Neurological Disorders

Coding Dimension ID: 
303
Coding Dimension path name: 
Neurological Disorders
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.

Grant Type: 
New Faculty I
Grant Number: 
RN1-00538-A
ICOC Funds Committed: 
$2 120 833
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Alzheimer’s disease is the most common cause of dementia in the elderly, affecting over 5 million people in the US alone. Boosting immune responses to beta-Amyloid (Aβ) has proven beneficial in mouse models and Alzheimer’s disease (AD) patients. Vaccinating Alzheimer’s mice with Aβ improves cognitive performance and lessens pathological features within the brain, such as Aβ plaque loads. However, human trials with direct Aβ vaccination had to be halted to brain inflammation in some patients. We have demonstrated that T cell immunotherapy also provides cognitive benefits in a mouse model for Alzheimer’s disease, and without any detectable brain inflammation. Translating this approach into a clinical setting requires that we first develop a method to stimulate the proliferation of Aβ-specific T cells without triggering generalized inflammatory response, as happens with vaccinations. Adaptive immune responses are provided by T cells and B cells, which are regulated by the innate immune system through antigen presenting cells, such as mature dendritic cells. We propose to leverage the power of embryonic stem (ES) cells by engineering dendritic cells that express a recombinant transgene that will specifically activate Aβ-specific T cells. We will test the effectiveness of this targeted stimulation strategy using real human T cells. If successful, this approach could provide a direct method to activate beneficial immune responses that may improve cognitive decline in Alzheimer’s disease.

Statement of Benefit to California: 

Alzheimer’s disease is the most common cause of dementia in the elderly, affecting more than 5 million people in the US. In addition to being home to more than 1 in 8 Americans, California is a retirement destination so a proportionately higher percentage of our residents are afflicted with Alzheimer’s disease. It has been estimated that the number of Alzheimer’s patients in the US will grow to 13 million by 2050, so Alzheimer’s disease is a pending health care crisis. Greater still is the emotional toll that Alzheimer’s disease takes on it’s patients, their families and loved one. Currently, there is no effective treatment or cure for Alzheimer’s disease. The research proposed here builds on more than 7 years of work showing that the body’s own immune responses keep Alzheimer’s in check in young and unaffected individuals, but deficiencies in T cell responses to beta-amyloid peptide facilitate disease progression. We have shown that boosting a very specific T cell immune response can provide cognitive and other benefits in mouse models for Alzheimer’s disease. Here we propose to use stem cell research to propel these findings into the clinical domain. This research may provide an effective therapeutic approach to treating and/or preventing Alzheimer’s disease, which will alleviate some of the financial burden caused by this disease and free those health care dollars to be spent for the well-being of all Californians.

Grant Type: 
New Faculty I
Grant Number: 
RN1-00538-B
Investigator: 
ICOC Funds Committed: 
$2 120 833
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Human Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Alzheimer’s disease is the most common cause of dementia in the elderly, affecting over 5 million people in the US alone. Boosting immune responses to beta-Amyloid (Aβ) has proven beneficial in mouse models and Alzheimer’s disease (AD) patients. Vaccinating Alzheimer’s mice with Aβ improves cognitive performance and lessens pathological features within the brain, such as Aβ plaque loads. However, human trials with direct Aβ vaccination had to be halted to brain inflammation in some patients. We have demonstrated that T cell immunotherapy also provides cognitive benefits in a mouse model for Alzheimer’s disease, and without any detectable brain inflammation. Translating this approach into a clinical setting requires that we first develop a method to stimulate the proliferation of Aβ-specific T cells without triggering generalized inflammatory response, as happens with vaccinations. Adaptive immune responses are provided by T cells and B cells, which are regulated by the innate immune system through antigen presenting cells, such as mature dendritic cells. We propose to leverage the power of embryonic stem (ES) cells by engineering dendritic cells that express a recombinant transgene that will specifically activate Aβ-specific T cells. We will test the effectiveness of this targeted stimulation strategy using real human T cells. If successful, this approach could provide a direct method to activate beneficial immune responses that may improve cognitive decline in Alzheimer’s disease.

Statement of Benefit to California: 

Alzheimer’s disease is the most common cause of dementia in the elderly, affecting more than 5 million people in the US. In addition to being home to more than 1 in 8 Americans, California is a retirement destination so a proportionately higher percentage of our residents are afflicted with Alzheimer’s disease. It has been estimated that the number of Alzheimer’s patients in the US will grow to 13 million by 2050, so Alzheimer’s disease is a pending health care crisis. Greater still is the emotional toll that Alzheimer’s disease takes on it’s patients, their families and loved one. Currently, there is no effective treatment or cure for Alzheimer’s disease. The research proposed here builds on more than 7 years of work showing that the body’s own immune responses keep Alzheimer’s in check in young and unaffected individuals, but deficiencies in T cell responses to beta-amyloid peptide facilitate disease progression. We have shown that boosting a very specific T cell immune response can provide cognitive and other benefits in mouse models for Alzheimer’s disease. Here we propose to use stem cell research to propel these findings into the clinical domain. This research may provide an effective therapeutic approach to treating and/or preventing Alzheimer’s disease, which will alleviate some of the financial burden caused by this disease and free those health care dollars to be spent for the well-being of all Californians.

Grant Type: 
New Faculty I
Grant Number: 
RN1-00577
Investigator: 
Name: 
Type: 
PI
ICOC Funds Committed: 
$2 626 937
Disease Focus: 
Neurological Disorders
Parkinson's Disease
oldStatus: 
Closed
Public Abstract: 

Embryonic stem cells have the capacity to self-renew and differentiate into other cell types. Understanding how this is regulated on the molecular level would enable us to manipulate the process and guide stem cells to generate specific types of cells for safe transplantation. However, complex networks of intracellular cofactors and external signals from the environment all affect the fate of stem cells. Dissecting these molecular interactions in stem cells is a very challenging task and calls for innovative new strategies. We propose to genetically incorporate novel amino acids into proteins directly in stem cells. Through these amino acids we will be able to introduce new chemical or physical properties selectively into target proteins for precise biological study in stem cells.

Nurr1 is a nuclear hormone receptor that has been associated with Parkinson’s disease (PD), which occurs when dopamine (DA) neurons begin to malfunction and die. Overexpression of Nurr1 and other proteins can induce the differentiation of neural stem cells and embryonic stem cells to dopamine (DA) neurons. However, these DA neurons did not survive well in a PD mouse model after transplantation. In addition, it is unclear how Nurr1 regulates the differentiation process and what other cofactors are involved. We propose to genetically introduce a novel amino acid that carries a photocrosslinking group into Nurr1 in stem cells. Upon illumination, molecules interacting with Nurr1 will be permanently linked for identification by mass spectrometry. Using this approach, we aim to identify unknown cofactors that regulate Nurr1 function or are controlled by Nurr1, and to map sites on Nurr1 that can bind agonists. The function of identified cofactors in DA neuron specification and maturation will be tested in mouse and human embryonic stem cells. These cofactors will be varied in combination to search for more efficient ways to induce embryonic stem cells to generate a pure population of DA neurons. The generated DA neurons will be evaluated in a mouse model of PD. Additionally, the identification of the agonist binding site on Nurr1 will facilitate future design and optimization of potent drugs.

Statement of Benefit to California: 

Parkinson’s disease (PD) is the second most common human neurodegenerative disorder, and primarily results from the selective and progressive degeneration of ventral midbrain dopamine (DA) neurons. Cell transplantation of DA neurons differentiated from neural stem cells or embryonic stem cells raised great hope for an improved treatment for PD patients. However, DA neurons derived using current protocols do not survive well in mouse PD models, and the details of DA neuron development from stem cells are unclear. Our proposed research will identify unknown cofactors that regulate the differentiation of embryonic stem cells to DA neurons, and determine how agonists activate Nurr1, an essential nuclear hormone receptor for DA neuron specification and maturation. This study may yield new drug targets and inspire novel preventive or therapeutic strategies for PD. These discoveries may be exploited by California’s biotech industry and benefit Californians economically. In addition, we will search for more efficient methods to differentiate human embryonic stem cells into DA neurons, and evaluate their therapeutic effects in PD mouse models. Therefore, the proposed research will also directly benefit California residents suffering from PD.

Grant Type: 
New Faculty I
Grant Number: 
RN1-00527
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$2 348 520
Disease Focus: 
Aging
Neurological Disorders
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 

The adult brain contains a pool of stem cells, termed adult neural stem cells, that could be used for regenerative purposes in diseases that affect the nervous system. The goal of this proposal is to understand the mechanisms that promote the maintenance of adult neural stem cells as an organism ages. Understanding the factors that maintain the pool of adult neural stem cells should open new avenues to prevent age-dependent decline in brain functions and to use these cells for therapeutic purposes in neurological and neurodegenerative diseases, such as Alzheimer’s or Parkinson’s diseases.

Our general strategy is to use genes that play a central role in organismal aging as we have recently discovered that two of these genes, Foxo and Sirt1, have profound effects on the maintenance and self-renewal of adult neural stem cells. We propose to use these genes as a molecular handle to understand the mechanisms of maintenance of neural stem cells. Harnessing the regenerative power of stem cells by acting on genes that govern aging will provide a novel angle to identify stem cell therapeutics for neurological and neurodegenerative diseases, most of which are age-dependent.

Statement of Benefit to California: 

As the population of the State of California ages, neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease affect increasing numbers of patients. There are no efficient treatments of cures for these diseases. In addition to the devastating effects of neurodegenerative diseases on the patients and their relatives, the cost of caring for California’s Alzheimer patients—about $22.4 billion in 2000—has been estimated to triple by 2040 due to the aging of the baby-boomer’s generation.

Stem cells from the brain, or neural stem cells, hold the promise of treatments and cures for these neurodegenerative diseases. One therapeutic strategy will be to replace degenerating cells in patients with stem cells. Another approach would be to identify strategy to better maintain the pool of neural stem cell with age. Both approaches will only be possible when the mechanisms controlling the maintenance of these stem cells and their capacity to produce their functional progeny are better understood in young and old individuals.

We propose to study the mode of action in neural stem cells of two genes, Foxo and Sirt, that are known to play major roles to extend lifespan in a variety of species. These genes are major targets for the development of stem cell therapeutic strategies that will benefit a wide range of patients suffering from age-dependent neurodegenerative disorders.

The development of effective replacement therapies in neurodegenerative diseases will be a benefit for the rapidly aging population of California; it will also alleviate the financial burden that these age-related disorders create for the State of California.

Grant Type: 
Early Translational I
Grant Number: 
TR1-01267
Investigator: 
Type: 
Partner-PI
ICOC Funds Committed: 
$5 416 003
Disease Focus: 
Neurological Disorders
Parkinson's Disease
Collaborative Funder: 
Victoria, Australia
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 

Parkinson's Disease (PD) is a devastating disorder, stealing vitality from vibrant, productive adults & draining our health care dollars. It is also an excellent model for studying other neurodegenerative conditions. We have discovered that human neural stem cells (hNSCs) may exert a significant beneficial impact in the most authentic, representative, & predictive animal model of actual human PD. Interestingly, we have learned that, while some of the hNSCs differentiate into replacement dopamine (DA) neurons, much of the therapeutic benefit derived from a stem cell action we discovered a called the “Chaperone Effect” – even hNSC-derived cells that do not become DA neurons contributed to the reversal of severe Parkinsonian symptoms by protecting endangered host DA neurons & their connections, restoring equipoise to the host nigrostriatal system, and reducing pathological hallmark of PD. While the ultimate goal may someday be to replace dead DA neurons, the Chaperone Effect represents a more tractable near-term method of using cells to address this serious condition. However, many questions remain in the process of developing these cellular therapeutic candidates. A major question is what is the best (safest, most efficacious) way to generate hNSCs? Directly from the fetal brain? From human embryonic stem cells? From skin cells reprogrammed to act like stem cells? Also, would benefits be even greater if, in addition to harnessing the Chaperone Effect, the number of stem cell-derived DA neurons was also increased? And could choosing the right stem cell type &/or providing the right supportive molecules help achieve this? This study seeks to answer these questions. Importantly, we will do so using the most representative model of human PD, a model that not only mimics all of the human symptomatology but also all the side-effects of treatment; inattention to this latter aspect plagued earlier clinical trials in PD. A successful therapy for PD would not only be of great benefit for the many patients who now suffer from the disease, or who are likely to develop it as they age, but the results will help with other potential disease applications due to greater understanding of stem cell biology (particularly the Chaperone Effect, which represents “low hanging fruit”) as well as their potential complications and side effects.

Statement of Benefit to California: 

Not only is Parkinson's Disease (PD) a devastating disease in its own right-- impairing typically vibrant productive adults & draining our health care dollars -- but it is also an excellent model for studying other neurodegenerative diseases. We have discovered that stem cells may actually exert a beneficial impact independent of dopamine neuron replacement. As a result of a multiyear study performed by our team, implanting human neural stem cells (hNSCs) into the most authentic, representative, and predictive animal model of actual human PD, we learned that the cells could reverse severe Parkinsonian symptoms by protecting endangered host dopaminergic (DA) neurons, restoring equipoise to the cytoarchitecture, preserving the host nigrostriatal pathway, and reducing alpha-synuclein aggregations (a pathological hallmark of PD). This action, called the "Chaperone Effect" represents a more tractible near-term method of using cells to address an unmet medical need. However, many questions remain in the process of developing these cellular therapeutic candidates. A major question is what is the best (safest & most efficacious way) to generate hNSCs? Directly from the fetal brain? From human embryonic stem cells? From human induced pluripotent cells? Also, would benefits be even greater if, in addition to harnessing the Chaperone Effect, the number of donor-derived DA neurons was also increased? And could choosing the right stem cell type &/or providing the right supportive molecules help achieve this? This study seeks to answer these questions. Importantly, we will continue to use the most representative model of human PD to do so, a model that not only mimics all of the human symptomatology but also all the side-effects of treatment; inattention to this latter aspect plagued earlier clinical trials in PD. Because of the unique team enlisted, these studies can be done at a fraction of the normal cost, allowing for parsimony in the use of research dollars, clearly a benefit to California taxpayers. Not only might California patients benefit in terms of their well-being, and the economy benefit from productive adults re-entering the work force & aging adults remaining in the work force, but it is likely that new intellectual property will emerge that will provide additional financial benefit to California stakeholders, both citizens & companies.

Grant Type: 
Early Translational I
Grant Number: 
TR1-01245
Investigator: 
Type: 
PI
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$3 599 997
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Collaborative Funder: 
Victoria, Australia
Human Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 

Alzheimer disease (AD), the most common cause of dementia among the elderly and the third leading cause of death, presently afflicts over 5 million people in the USA, including over 500,000 in California. Age is the major risk factor, with 5% of the population over age 65 affected, with the incidence doubling every 5 years thereafter, such that 40-50% of those over age 85 are afflicted. Being told that one suffers from AD is one of the most devastating diagnoses a patient (and their family/caregivers) can ever receive, dooming the patient to a decade or more of progressive cognitive decline and eventual loss of all memory. At the terminal stages, the patients have lost all reasoning ability and are usually bed-ridden and unable to care for themselves. As the elderly represent the fastest growing segment of our society, there is an urgent need to develop therapies to delay, prevent or treat AD. If the present trend continues and no therapy is developed, over 16 million Americans will suffer from AD by 2050, placing staggering demands on our healthcare and economic systems. Thus, supporting AD research is a wise and prudent investment, particularly focusing on the power that stem cell biology offers.

Currently, there is no cure or means of preventing AD. Existing treatments provide minor symptomatic relief– often associated with severe side effects. Multiple strategies are likely needed to prevent or treat AD, including the utilization of cell based approaches. In fact, our preliminary studies indicate that focusing on the promise of human stem cell biology could provide a meaningful therapy for a disease for which more traditional pharmaceutical approaches have failed.

We aim to test the hypothesis that neural stem cells represent a novel therapeutic strategy for the treatment of AD. Our broad goal is to determine whether neural stem cells can be translated from the bench to the clinic as a therapy for AD.

This proposal builds on extensive preliminary data that support the feasibility of neural stem cell-based therapies for the treatment of AD. Thus, this proposal focuses on a development candidate for treating Alzheimer disease. To translate our initial stem cell findings into a future clinical application for treating AD, we assembled a world class multi-disciplinary team of scientific leaders from the fields of stem cell biology, animal modeling, neurodegeneration, immunology, genomics, and AD clinical trials to collaborate in this early translational study aimed at developing a novel treatment for AD. Our broad goal is to examine the efficacy of human neural stem cells to rescue the cognitive phenotype in animal models of AD. Our studies aim to identify a clear developmental candidate and generate sufficient data to warrant Investigational New Drug (IND) enabling activity. The proposed studies represent a novel and promising strategy for treating AD, a major human disorder for which there is currently no effective therapy.

Statement of Benefit to California: 

Neurological disorders have devastating consequences for the quality of life, and among these, perhaps none is as dire as Alzheimer disease. Alzheimer disease robs individuals of their memory and cognitive abilities, such that they are no longer able to function in society or even interact with their family. Alzheimer disease is the most common cause of dementia among the elderly and the most significant and costly neurological disorder. Currently, 5.2 million individuals are afflicted with this insidious disorder, including over 588,000 in the State of California. Hence, over 10% of the nation's Alzheimer patients reside in California. Moreover, California has the dubious distinction of ranking first in terms of states with the largest number of deaths due to this disorder.

Age is the major risk factor for Alzheimer disease, with 5% of the population over age 65 afflicted, with the incidence doubling every 5 years such that 40-50% of the population over age 85 is afflicted. As the elderly represent the fastest growing segment of our society, there is an urgent need to develop therapies to prevent or treat Alzheimer disease. By 2030, the number of Alzheimer patients living in California will double to over 1.1 million. All ethnic groups will be affected, although the number of Latinos and Asians living with Alzheimer will triple by 2030, and it will double among African-Americans within this timeframe. To further highlight the direness, at present, one person develops Alzheimer disease every 72 seconds, and it is estimated that by 2050, one person will develop the disease every 33 seconds! Clearly, the sheer volume of new cases will create unprecedented burdens on our healthcare system and have a major impact on our economic system. As the most populous state, California will be disproportionately affected, stretching our public finances to their limits. To illustrate the economic impact of Alzheimer disease, studies show that an estimated $8.5 billion of care were provided in one year in the state of California alone (this value does not include other economic aspects of Alzheimer disease). Therefore, it is prudent and necessary to invest resources to try and develop strategies to delay, prevent, or treat Alzheimer disease now.

California has taken the national lead in conducting stem cell research. Despite this, there has not been a significant effort to utilize the power of stem cell biology for Alzheimer disease. This proposal seeks to reverse this trend, as we have assembled a world class group of investigators throughout the State of California and in [REDACTED] to tackle the most significant and critical questions that arise in translating basic research on human stem cells into a clinical application for the treatment of Alzheimer disease. This proposal is based on an extensive body of preliminary data that attest to the feasibility of further exploring human stem cells as a treatment for Alzheimer disease.

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