Alzheimer's Disease

Coding Dimension ID: 
304
Coding Dimension path name: 
Neurological Disorders / Alzheimer's Disease

Systemic Protein Factors as Modulators of the Aging Neurogenic Niche

Funding Type: 
Basic Biology II
Grant Number: 
RB2-01637
ICOC Funds Committed: 
$1 522 800
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Active
Public Abstract: 
Approaches to repair the injured brain or even prevent age-related neurodegeneration are in their infancy but there is growing interest in the role of neural stem cells in these conditions. Indeed, there is hope that some day stem cells can be used for the treatment of spinal cord injury, stroke, or Parkinson’s disease and stem cells are even mentioned in the public with respect to Alzheimer’s disease. To utilize stem cells for these conditions and, equally important to avoid potential adverse events in premature clinical trials, we need to understand the environment that supports and controls neural stem cell survival, proliferation, and functional integration into the brain. This “neurogenic” environment is controlled by local cues in the neurogenic niche, by cell-intrinsic factors, and by soluble factors which can act as mitogens or inhibitory factors potentially over longer distances. While some of these factors are starting to be identified very little is known why neurogenesis decreases so dramatically with age and what factors might mediate these changes. Because exercise or diet can increase stem cell activity even in old animals and lead to the formation of new neurons there is hope that neurogenesis in the aged brain could be restored to that seen in younger brains and that stem cell transplants could survive in an old brain given the right “young” environmental factors. Indeed, our preliminary data demonstrate that systemic factors circulating in the blood are potent regulators of neurogenesis. By studying how the most promising of these factors influence key aspects of the neurogenic niche in vitro and in vivo we hope to gain an understanding about the molecular interactions that support stem cell activity and the generation of new neurons in the brain. The experiments supported under this grant will help us to identify and understand the minimal signals required to regulate adult neurogenesis. These findings could be highly significant for human health and biomedical applications if they ultimately allow us to stimulate neurogenesis in a controlled way to repair, augment, or replace neural networks that are damaged or lost due to injury and degeneration.
Statement of Benefit to California: 
In California there are hundreds of thousands of elderly individuals with age-related debilitating brain injuries, ranging from stroke to Alzheimer’s and Parkinson’s disease. Approaches to repair the injured brain or even prevent age-related neurodegeneration are in their infancy but there is growing interest in the role of neural stem cells in these conditions. However, to potentially utilize such stem cells we need to understand the basic mechanisms that control their activity in the aging brain. The proposed research will start to address this problem using a novel and innovative approach and characterize protein factors in blood that regulate stem cell activity in the old brain. Such factors could be used in the future to support stem cell transplants into the brain or to increase the activity of the brain’s own stem cells.
Progress Report: 
  • We are interested in identifying soluble protein factors in blood which can either promote or inhibit stem cell activity in the brain. Through a previous aging study and the transfer of blood from young to old mice and vice versa we had identified several proteins which correlated with reduced stem cell function and neurogenesis in young mice exposed to old blood. Over the past year we studied two factors, CCL11/eotaxin and beta2-microglobulin in more detail in tissue culture and in mice. We could demonstrate that both factors administered into the systemic environment of mice reduce neurogenesis in a brain region involved in learning and memory. We have also begun to test the effect of these factors on human neural stem cells and we started experiments to try to identify protein factors which can enhance neurogenesis.
  • While age-related cognitive dysfunction and dementia in humans are clearly distinct entities and affect different brain regions, the aging brain shows the telltale molecular and cellular changes that characterize most neurodegenerative diseases. Remarkably, the aging brain remains plastic and exercise or dietary changes can increase cognitive function in humans and animals, with animal brains showing a reversal of some of the aforementioned biological changes associated with aging. We showed recently that blood-borne factors coming outside the brain can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing an old mouse to a young systemic environment or to plasma from young mice increased neurogenesis, synaptic plasticity, and improved contextual fear conditioning and spatial learning and memory. Preliminary proteomic studies show several proteins with stem cell activity increase in old “rejuvenated” mice supporting the notion that young blood may contain increased levels of beneficial factors with regenerative capacity. We believe we have identified some of these factors now and tested them on cultured mouse and human neural stem cell derived cells. Preliminary data suggest that these factors have beneficial effects and we will test whether these effects hold true in living mice.
  • Cognitive function in humans declines in essentially all domains starting around age 50-60 and neurodegeneration and Alzheimer’s disease seems to be inevitable in all but a few who survive to very old age. Mice with a fraction of the human lifespan show similar cognitive deterioration indicating that specific biological processes rather than time alone are responsible for brain aging. While age-related cognitive dysfunction and dementia in humans are clearly distinct entities the aging brain shows the telltale molecular and cellular changes that characterize most neurodegenerative diseases including synaptic loss, dysfunctional autophagy, increased inflammation, and protein aggregation. Remarkably, the aging brain remains plastic and exercise or dietary changes can increase cognitive function in humans and animals. Using heterochronic parabiosis or systemic application of plasma we showed recently that blood-borne factors present in the systemic milieu can rejuvenate brains of old mice. Accordingly, exposing an old mouse to a young systemic environment or to plasma from young mice increased neurogenesis, synaptic plasticity, and improved contextual fear conditioning and spatial learning and memory. Unbiased genome-wide transcriptome studies from our lab show that hippocampi from old “rejuvenated” mice display increased expression of a synaptic plasticity network which includes increases in c-fos, egr-1, and several ion channels. In our most recent studies, plasma from young but not old humans reduced neuroinflammation in brains of immunodeficient mice (these mice allow us to avoid an immune response against human plasma). Together, these studies lend strong support to the existence of factors with beneficial, “rejuvenating” activity in young plasma and they offer the opportunity to try to identify such factors.
  • Cognitive function in humans declines in essentially all domains starting around age 50-60 and neurodegeneration and dementia seem to be inevitable in all but a few who survive to very old age. Mice with a fraction of the human lifespan show similar cognitive deterioration indicating that specific biological processes rather than time alone are responsible for brain aging. While age-related cognitive dysfunction and dementia in humans are clearly distinct entities and affect different brain regions the aging brain shows the telltale molecular and cellular changes that characterize most neurodegenerative diseases including synaptic loss, dysfunctional autophagy, increased inflammation, and protein aggregation. Remarkably, the aging brain remains plastic and exercise or dietary changes can increase cognitive function in humans and animals, with animal brains showing a reversal of some of the aforementioned biological changes associated with aging. Using heterochronic parabiosis we showed recently that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing an old mouse to a young systemic environment or to plasma from young mice increased neurogenesis, synaptic plasticity, and improved contextual fear conditioning and spatial learning and memory. Over the past three years we discovered that factors in blood can actively change the number of new neurons that are being generated in the brain and that local cells in areas were neurons are generated respond to cues from the blood. We have started to identify some of these factors and hope they will allow us to regulate the activity of neural stem cells in the brain and hopefully improve cognition in diseases such as Alzheimer's.

The CIRM Human Pluripotent Stem Cell Biorepository – A Resource for Safe Storage and Distribution of High Quality iPSCs

Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
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.

Generation and characterization of high-quality, footprint-free human induced pluripotent stem cell lines from 3,000 donors to investigate multigenic diseases

Funding Type: 
hiPSC Derivation
Grant Number: 
ID1-06557
ICOC Funds Committed: 
$16 000 000
Disease Focus: 
Developmental Disorders
Genetic Disorder
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Induced pluripotent stem cells (iPSCs) have the potential to differentiate to nearly any cells of the body, thereby providing a new paradigm for studying normal and aberrant biological networks in nearly all stages of development. Donor-specific iPSCs and differentiated cells made from them can be used for basic and applied research, for developing better disease models, and for regenerative medicine involving novel cell therapies and tissue engineering platforms. When iPSCs are derived from a disease-carrying donor; the iPSC-derived differentiated cells may show the same disease phenotype as the donor, producing a very valuable cell type as a disease model. To facilitate wider access to large numbers of iPSCs in order to develop cures for polygenic diseases, we will use a an episomal reprogramming system to produce 3 well-characterized iPSC lines from each of 3,000 selected donors. These donors may express traits related to Alzheimer’s disease, autism spectrum disorders, autoimmune diseases, cardiovascular diseases, cerebral palsy, diabetes, or respiratory diseases. The footprint-free iPSCs will be derived from donor peripheral blood or skin biopsies. iPSCs made by this method have been thoroughly tested, routinely grown at large scale, and differentiated to produce cardiomyocytes, neurons, hepatocytes, and endothelial cells. The 9,000 iPSC lines developed in this proposal will be made widely available to stem cell researchers studying these often intractable diseases.
Statement of Benefit to California: 
Induced pluripotent stem cells (iPSCs) offer great promise to the large number of Californians suffering from often intractable polygenic diseases such as Alzheimer’s disease, autism spectrum disorders, autoimmune and cardiovascular diseases, diabetes, and respiratory disease. iPSCs can be generated from numerous adult tissues, including blood or skin, in 4–5 weeks and then differentiated to almost any desired terminal cell type. When iPSCs are derived from a disease-carrying donor, the iPSC-derived differentiated cells may show the same disease phenotype as the donor. In these cases, the cells will be useful for understanding disease biology and for screening drug candidates, and California researchers will benefit from access to a large, genetically diverse iPSC bank. The goal of this project is to reprogram 3,000 tissue samples from patients who have been diagnosed with various complex diseases and from healthy controls. These tissue samples will be used to generate fully characterized, high-quality iPSC lines that will be banked and made readily available to researchers for basic and clinical research. These efforts will ultimately lead to better medicines and/or cellular therapies to treat afflicted Californians. As iPSC research progresses to commercial development and clinical applications, more and more California patients will benefit and a substantial number of new jobs will be created in the state.

Restoration of memory in Alzheimer’s disease: a new paradigm using neural stem cell therapy

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05416
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the US, someone develops AD every 69 seconds and there are over 5 million individuals suffering from AD, including approximately 600,000 Californians. Current treatments do not alter the disease course. The absence of effective therapies coupled with the sheer number of affected patients renders AD a medical disorder of unprecedented need and a public health concern of significant magnitude. In 2010, the global economic impact of dementias was estimated at $604 billion, a figure far beyond the costs of cancer or heart disease. These numbers do not reflect the devastating social and emotional tolls that AD inflicts upon patients and their families. Efforts to discover novel and effective treatments for AD are ongoing, but unfortunately, the number of active clinical studies is low and many traditional approaches have failed in clinical testing. An urgent need to develop novel and innovative approaches to treat AD is clear. We propose to evaluate the use of human neural stem cells as a potential innovative therapy for AD. AD results in neuronal death and loss of connections between surviving neurons. The hippocampus, the part of the brain responsible for learning and memory, is particularly affected in AD, and is thought to underlie the memory problems AD patients encounter. Evidence from animal studies shows that transplanting human neural stem cells into the hippocampus improves memory, possibly by providing growth factors that protect neurons from degeneration. Translating this approach to humans could markedly restore memory and thus, quality of life for patients. The Disease Team has successfully initiated three clinical trials involving transplantation of human neural stem cells for neurological disorders. These trials have established that the cells proposed for this therapeutic approach are safe for transplantation into humans. The researchers in this Disease Team have shown that AD mice show a dramatic improvement in memory skills following both murine and human stem cell transplantation. With proof-of-concept established in these studies, the Disease Team intends to conduct the animal studies necessary to seek authorization by the FDA to start testing this therapeutic approach in human patients. This project will be conducted as a partnership between a biotechnology company with unique experience in clinical trials involving neural stem cell transplantation and a leading California-based academic laboratory specializing in AD research. The Disease Team also includes expert clinicians and scientists throughout California that will help guide the research project to clinical trials. The combination of all these resources will accelerate the research, and lead to a successful FDA submission to permit human testing of a novel approach for the treatment of AD; one that could enhance memory and save lives.
Statement of Benefit to California: 
The number of AD patients in the US has surpassed 5.4 million, and the incidence may triple by 2050. Roughly 1 out of every 10 patients with AD, over 550,000, is a California resident, and alarmingly, because of the large number of baby-boomers that reside in this state, the incidence is expected to more than double by 2025. Besides the personal impact of the diagnosis on the patient, the rising incidence of disease, both in the US and California, imperils the federal and state economy. The dementia induced by AD disconnects patients from their loved ones and communities by eroding memory and cognitive function. Patients gradually lose their ability to drive, work, cook, and carry out simple, everyday tasks, ultimately losing all independence. The quality of life for AD patients is hugely diminished and the burden on their families and caregivers is extremely costly to the state of California. Annual health care costs are estimated to exceed $172 billion, not including the additional costs resulting from the loss of income and physical and emotional stress experienced by caregivers of Alzheimer's patients. Given that California is the most populous state and the state with the highest number of baby-boomers, AD’s impact on California families and state finances is proportionally high and will only increase as the AD prevalence rises. Currently, there is no cure for AD and no means of prevention. Most approved therapies address only symptomatic aspects of AD and no disease-modifying approaches are currently available. By enacting Proposition 71, California voters acknowledged and supported the need to investigate the potential of novel stem cell-based therapies to treat diseases with a significant unmet medical need such as AD. In a disease like AD, any therapy that exerts even a modest impact on the patient's ability to carry out daily activities will have an exponential positive effect not only for the patients but also for their families, caregivers, and the entire health care system. We propose to evaluate the hypothesis that neural stem cell transplantation will delay the progression of AD by slowing or stabilizing loss of memory and related cognitive skills. A single, one-time intervention may be sufficient to delay progression of neuronal degeneration and preserve functional levels of memory and cognition; an approach that offers considerable cost-efficiency. The potential economic impact of this type of therapeutic research in California could be significant, and well worth the investment of this disease team proposal. Such an approach would not only reduce the high cost of care and improve the quality of life for patients, it would also make California an international leader in a pioneering approach to AD, yielding significant downstream economic benefits for the state.

Identifying Drugs for Alzheimer's Disease with Human Neurons Made From Human IPS cells

Funding Type: 
Early Translational III
Grant Number: 
TR3-05577
ICOC Funds Committed: 
$1 857 600
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
We propose to discover new drug candidates for Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel candidates by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drugs by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.
Statement of Benefit to California: 
Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drugs to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches to drug discovery for AD.
Progress Report: 
  • We have made steady and significant progress in developing a way to use human reprogrammed stem cells to develop drugs for Alzheimer's disease. In the more recent project term we have further refined our key assay, and generated sufficient cells to enable screening of 50,000 different chemical candidates that might reveal potential drugs for this terrible disease. With a little bit of additional refinement, we will be able to begin our search in earnest in collaboration with the Sanford-Burnham Prebys Screening Center.

Developing a method for rapid identification of high-quality disease specific hIPSC lines

Funding Type: 
Tools and Technologies II
Grant Number: 
RT2-01927
ICOC Funds Committed: 
$1 816 157
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Elucidating how genetic variation contributes to disease susceptibility and drug response requires human Induced Pluripotent Stem Cell (hIPSC) lines from many human patients. Yet, current methods of hIPSC generation are labor-intensive and expensive. Thus, a cost-effective, non-labor intensive set of methods for hIPSC generation and characterization is essential to bring the translational potential of hIPSC to disease modeling, drug discovery, genomic analysis, etc. Our project combines technology development and scaling methods to increase throughput and reduce cost of hiPSC generation at least 10-fold, enabling the demonstration, and criterion for success, that we can generate 300 useful hiPSC lines (6 independent lines each for 50 individuals) by the end of this project. Thus, we propose to develop an efficient, cost effective, and minimally labor-intensive pipeline of methods for hIPSC identification and characterization that will enable routine generation of tens to hundreds of independent hIPSC lines from human patients. We will achieve this goal by adapting two simple and high throughput methods to enable analysis of many candidate hIPSC lines in large pools. These methods are already working in our labs and are called "fluorescence cell barcoding" (FCB) and expression cell barcoding (ECB). To reach a goal of generating 6 high quality hIPSC lines from one patient, as many as 60 candidate hIPSC colonies must be expanded and evaluated individually using labor and cost intensive methods. By improving culturing protocols, and implementing suitable pooled analysis strategies, we propose to increase throughput at least 10-fold with a substantial drop in cost. In outline, the pipeline we propose to develop will begin with the generation of 60 candidate hIPSC lines per patient directly in 96 well plates. All 60 will be analyzed for diagnostic hIPSC markers by FCB in 1 pooled sample. The 10 best candidates per patient will then be picked for expression and multilineage differentiation analyses with the goal of finding the best 6 from each patient for digital karyotype analyses. Success at 10-fold scaleup as proposed here may be the first step towards further scaleup once these methods are fully developed. Aim 1: To develop a cost-effective and minimally labor-intensive set of methods/pipeline for the generation and characterization high quality hIPSC lines from large numbers of human patients. We will test suitability/develop a set of methods that allow inexpensive and rapid characterization of 60 candidate hIPSC lines per patient at a time. Aim 2: To demonstrate/test/evaluate the success and cost-effectiveness of our pipeline by generating 6 high quality hIPSC lines from each of 50 human patients from [REDACTED]. We will obtain skin biopsies and expand fibroblasts from 50 patients, and generate and analyze a total of 6 independent hIPSC lines from each using the methods developed in Aim 1.
Statement of Benefit to California: 
Many Californians suffer from diseases whose origin is poorly understood, and which are not treatable in an effective or economically advantageous manner. Part of solving this problem relies upon elucidating how genetic variation contributes to disease susceptibility and drug response and better understanding disease mechanism. Achieving these goals can be accelerated through the use of human Induced Pluripotent Stem Cell (hIPSC) lines from many human patients. Yet, current methods of hIPSC generation are labor-intensive and expensive. Thus, a cost-effective, non-labor intensive set of methods for hIPSC generation and characterization is essential to bring the translational potential of hIPSC to disease modeling, drug discovery, genomic analysis, etc. If successful, our project will lead to breakthroughs in understanding of disease, development of better therapies, and economic development in California as businesses that use our methods are launched. In addition, new therapies will bring cost-savings in healthcare to Californians, stimulate employment since Californians will be employed in businesses that develop and sell these therapies, and relieve much suffering from the burdens of chronic disease.
Progress Report: 
  • An important problem in stem cell and regenerative medicine research has been the ability to quickly and cheaply generate and characterize reprogrammed stem cells from defined human patients. The primary goal of our project is to address this need by developing new technologies that allow stem cell lines to be characterized in large mixed pools as opposed to one by one. Our new methods use flow cytometry and highly sensitive methods for detecting the activity of genes in the cell lines. We made excellent progress in the first year and reduced flow cytometry methods to practice taking advantage of a method called fluorescence cell barcoding. Methods for analyzing activity of genes and chromosome number are in progress and being tested. Our ultimate goal is to reduce cost tenfold and increase speed by about tenfold and our methods development is on track to accomplish this aim.
  • A key bottleneck in reprogramming technology to make induced pluripotent stem (IPS) cell lines is the ability to make large numbers of lines from large numbers of patients in a way that is cost effective and minimizes labor. Our project has focused primarily on dropping the cost of characterization of candidate lines. We have made a number of discoveries about the behavior of candidate reprogrammed lines that allow us to drop cost and labor needed for candidate reprogrammed line characterization. We measured the frequency of candidate lines that were well-behaved in a large retroviral reprogramming experiment, which allows us to rigorously estimate how many candidate lines must be picked and analyzed if 4-6 high-quality lines are to be generated for every patient fibroblast sample subjected to typical retroviral reprogramming technology. We then continued our work on developing a combination of different array and microfluidic chip technologies to measure the chromosome number in each candidate line and the ability of each line to be pluripotent, i.e., to be able to generate many different type of cells similar to embryonic stem cells. We are optimistic that our work will simplify and drop the cost of the characterization process so that it costs far less than before our work was initiated.
  • Reprogrammed stem cell lines, i.e., induced pluripotent stem cell lines, have the potential to revolutionize research into causes of disease and genetic contributions to the causes of disease. One key limitation, however, is the ability to generate large numbers of different stem cell lines from different people to sample the range of genetic variation in the human population as it relates to disease development. A key bottleneck is the speed and cost with which reprogrammed stem cell lines can be generated and validated for usefulness. We have succeeded in developing a streamlined workflow for characterization of reprogrammed stem cell lines that drops the cost for characterization from several thousand dollars to a few hundred dollars and increases the speed and number of lines that can be handled substantially. We take advantage of novel genetic characterization methods to analyze genetic stability and the pattern of gene expression as it reveals the capabilities of the stem cell lines. We are finishing up the loose ends on this project now and should have a high quality publication prepared for submission shortly that describes this simple and inexpensive workflow that we have developed with modern gene characterization methods.

Elucidating pathways from hereditary Alzheimer mutations to pathological tau phenotypes

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07011
ICOC Funds Committed: 
$1 161 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Closed
Public Abstract: 
We propose to elucidate pathways of genes that lead from early causes to later defects in Alzheimer’s Disease (AD), which is common, fatal, and for which no effective disease-modifying drugs are available. Because no effective AD treatment is available or imminent, we propose to discover novel genetic pathways by screening purified human brain cells made from human reprogrammed stem cells (human IPS cells or hIPSC) from patients that have rare and aggressive hereditary forms of AD. We have already discovered that such human brain cells exhibit an unique biochemical behavior that indicates early development of AD in a dish. Thus, we hope to find new drug targets by using the new tools of human stem cells that were previously unavailable. We think that human brain cells in a dish will succeed where animal models and other types of cells have thus far failed.
Statement of Benefit to California: 
Alzheimer’s Disease (AD) is a fatal neurodegenerative disease that afflicts millions of Californians. The emotional and financial impact on families and on the state healthcare budget is enormous. This project seeks to find new drug targets to treat this terrible disease. If we are successful our work in the long-term may help diminish the social and familial cost of AD, and lead to establishment of new businesses in California using our approaches.

Collection of skin biopsies to prepare fibroblasts from patients with Alzheimer's disease and cognitively healthy elderly controls

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06589
ICOC Funds Committed: 
$643 693
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
oldStatus: 
Active
Public Abstract: 
Alzheimer's Disease (AD), the most common form of dementia in the elderly, affects over 5 million Americans. There are no treatments to slow progression or prevent AD. This reflects limitations in knowledge of mechanisms underlying AD, and in tools and models for early development and testing of treatment. Genetic breakthroughs related to early onset AD led to initial treatment targets related to a protein called amyloid, but clinical trials have been negative. Extensive research links genetic risk to AD, even when the age at onset is after the age of 65. AD affects the brain alone, therefore studying authentic nerve cells in the laboratory should provide the clearest insights into mechanisms and targets for treatment. This has recently become feasible due to advances in programming skin cells into stem cells and then growing (differentiating) them into nerve cells. In this project we will obtain skin biopsies from a total of 220 people with AD and 120 controls, who are extensively studied at the [REDACTED] AD Research Center. These studies include detailed genetic (DNA) analysis, which will allow genetic risks to be mapped onto reprogrammed cells. These derived cells that preserve the genetic background of the person who donated the skin biopsy will be made available to the research community, and have the promise to accelerate studies of mechanisms of disease, understanding genetic risk, new treatment targets, and screening of new treatments for this devastating brain disorder.
Statement of Benefit to California: 
The proposed project will provide a unique and valuable research resource, which will be stored and managed in California. This resource will consist of skin cells or similar biological samples, suitable for reprogramming, obtained from well-characterized patients with Alzheimer's Disease and cognitively healthy elderly controls. Its immediate impact will be to benefit CIRM-funded researchers as well as the greater research community, by providing them access to critical tools to study, namely nerve cells that can be grown in a dish (cultured) that retain the genetic background of the skin cell donors. This technology to develop and reprogram cells into nerve cells or other cell types results from breakthroughs in stem cell research, many of which were developed using CIRM funding. Alzheimer's Disease affects over 600,000 Californians, and lacks effective treatment. Research into mechanisms of disease, identifying treatment targets, and screening novel drugs will be greatly improved and accelerated through the availability of the resources developed by this project, which could have a major impact on the heath of Californians. California is home to world class academic and private research institutes, Biotechnology and Pharmaceutical Companies, many of whom are already engaged in AD research. This project could provide them with tools to make research breakthroughs and pioneer the development of novel treatments for AD.

Stem cell based small molecule therapy for Alzheimer's disease

Funding Type: 
Early Translational III
Grant Number: 
TR3-05669
ICOC Funds Committed: 
$1 673 757
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Over 6 million people in the US suffer from AD. There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate their replacement. Even if nerve cells could be replaced, the toxic environment of the brain will kill them unless they are 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 embryonic stem cells (hESCs) as a screen for neurogenic compounds, it should now be possible to identify and tailor drugs for therapeutic use in AD. Our laboratory has developed a drug discovery scheme based upon using hESCs to screen drug candidates. We have recently identified a very potent drug that is exceptionally effective in rodent models of AD. However, this molecule needs to be optimized for human use. In this proposal, we will harness the power of hESCs to develop derivatives of J147 specifically tailored to stimulate neurogenesis and be neuroprotective in human cells. 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. This work could lead to a paradigm shift in the treatment of neurodegenerative disease.
Statement of Benefit to California: 
Over 6 million people in the US suffer from Alzheimer’s disease (AD). Unless a viable therapeutic is identified it is estimated that this number will increase to 16 million by 2050, with a cost of well over $1 trillion per year, overwhelming California and national health care systems. Among the top 10 causes of death, AD (6th) is the only one with no treatment available to prevent, cure or slow down the condition. An enormous additional burden to families is the emotional and physical stress of having to deal with a family member with a disease which is going to become much more frequent with our aging population. In this application we use new human stem cell technologies to develop an AD drug candidate based upon a strong lead compound that we have already made 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 stem 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.
Progress Report: 
  • Introduction: Over 6 million people in the US suffer from AD. There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate their replacement. Even if nerve cells could be replaced, the toxic environment of the brain will kill them unless they are 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 embryonic stem cells (hESCs) as a screen for neurogenic compounds, it should now be possible to identify and tailor drugs for therapeutic use in AD. This is the overall goal of this application.
  • Year One Progress: Using a novel drug discovery paradigm, we have made a very potent drug called J147 that is exceptionally effective in rodent models of AD and also stimulates neurogenesis in both young and very old mice. Very few, if any, drugs or drug candidates are both neuroprotective and neurogenic, particularly in old animals. In the first year of this application we harnessed the power of hESCs and medicinal chemistry to develop derivatives of J147 specifically tailored to stimulate neurogenesis and be neuroprotective in human cells. Using iterative chemistry, we synthesized over 200 new compounds, tested them for neurogenic properties in ES-derived neural precursor cells, assayed their ability to protect from the amyloid toxicity associated with AD, and determined their metabolic stability. All of the year one milestones we met and we now have the required minimum of six compounds to move into year two studies. In addition, we have made a good start on the work for year two in that some pharmacokinetics and safety studies has been completed.
  • 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. This work could lead to a paradigm shift in the treatment of neurodegenerative disease.

A CIRM Disease Team to Develop Allopregnanolone for Prevention and Treatment of Alzheimer's Disease

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
DR2-05410
ICOC Funds Committed: 
$107 989
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
oldStatus: 
Closed
Public Abstract: 
Alzheimer’s disease (AD) is now a nation-wide epidemic and California is at the epicenter of the epidemic. One-tenth of all people in the United States diagnosed with AD live in California. In the US, 5.4 million people have AD and another American develops AD every 69 seconds. No therapeutic strategies exist to prevent or treat AD. And the situation is worse than expected. Results of a recent two year clinical study show that the currently available medications for managing AD symptoms are ineffective in patients with mild cognitive impairment or mild AD. We seek to develop a small molecule therapeutic, allopregnanolone (APα) to prevent and treat AD. APα promotes the ability of brain to regenerate itself by increasing the number and survival of newly generated neurons. The APα-induced increase in newly generated neurons was associated with a reversal of cognitive deficits and restored learning and memory function to normal in a preclinical mouse model of AD. Further, APα reduced the amount of AD pathology in the brain. Importantly, when given peripherally either by injection under the skin or applied topically to the skin, APα was able to enter the brain to increase the generation of new neurons. The unique mechanism of APα action reduces the risk that APα would cause proliferation of other cells in the body. Because APα was efficacious in both pre-pathology and post-pathology stages of AD progression, APα has the potential to be effective for both the prevention of and early stage treatment of Alzheimer’s disease. Further, APα induced neurogenesis and restoration of cognitive function in normal aged mice suggesting that APα could be efficacious to sustain cognitive function and prevent development of AD in a normal aged population. In other clinical studies, APα has been proven safe in animals and humans and in both men and women. Together, these findings provide a strong foundation on which to plan a clinical trial of APα in persons with prodromal and diagnosed Alzheimer’s disease. To plan for a Phase I-IIa clinical trial to determine safety, dosing and clinical efficacy, we have assembled an interdisciplinary team of clinicians, scientists, therapeutic development, regulatory, data management and statistical analysis experts. The objectives of this proposal are to: a) develop allopregnanolone as a therapeutic for Alzheimer’s disease; to plan an early clinical development program for its use as a neurogenesis agent; b) file a complete and well-supported IND with the Food and Drug Administration (FDA); c) complete phase I/IIa clinical studies to evaluate safety, biological activity, and early efficacy in humans; and (d) complete a phase II clinical trial that will evaluate efficacy and lead to larger multisite clinical studies of efficacy.
Statement of Benefit to California: 
California is at the epicenter of the epidemic of Alzheimer’s disease (AD). Nationwide there are 5.4 million persons living with AD. Ten percent or over half a million Californians have AD. Among California’s baby boomers aged 55 and over, one in eight will develop AD. It is estimated that one in six Californians will develop a form of dementia. By 2030 the number of Californians living with AD will double to over 1.1 million. While all races and ethnic groups and regions of the state will be affected, not all regions within California will be equally affected. Los Angeles County has the greatest population in the state and thus will be the true epicenter of the Alzheimer’s epidemic in California. Alzheimer’s is a disease that affects an entire family, community and health care system. Nation-wide there are nearly 15 million Alzheimer and dementia care givers providing 17 billion hours of unpaid care per year. Total costs for caring for people with AD, totals $183 billion per year. California shouldered $18.3 billion of those costs and most of those costs were born by persons and health care services in Los Angeles County. Because of the psychological and physical toll of caring for people with Alzheimer’s, caregivers had $7.9 billion in additional health care costs. Proportionally that translates into $790 million of health care costs for Californians. In total, California spent over $19 billion per year for costs associated with Alzheimer’s disease. Multiple analyses indicate that a delay of just 5 years can reduce the number of persons diagnosed with Alzheimer’s by 50% and dramatically reduce the associated costs. We seek to develop a small molecule therapeutic, allopregnanolone (APα) to prevent and treat AD. APα promotes the innate regenerative capacity of the brain to increase the pool of neural progenitor cells. The APα-induced increase in neurogenesis was associated with a reversal of cognitive deficits and restored learning and memory function to normal in a preclinical mouse model of AD. Further, APα reduced the development of AD pathology. APα crosses the blood brain barrier and acts through a mechanism unique to neural progenitor cells and thus is unlikely to exert proliferative effects in other organs. Because APα was efficacious in both pre-pathology and post-pathology stages of AD progression, APα has the potential to be effective for both the prevention of and early stage treatment .
Progress Report: 
  • As a result of the planning grant award, the Allopregnanolone (APα) team accomplished the following that enabled submission of the CIRM Disease Team Therapy Development Research Awards Proposal:
  • 1) Created a team of experts in regeneration, neurology and Alzheimer's disease drug development to generate strategy and overall development plan. Through the team’s efforts we developed preclinical and clinical studies, determined correct dosing parameters for clinical studies, identified an optimal route of administration, developed chemistry, manufacturing and controls, and submitted our Pre-IND documents to the FDA.
  • 2) Filed a Pre-IND document with the FDA and held a Pre-IND meeting with the FDA and obtained feedback from the FDA on our program. FDA provided guidance on requirements for the preclinical plan along with input on the design of our two Phase 2 clinical studies. We also obtained agreement that we may cross-reference the existing IND of our academic partner, Michael Rogawski at UC Davis and utilize product manufactured at UC Davis.
  • 3) We developed an integrated CMC plan to manufacture allopregnanolone (clinical API) and established compliant processes to ensure material requirements are met for the preclinical and clinical studies. Manufacture of clinical API will be conducted at the UC Davis CIRM GMP facility.
  • 4) FDA required preclinical IND-enabling research strategy was developed. Teams at USC and a California-based CRO, were identified to conduct three studies: 1) Bridging Study: subcutaneous to IV dosing and administration to bridge from previous subcutaneous preclinical analyses to clinical studies using IV APα administration to determine a) optimal IV dose to promote neurogenesis and b) optimal infusion rate to achieve required peak of APα and area under the curve. 2) Cerebral Microhemorrhage: The FDA advised a safety test for the occurrence of cerebral microhemorrhages localized to the cerebral vasculature in areas of cerebral amyloid angiopathy with various anti-Aβ immunotherapies. 3) Chronic GLP Toxicity Analyses: Based on FDA guidance, safety studies will be required for chronic exposure of Alzheimer’s patients to APα. To initiate the chronic exposure Phase 2a Proof of Concept trial, chronic preclinical toxicology is required. We have designed 6-month and 9-month IV dose GLP toxicity studies in rat and dog, respectively. The studies include systemic toxicology and toxicokinetic evaluation.
  • 5) In support of developing ideal dosing parameters for the Phase 2 clinical studies, the California CRO, Simulations Plus was utilized. ADMET Predictor™ was used to estimate the biopharmaceutical properties of APα. Predictive modeling of optimal dosing regimen and expected human exposure in Alzheimer’s patients was performed.
  • 6) Designed two Phase 2 clinical trials, a Multiple Ascending Dose (MAD) and a Proof of Concept. A California-based CRO, Worldwide Clinical Trials and Alzheimer's clinical trials expert were identified to partner with USC to design and conduct our clinical trials. Phase 2 MAD study primary objectives are to evaluate safety, tolerability and pharmacokinetics. MAD exploratory objectives are to evaluate effect of allopregnanolone on MRI biomarker outcomes and cognition. Proposed MRI biomarkers include hippocampal volume, white matter integrity, and functional connectivity. Phase 2 Proof of Concept trial primary objectives are to evaluate safety and tolerability with long-term exposure. Therapeutic efficacy of allopregnanolone will be determined by outcomes on cognition and biomarkers of regeneration in brain.
  • 7) A Steering Committee and Advisory Board were established. Both advisory groups are composed of internationally recognized researchers, translational scientists, regulatory experts and therapeutic development experts. The charge of the Steering Committee is to provide oversight that CIRM allopregnanolone team progress is on track to meet milestones, ensure that processes and strategies are aligned. The Advisory Board is comprised of internationally recognized experts in Alzheimer’s disease and experts in stem cell biology. Advisory Board members will provide an objective evaluation of CIRM allopregnanolone project progress. The functions of Advisory Board are: 1) Advise CIRM allopregnanolone project leadership on identifying key milestones; 2) Review progress on meeting milestones and hitting development targets; 3) Provide strategic and tactical counsel to the Leadership team and Steering Committee.
  • 8) Generated viable commercial potential through partnership with SAGE Therapeutics. Ensured patent progression and prosecution through USC. Engaged key opinion leaders in the field and educated these experts regarding therapeutic potential of allopregnanolone as a first in class drug for neuroregeneration in Alzheimer's disease.

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