient-specific stem cells (called iPSCs) from patients’ skin cells, and then coax these stem cells into specific types of corrective neural precursors using methods established in our laboratories in order to develop a therapeutic candidate for this disease. By use of a mouse model of Canavan disease, we will determine the ability of these genetically corrected cells to successfully treat the disease. These results will form the basis for an eventual clinical trial in humans, and if successful, would be the first treatment for this terrible disease.

There are many families affected by this disease, and other diseases similar to it. Results from this work could have applications to this and other similar genetic diseases. Through the proposed research, maybe no parents will have to watch their child suffer and die as a result of these dreadful diseases in one day. What a wonderful day that would be!

Statement of Benefit to California: 

It is estimated that California has ~12% of all cases of Canavan disease in the U.S. Besides the tremendous emotional and physical pain that this disease inflicts on families, it produces in California a medical and fiscal burden that is larger than any other states. Thus, there is a real need to develop a strategy of treatment for this disease. Stem cells provide great hope for the treatment of a variety of human diseases that affect the citizens of California. Combination of gene therapy and iPSC technology will enable the development of therapeutic candidates of human genetic diseases via the creation of genetically-corrected patient-specific iPSCs. Our proposal aims to establish a therapeutic development candidate for Canavan disease, a devastating neurodegenerative disease that leads to mental retardation and early death. The generation of genetically-repaired and patient-specific iPSC lines will represent great potential not only for California health care patients but also for pharmaceutical and biotechnology industries in California. Moreover, California is a strong leader in pre-clinical and clinical research developments. To maintain this position, we need to create patient-specific stem cells as autologous therapeutic candidates, in order to overcome the challenges of immune rejection faced by today’s cell therapy field. This proposal addresses the very issue by generating “disease-corrected” and patient-specific iPSCs as a therapeutic candidate with the potential to create safer and more effective cell replacement therapies.

Grant Type: 
Early Translational II
Grant Number: 
TR2-01778
Investigator: 
Name: 
Type: 
PI
Type: 
Partner-PI
ICOC Funds Committed: 
$2 472 839
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Collaborative Funder: 
Germany
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Parkinson’s Disease (PD) is the most common neurodegenerative movement disorder. It is characterized by motor impairment such as slowness of movements, shaking and gait disturbances. Age is the most consistent risk factor for PD, and as we have an aging population, it is of upmost importance that we find therapies to limit the social, economic and emotional burden of this disease. Most of the studies to find better drugs for PD have been done in rodents. However, many of these drugs failed when tested in PD patients. One problem is that we can only investigate the diseased neurons of the brain after the PD patients have died. We propose to use skin cells from PD patients and reprogram these into neurons and other surrounding cells in the brain called glia. This is a model to study the disease while the patient is still alive. We will investigate how the glial surrounding cells affect the survival of neurons. We will also test drugs that are protective for glial cells and neurons. Overall, this approach is advantageous because it allows for the study of pathological development of PD in a human system. The goal of this project is to identify key molecular events involved at early stages in PD and exploit these as potential points of therapeutic intervention.

Statement of Benefit to California: 

The goal of this proposal is to create human cell-based models for neurodegenerative disease using transgenic human embryonic stem cells and induced pluripotent stem cells reprogrammed from skin samples of highly clinically characterized Parkinson’s Disease (PD) patients and age-matched controls. Given that age is the most consistent risk factor for PD, and we have an aging population, it is of utmost importance that we unravel the cellular, molecular, and genetic causes of the highly specific cell death characteristic of PD. New drugs can be developed out of these studies that will also benefit the citizens of the State of California. In addition, if our strategy can go into preclinical development, this approach would most likely be performed in a pharmaceutical company based in California.

Grant Type: 
Early Translational II
Grant Number: 
TR2-01856
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$6 016 624
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Collaborative Funder: 
Maryland
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

Parkinson's disease (PD) is a devastating movement disorder caused by the death of dopaminergic neurons (a type of nerve cells in the central nervous system) present in the midbrain. These neurons secrete dopamine (a signaling molecule) and are a critical component of the motor circuit that ensures movements are smooth and coordinated.

All current treatments attempt to overcome the loss of these neurons by either replacing the lost dopamine, or modulating other parts of the circuit to balance this loss or attempting to halt or delay the loss of dopaminergic neurons. Cell replacement therapy (that is, transplantation of dopaminergic neurons into the brain to replace lost cells and restore function) as proposed in this application attempts to use cells as small pumps of dopamine that will be secreted locally and in a regulated way, and will therefore avoid the complications of other modes of treatment. Indeed, cell therapy using fetal tissue-derived cells have been shown to be successful in multiple transplant studies. Work in the field has been limited however, partially due to the limited availability of cells for transplantation (e.g., 6-10 fetuses of 6-10 weeks post-conception are required for a single patient).

We believe that human embryonic stem cells (hESCs) may offer a potentially unlimited source of the right kind of cell required for cell replacement therapy. Work in our laboratories and in others has allowed us to develop a process of directing hESC differentiation into dopaminergic neurons. To move forward stem cell-based therapy development it is important to develop scale-up GMP-compatible process of generating therapeutically relevant cells (dopaminergic neurons in this case).

The overall goal of this proposal is to develop a hESC-based therapeutic candidate (dopaminergic neurons) by developing enabling reagents/tools/processes that will allow us to translate our efforts into clinical use. We have used PD as a model but throughout the application have focused on generalized enabling tools. The tools, reagents and processes we will develop in this project will allow us to move towards translational therapy and establish processes that could be applied to future IND-enabling projects. In addition, the processes we will develop would be of benefit to the CIRM community.

Statement of Benefit to California: 

Parkinson’s disease affects more than a million patients United States with a large fraction being present in California. California, which is the home of the Parkinson’s Institute and several Parkinson’s related foundations and patient advocacy groups, has been at the forefront of this research and a large number of California based scientists supported by these foundations and CIRM have contributed to significant breakthroughs in this field.

In this application we and our collaborators in California aim propose to develop a hESC-based therapeutic candidate (dopaminergic neurons) that will allow us to move towards translational therapy and establish processes that could be applied to future IND-enabling projects for this currently non-curable disorder. We believe that this proposal includes the basic elements that are required for the translation of basic research to clinical research. We believe these experiments not only provide a blueprint for moving Parkinson’s disease towards the clinic for people suffering with the disorder but also a generalized blueprint for the development of stem cell therapy for multiple neurological disorders including motor neuron diseases and spinal cord injury. The tools and reagents that we develop will be made widely available to Californian researchers. We expect that the money expended on this research will benefit the Californian research community and the tools and reagents we develop will help accelerate the research of our colleagues in both California and worldwide.

Grant Type: 
Early Translational II
Grant Number: 
TR2-01844
Investigator: 
Name: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$5 665 887
Disease Focus: 
Neurological Disorders
Pediatrics
Spinal Muscular Atrophy
Human Stem Cell Use: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 

Spinal muscular atrophy (SMA) is the leading genetic cause of infant death in the U.S. This devastating disease affects 1 child in every 6,000-10,000 live births, with a North American prevalence of approximately 14,000 individuals. The disease is characterized by the death of spinal cord cells called motor neurons that connect the brain to muscle. Death of these cells causes muscle weakness and atrophy, which progresses to paralysis, respiratory failure and frequently death. The three different types of SMA differ in severity and prognosis, with Type I being the most severe. SMA is caused by a genetic defect that leads to reduced levels of a single protein called SMN.

There are currently no approved therapies for the disease. The existing treatments for SMA consist of supportive care for the respiratory and nutritional deficits, for example ventilation and feeding tubes. Previous attempts to develop drugs using conventional technologies, such as cultured cancer cells or cells derived from animals have been unsuccessful. These failures are likely due the fact that previous attempts used cell types that don’t reflect the disease or aren’t affected by low levels of the SMN protein.

Our approach uses patient-derived motor neurons, the specific cell type that dies. We will conduct drug discovery experiments using these motor neurons to find potential therapeutics that increase the levels of the SMN protein in these diseased cells. Induced pluripotent stem cell (iPSC) technology allows us to take skin cells from patients with SMA, grow them in a dish, and turn them into motor neurons. We are conducting high-throughput screens of potential drugs with these cells to identify drug candidates that increase SMN protein levels in motor neurons derived from SMA patients. An added advantage to our approach is that we can test our drug candidates in motor neurons from many different patients, with different disease subtypes and from different ethnic backgrounds. We have generated iPSCs from many patients with SMA and we will test compounds for effectiveness against this cohort. These studies will give us an indication of the effectiveness of our compounds across patients before moving into costly and lengthy clinical trials.

If our drug candidate is successful, it could be the first effective therapeutic available for SMA. It will increase the amount of SMN protein and prevent motor neuron death. Halting the death of spinal cord motor neurons prevents the progressive weakness and muscle atrophy. We anticipate that this would prevent disability in Type III patients. For Type I and II patients, we believe such a therapy would mitigate respiratory and feeding challenges and allow lifespan increase.

The sponsoring institution has integrated iPSC-based drug discovery capabilities, ranging from stem cell line production, high throughput drug screening and medicinal chemistry. Accordingly, this institution is uniquely positioned to achieve the aims of this grant.

Statement of Benefit to California: 

Spinal muscular atrophy (SMA) is the second-most common autosomal-recessive disorder and leading genetic cause of death of infants in the U.S. We estimate that there are up to 1,500 SMA patients currently living in California, with 100 new cases diagnosed in California every year. The CIRM Early Translational II Awards is intended to fund studies that will propel drug discovery forward for many devastating diseases. In keeping with this mission, we propose to leverage iPSC technology to generate disease-relevant cell types from patients themselves for a high throughput drug screen. A successful therapy for SMA would lead to significant cost savings to California’s health care system, and would provide relief to families of patients with this devastating disorder.

Given that there are not many successful drugs in the making for neurological diseases such as ALS, SMA, Parkinson’s disease or Alzheimer’s disease, our project should significantly impact drug discovery in this area by introducing iPSC technologies as a valid drug discovery and development platform. The application of iPSC-based disease modeling and drug discovery to SMA is highly innovative and represents the opportunity to establish worldwide leadership for California in this emerging field.

Furthermore, the sponsoring institution will fund over 70% of the direct costs during the timeframe of this award. Accordingly, the 3:1 leverage provides great opportunity to magnify the effect of a CIRM award. Our research program will also create new, high-paying jobs in California, and will stimulate California’s economy by creating new research and clinical tools. These activities will continue to strengthen California’s leadership position at the forefront of the stem cell and regenerative medical revolution of the 21st century.

Grant Type: 
Early Translational II
Grant Number: 
TR2-01814
Investigator: 
ICOC Funds Committed: 
$1 491 471
Disease Focus: 
Autism
Neurological Disorders
Pediatrics
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Autism and autism spectrum disorders (ASD) are complex neurodevelopmental diseases that affect 1 in 150 children in the United States. Such diseases are mainly characterized by deficits in verbal communication, impaired social interaction, and limited and repetitive interests and behavior. Because autism is a complex spectrum of disorders, a different combination of genetic mutations is likely to play a role in each individual. One of the major impediments to ASD research is the lack of relevant human disease models. ASD animal models are limited and cannot reproduce the important language and social behavior impairment of ASD patients. Moreover, mouse models do not represent the vast human genetic variation. Reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, iPSCs) has been accomplished using human cells. Isogenic pluripotent cells are attractive from the prospective to understanding complex diseases, such as ASD. Our preliminary data provide evidence for an unexplored developmental window in ASD wherein potential therapies could be successfully employed. The model recapitulates early stages of ASD and represents a promising cellular tool for drug screening, diagnosis and personalized treatment. By testing whether drugs have differential effects in iPSC-derived neurons from different ASD backgrounds, we can begin to unravel how genetic variation in ASD dictates responses to different drugs or modulation of different pathways. If we succeed, we may find new molecular mechanisms in ASD and new compounds that may interfere and rescue these pathways. The impact of this approach is significant, since it will help better design and anticipate results for translational medicine. Moreover, the collection and molecular/cellular characterization of these iPSCs will be an extremely valuable tool to understand the fundamental mechanism behind ASD. The current proposal uses human somatic cells converted into iPSC-derived neurons. The proposed experiments bring our analyses to real human cell models for the first time. We anticipate gaining insights into the causal molecular mechanisms of ASD and to discover potential biomarkers and specific therapeutic targets for ASD.

Statement of Benefit to California: 

Autism spectrum disorders, including Rett syndrome, Angelman syndrome, Timothy syndrome, Fragile X syndrome, Tuberous sclerosis, Asperger syndrome or childhood disintegrative disorder, affect many Californian children. In the absence of a functionally effective cure or early diagnostic tool, the cost of caring for patients with such pediatric diseases is high, in addition to a major personal and family impact since childhood. The strikingly high prevalence of ASD, dramatically increasing over the past years, has led to the emotional view that ASD can be traced to a single source, such as vaccine, preservatives or other environmental factors. Such perspective has a negative impact on science and society in general. Our major goal is to develop a drug-screening platform to rescue deficiencies showed from neurons derived from induced pluripotent stem cells generated from patients with ASD. If successful, our model will bring novel insights on the dentification of potential diagnostics for early detection of ASD risk, or ability to predict severity of particular symptoms. In addition, the development of this type of pharmacological therapeutic approach in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop these types of therapies (providing banks of inducible pluripotent stem cells) in California with consequent economic benefit.

Grant Type: 
Early Translational II
Grant Number: 
TR2-01841
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$4 045 253
Disease Focus: 
Huntington's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 

Huntington’s disease (HD) is a devastating degenerative brain disease with 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 caregiving. 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) 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 fetal brain tissue in HD patients suggests that replacing neurons that are lost may also be effective. The ability to differentiate hESCs into neuronal populations offers a powerful and sustainable alternative for cell replacement. Further, hESCs offer an opportunity to create cell models in which to identify earlier markers of disease onset and progression and for drug development.

We have assembled a multidisciplinary team of investigators and consultants who will integrate basic and translational research with the goal of generating a lead developmental candidate having disease modifying activity with sufficient promise to initiate IND-enabling activities for HD clinical trials. The collaborative research team is comprised of investigators from multiple California institutions and has been assembled to maximize leverage of existing resources and expertise within the HD and stem cell fields.

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, a very forward-thinking team effort will allow highly experienced investigators in HD, stem cell research and clinical trials to come together and identify a lead development candidate for treatment of HD. This early translation grant will allow for a comprehensive and systematic evaluation of hESC-derived cell lines to identify a candidate and develop a candidate line into a viable treatment option. 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.

We have assembled a strong team of California-based investigators to carry out the proposed studies. 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 significant.

Grant Type: 
Research Leadership
Grant Number: 
LA1-08015
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$6 368 285
Disease Focus: 
Heart Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 

Tissues derived from stem cells can serve multiple purposes to enhance biomedical therapies. Human tissues engineered from stem cells hold tremendous potential to serve as better substrates for the discovery and development of new drugs, accurately model development or disease progression, and one day ultimately be used directly to repair, restore and replace traumatically injured and chronically degenerative organs. However, realizing the full potential of stem cells for regenerative medicine applications will require the ability to produce constructs that not only resemble the structure of real tissues, but also recapitulate appropriate physiological functions. In addition, engineered tissues should behave similarly regardless of the varying source of cells, thus requiring robust, reproducible and scalable methods of biofabrication that can be achieved using a holistic systems engineering approach. The primary objective of this research proposal is to create models of cardiac and neural human tissues from stem cells that can be used for various purposes to improve the quality of human health.

Statement of Benefit to California: 

California has become internationally renowned as home to the world's most cutting-edge stem cell biology and a global leader of clinical translation and commercialization activities for stem cell technologies and therapies. California has become the focus of worldwide attention due in large part to the significant investment made by the citizens of the state to prioritize innovative stem cell research as a critical step in advancing future biomedical therapies that can significantly improve the quality of life for countless numbers of people suffering from traumatic injuries, congenital disorders and chronic degenerative diseases. At this stage, additional investment in integration of novel tissue engineering principles with fundamental stem cell research will enable the development of novel human tissue constructs that can be used to further the translational use of stem cell-derived tissues for regenerative medicine applications. This proposal would enable the recruitment of a leading biomedical engineer with significant tissue engineering experience to collaborate with leading cardiovascular and neural investigators. The expected result will be development of new approaches to engineer transplantable tissues from pluripotent stem cell sources leading to new regenerative therapies as well as an enhanced understanding of mechanisms regulating human tissue development.

Grant Type: 
Research Leadership
Grant Number: 
LA1-06919
Investigator: 
Type: 
PI
ICOC Funds Committed: 
$6 443 455
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Spinal Cord Injury
Human Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 

Stem cells offer tremendous potential to treat previously intractable diseases. The clinical translation of these therapies, however, presents unique challenges. One challenge is the absence of robust methods to monitor cell location and fate after delivery to the body. The delivery and biological distribution of stem cells over time can be much less predictable compared to conventional therapeutics, such as small-molecule therapeutic drugs. This basic fact can cause road blocks in the clinical translation, or in the regulatory path, which may cause delays in getting promising treatments into patients. My research aims to meet these challenges by developing new non-invasive cell tracking platforms for emerging stem cell therapies. Recent progress in magnetic resonance imaging (MRI) has demonstrated the feasibility of non-invasive monitoring of transplanted cells in patients. This project will build on these developments by creating next-generation cell tracking technologies with improved detectability and functionality. Additionally, I will provide leadership in the integration of non-invasive cell tracking into stem cell clinical trials. Specifically, this project will follow three parallel tracks. (1) The first track leverages molecular genetics to develop new nucleic acid-based MRI reporters. These reporters provide instructions to program a cell’s innate machinery so that they produce special proteins with magnetic properties that impart MRI contrast to cells, and allow the cells to be seen. My team will create neural stem cell lines with MRI reporters integrated into their genome so that those neural stem cell lines, and their daughter cells, can be tracked days and months after transfer into a patient. (2) The second track will develop methods to detect stem cell viability in vivo using perfluorocarbon-based biosensors that can measure a stem cell's intracellular oxygen level. This technology can potentially be used to measure stem cell engraftment success, to see if the new cells are joining up with the other cells where they are placed. (3) The third project involves investigating the role that the host’s inflammatory response plays in stem cell engraftment. These studies will employ novel perfluorocarbon imaging probes that enable MRI visualization and quantification of places in the body where inflammation is occurring. Overall, MRI cell tracking methods will be applied to new stem cell therapies for amyotrophic lateral sclerosis, spinal cord injury, and other disease states, in collaboration with CIRM-funded investigators.

Statement of Benefit to California: 

California leads the nation in supporting stem cell research with the aim of finding cures for major diseases afflicting large segments of the state’s population. Significant resources are invested in the design of novel cellular therapeutic strategies and associated clinical trials. To accelerate the clinical translation of these potentially live saving therapies, many physicians need method to image the behavior and movement of cells non-invasively following transplant into patients. My research aims to meet these challenges by developing new cell tracking imaging platforms for emerging stem cell therapies. Recent progress in magnetic resonance imaging (MRI) has demonstrated the feasibility of non-invasive monitoring of transplanted cells in patients. This project will build on these developments by leading the integration of MRI cell tracking into stem cell clinical trials and by developing next-generation technologies with improved sensitivity and functionality. Initially, MRI cell tracking methods will be applied to new stem cell therapies for amyotrophic lateral sclerosis and spinal cord injury. In vivo MRI cell tracking can accelerate the process of deciding whether to continue at the preclinical and early clinical trial stages, and can facilitate smaller, less costly trials by enrolling smaller patient numbers. Imaging can potentially yield data about stem cell engraftment success. Moreover, MRI cell tracking can help improve safety profiling and can potentially lower regulatory barriers by verifying survival and location of transplanted cells. Overall, in vivo MRI cell tracking can help maximize the impact of the State’s investment in stem cell therapies by speeding-up clinical translation into patients. These endeavors are intrinsically collaborative and multidisciplinary. My project will create a new Stem Cell Imaging Center (SCIC) in California with a comprehensive set of ways to elucidate anatomical, functional, and molecular behavior of stem cells in model systems. The SCIC will provide scientific leadership to stem cell researchers and clinicians in the region, including a large number of CIRM-funded investigators who wish to bring state-of-the-art imaging into their clinical development programs. Importantly, the SCIC will focus intellectual talent on biological imaging for the state and the country. This project will help make MRI cell tracking more widespread clinically and position California to take a leadership role in driving this technology. An extensive infrastructure of MRI scanners already exist in California, and these advanced MRI methods would use this medical infrastructure better to advance stem cell therapies. Moreover, this project will lead to innovative new MRI tools and pharmaceutical imaging agents, thus providing economic benefits to California via the formation of new commercial products, industrial enterprises, and jobs.

Grant Type: 
New Faculty I
Grant Number: 
RN1-00530
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$2 200 715
Disease Focus: 
Amyotrophic Lateral Sclerosis
Neurological Disorders
Human Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

One of the most exciting possibilities in stem cell biology is the potential to replace damaged or diseased neural tissues affected by neurodegenerative disorders. Stem-cell-derived neurons provide a potentially limitless supply of replacement cells to repair damaged or diseased neurons. Typically, only one or a very few types of neurons are affected in most neurodegenerative diseases, and simply transplanting stem cells directly into a degenerating or damaged brain will not guarantee that the stem cells will differentiate into the specific neurons types needed. In fact, they may instead cause tumor formation. Thus, we must learn how to guide stem cells, cultured in a laboratory, toward a specific differentiation pathway that will produce neurons of the specified type. These cells would then provide a safe, effective way to treat neurodegenerative diseases and central nervous system injuries.

Since there are hundreds or thousands of types of neurons in the cerebral cortex, functionally repairing damaged neurons in the cortex will require a detailed understanding of the mechanisms controlling differentiation, survival, and connectivity of specific neuronal subtypes. In this proposal, I propose to investigate the molecular mechanisms that guide the neural stem cells in developing embryonic brains to generate two specific types of neurons – corticospinal motor neurons (CSMNs) and corticothalamic projection neurons (CTNs).

Our first goal is to understand what regulates the development of CSMNs. CSMNs are clinically important neurons that degenerate in Amyotrophic Lateral Sclerosis (ALS), and are damaged in spinal cord injuries. With our current technology, replacing damaged CSMNs has been impossible, due largely to a lack of understanding of what signals regulate their development. Our second goal is to identify genes that direct the neural stem cells to generate the CTNs. Despite their essential importance in sensory processing and involvement in epilepsy, mechanisms governing the development of CTNs have not yet been revealed. CSMNs and CTNs express many identical genes, and are generated from common neural stem cells in the embryonic brains. Yet it is unclear how they are specified from common stem cells. Our third goal is to identify transcription factor codes that neural stem cells employ to specifically generate either CSMNs or CTNs.

Currently, there is no cure for neurodegenerative diseases. Understanding how CSMNs and CTNs are generated during development provides the opportunity to design procedures to direct the stem cells cultured in a laboratory to specifically produce CSMNs or CTNs, which can then be used to replaced damaged or diseased neurons, such as those affected by ALS, or spinal cord injuries.

Statement of Benefit to California: 

Neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), affect tens of thousands of Californians. There are no cures for these devastating diseases, nor effective treatments that consistently slow or stop them. The research proposed in this application may provide the basis for a novel, cost-effective, cell replacement therapy for ALS, thereby benefiting the State of California and its citizens.

Stem cells offer a potential renewable source of a wide range of cell types that could be used to replace damaged cells involved in neurodegenerative diseases or in spinal cord injuries. At present, transplanting stem cells directly into patients is problematic, because this approach may instead cause tumor growth. To support safe and effective cell transplants, it is important to differentiate stem cells prior to the therapy into the specific cell types affected by the diseases. Understanding how different types of neurons are generated during development provides an opportunity to develop new methods to guide the differentiation of stem cells into the proper neuron types.

In this application, we propose to uncover the mechanisms that regulate the neural stem cells in developing mouse brains to generate different neuronal types in the cerebral cortex, including the corticospinal motor neurons (CSMNs) and the corticothalamic neurons (CTNs). CSMNs are the neurons that degenerate in ALS and are affected in spinal cord injuries. Dysfunction of CTNs has been implicated in epilepsy. Understanding the mechanisms regulating neural stem cells to generate CSMNs and CTNs in vivo will help scientists and physicians to direct stems cells to produce CSMNs or CTNs to replace damaged neurons in patients with neurodegenerative conditions.

Grant Type: 
New Faculty I
Grant Number: 
RN1-00564
Investigator: 
ICOC Funds Committed: 
$2 229 427
Disease Focus: 
Neurological Disorders
Rett's Syndrome
Human Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

Embryonic stem (ES) cells are remarkable cells in that they can replicate themselves indefinitely and have the potential to turn into all possible cell type of the body under appropriate environmental conditions. These characteristics make ES cells a unique tool to study development in the culture dish and put them at center stage for regenerative medicine. Two techniques, one called somatic cell nuclear transfer (SCNT) and the other in vitro reprogramming, have shown that adult cells from the mouse can be reverted to an ES like state. In SCNT, adult cell nuclei are transferred into oocytes and allowed to develop as early embryos from which ES cells can be derived, while in the in vitro method four genes are ectopically activated in the adult cell nucleus to induce an embryonic state in the culture dish. Key requirement for both processes is to erase the memory of the adult cell that specifies it as an adult cell and set up the ES cell program. How this happens remains unclear, and if it can be reproduced with human adult cells is an open question. Therefore, we will attempt to use the in vitro reprogramming method to generate human ES cells from adult cells and begin to understand the mechanism of the reprogramming process in both human and mouse cells. In addition to being integral to improving our understanding of how ES cells develop, if successful, this work will provide an important milestone for regenerative medicine. Many debilitating diseases and conditions are caused by damage to cells and tissue. In vitro reprogramming could provide a way to generate patient-specific stem cells that, in culture, could be turned into the type of cell or tissue needed to cure the patient’s disease or injury and transplanted back into the patient’s body. For example, Parkinson’s disease is caused by the loss or destruction of nerve cells. If reprogramming becomes possible, we could take a skin biopsy from a patient with Parkinson’s disease, induce the embryonic state in those skin cells to then be able to turn them into nerve cells and transplant them back into the same donor patient. Reprogramming could also be used to repair spinal cord injuries, allowing people who are paralyzed by accidents to walk again, or be helpful for patients with juvenile diabetes. One important advantage of patient-specific self-transplants is that they obviate the need for immunosuppression, which is often problematic for the patient. In addition, human cell reprogramming could be a new way to study how diseases progress at the cellular level as reprogramming could generate ES cells from patients with complex diseases that can be studied in detail for what makes them go awry during development. This knowledge could speed the search for new treatments and possibly cures for some of the most complex diseases that affect societies. We hope that the knowledge gained from our studies on reprogramming can, someday, support research that will help to put these idea to clinical use.

Statement of Benefit to California: 

Donated organs and tissues are often used to replace those that are diseased or destroyed, but unfortunately, the number of people needing a transplant exceeds the number of organs available for transplantation. Embryonic stem (ES) cells can be propagated in the laboratory for an unlimited period of time and can turn into all the specialized cell types that make us a human being. Therefore, ES cells offer the possibility of a renewable source of replacement cells and tissues to treat diseases, conditions, and disabilities such as Parkinson’s and Alzheimer’s, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis and rheumatoid arthritis. Our research is aimed to generate ES cells from adult cells through a method called in vitro reprogramming and to understand the mechanism by which the ES cell program can be reinstated in the adult cells. This work will not only provide the foundation for a better understanding of how human ES cells develop, but, if successful, be an important milestone for regenerative medicine. The advantage of using ES cells derived from adult cells by in vitro reprogramming would be that the patient’s own cells could be reprogrammed to an ES cell state and therefore, when transplanted back into the patient, not be attacked and destroyed by the body’s immune system. This would be beneficial to the people of California as tens of millions of Americans suffer from diseases and injuries that could benefit from research of in vitro reprogramming. Such advances would benefit the health as well as the economy of the state of California.

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