Alzheimer's Disease

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

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

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.
  • Introduction: Over 6 million people in the US suffer from Alzheimer’s disease (AD). There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate 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 to identify neurogenic compounds, we have shown that it is now be possible to identify and tailor drugs for therapeutic use in AD. This was the overall goal of this application, and to date we have made outstanding progress, making a drug that is both neurogenic for human cells and has therapeutic efficacy in a rigorous mouse model of AD.
  • Year 2 Progress: Using a novel drug discovery paradigm based upon human stem cell derived nerve precursor cells, we have made a very potent drug called CAD-31. CAD-31 potently stimulates neurogenesis in human cells in culture and in mice, and prevents nerve cell death in cell culture models of toxicities associated with old age and AD. Very few, if any, drugs or drug candidates are both neuroprotective and neurogenic, particularly in animals. In the first year of this project, we harnessed the power of hESCs and medicinal chemistry to develop CAD-31. All of the Year 1 milestones were met. In Year 2 we completed all of the required pharmacokinetics and safety studies on the six best compounds synthesized in Year 1. Of those six, one compound, CAD-31, was the best in terms of medicinal chemical, pharmacokinetic, neuroprotective and neurogenic properties. This compound underwent extensive testing for safety and passed with flying colors. It was then put into an AD mouse model where it stimulated neurogenesis, prevented behavioral deficits and some of the disease pathology. All Year 2 milestones were completed. In Year 3 of the project we will determine if CAD-31 is able to reverse AD symptoms in old AD mice that already have the disease. This is the most clinically relevant model of AD since therapies can only be initiated once the disease is identified.
  • This work has produced a novel AD drug candidate that is developed based upon a set of assays never before used by pharmaceutical companies. It 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 drug discovery for the treatment of neurodegenerative disease.

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.
  • During the past year we completed screening of our Alzheimers “disease in a dish” cultured stem cell lines for response of a critical measure of Alzheimers disease in a dish to FDA approved drugs and other potentially promising drug like compounds. We found several reproducible and interesting categories of potential drugs some of which are already in common use in human patients and therefore might be readily available to the Alzheimer's disease population. We are conducting more careful analyses of these drugs for their mechanism and behavior in human neurons with different types of Alzheimer like behavior and we are beginning to test whether all human variants behave the same way as preparation for potential clinical trials. We are also initiating analysis of new chemical entities for possible modification to improve potency.

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.

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.

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.

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.

Using Human Embryonic Stem Cells to Understand and to Develop New Therapies for Alzheimer's Disease

Funding Type: 
Comprehensive Grant
Grant Number: 
RC1-00116
ICOC Funds Committed: 
$2 512 664
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Genetic Disorder
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Cell Line Generation: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Closed
Public Abstract: 
Alzheimer’s Disease (AD) is a progressive incurable disease that robs people of their memory and ability to think and reason. It is emotionally, and sometimes financially devastating to families that must cope when a parent or spouse develops AD. Unfortunately, however, we currently lack an understanding of Alzheimer’s Disease (AD) that is sufficient to drive the development of a broad range of therapeutic strategies. Compared to diseases such as cancer or heart disease, which are treated with a variety of therapies, AD lacks even one major effective therapeutic approach. A key problem is that there is a paucity of predictive therapeutic hypotheses driving the development of new therapies. Thus, there is tremendous need to better understand the cellular basis of AD so that effective drug and other therapies can be developed. Several key clues come from rare familial forms of AD (FAD), which identify genes that can cause disease when mutant and which have led to the leading hypotheses for AD development. Recent work on Drosophila and mouse models of Alzheimer’s Disease (AD) has led to a new suggestion that early defects in the physical transport system that is responsible for long-distance movements of vital supplies and information in neurons causes neuronal dysfunction. The type of neuronal failure caused by failures of the transport systems is predicted to initiate an autocatalytic spiral of biochemical events terminating in the classic pathologies, i.e., plaques and tangles, and the cognitive losses characteristic of AD. The problem, however, is how to test this new model and the prevailing “amyloid cascade” model, or indeed any model of human disease developed from studies in animal models, in humans. It is well known that mouse models of AD do not fully recapitulate the human disease, perhaps in part because of human-specific differences that alter the details of the biochemistry and cell biology of human neurons. One powerful approach to this problem is to use human embryonic stem cells to generate human neuronal models of hereditary AD to test rigorously the various hypotheses. These cellular models will also become crucial reagents for finding and testing new drugs for the treatment of AD. 
 
Statement of Benefit to California: 
Alzheimer’s Disease (AD) is emotionally devastating to the families it afflicts as well as causing substantial financial burdens to individuals, to families, and to society as a whole. In California, the burden of Alzheimer’s Disease is substantial, so that progress in the development of therapeutics would make a significant financial impact in the state. Although there are not a great deal of data about the burden of AD in California specifically, the population of California is 12% of that of the United States and most information suggests that California has a “typical” American burden of this disease. For example, information from the Alzheimer’s Association (http://www.alz.org/alzheimers_disease_alzheimer_statistics.asp) reveals: 1) An estimated 4.5 million Americans have Alzheimer’s disease, which has more than doubled since 1980. This creates an estimated nationwide financial burden of direct and indirect annual costs of caring for individuals with AD of at least $100 billion. Thus, a reasonable estimate is that California has more than half a million AD patients with an estimated cost to California of $12 billion per year! 2) One in 10 individuals over 65 and nearly half of those over 85 are affected, which means that as our population ages, we will be facing a tidal wave of AD. Current estimates are that with current rates of growth that the AD patient population will double or triple in the next 4 decades. 3) The potential benefit of research such as that proposed in this grant application is that finding a treatment that could delay onset by five years could reduce the number of individuals with Alzheimer’s disease by nearly 50 percent after 50 years. This would be significant since a person with Alzheimer’s disease will live an average of eight years and as many as 20 years or more from the onset of symptoms. Finding better treatments will thus have significant financial benefits to California. 4) After diagnosis, people with Alzheimer’s disease survive about half as long as those of similar age without AD or other dementia. 5) In terms of financial impact on California families, the statistics (http://www.alz.org/alzheimers_disease_alzheimer_statistics.asp) are that more than 7 out of 10 people with Alzheimer’s disease live at home. Almost 75 percent of their care is provided by family and friends. The remainder is “paid’ care costing an average of $19,000 per year. Families pay almost all of that out of pocket. The average cost for nursing home care is $42,000 per year but can exceed $70,000 per year in some areas of the country. The average lifetime cost of care for an individual with Alzheimer’s is $174,000. Thus, any progress in developing better therapy for AD will have a substantial positive impact to California. 
 
Progress Report: 
  • We have made significant progress on developing human stem cell based systems to probe the causes and features of Alzheimer's Disease. We are focusing on using human embryonic and human pluripotent stem cell lines carrying genetic changes that cause hereditary Alzheimer's Disease (AD). In one approach, we have made progress by developing iPS cells carrying small genetic changes in the presenilin 1 gene, which cause severe early onset AD. We also made substantial progress on developing methods to measure the distribution within neurons of products linked to Alzheimer's Disease. Finally, we have completed development of a cell sorting method to purify neuronal stem cells, neurons, and glia from human embryonic stem cells and human IPS cells. Together, these methods should allow us to continue making progress on using pluripotent human stem cells to probe the molecular basis for how cellular changes found in neurons in the brain of AD patients are generated. In addition, these methods we are developing are moving us closer to having sources of normal and AD human neurons generated in the laboratory for drug-testing and development.
  • We continue to make significant progress developing human stem cell based disease models to probe the causes of Alzheimer's Disease (AD) and to eventually develop drugs. In the past year we generated and analyzed several new human pluripotent stem cell lines (hIPS) carrying genetic changes that cause hereditary AD or that increase the risk of developing AD. We detected AD related characteristics in neurons with hereditary and in one case of a sporadic genetic type. While considerable confirmatory work needs to be done, our data raise the possibility that AD can be modeled in human neurons made from hIPS cells. In the coming year, we hope to continue making progress on using pluripotent human stem cells to probe the molecular basis for how cellular changes found in neurons in the brain of AD patients are generated. In addition, the methods we are developing are moving us closer to having sources of normal and AD human neurons generated in the laboratory for drug-testing and development.
  • In our final year of funding, we made significant progress developing human stem cell based disease models to probe the causes of Alzheimer's Disease (AD) and to eventually develop drugs. We generated and analyzed several new human pluripotent stem cell lines (hIPS) carrying genetic changes that cause hereditary AD or that increase the risk of developing AD. We detected AD related characteristics in neurons with hereditary and in one case of a sporadic genetic type. While considerable confirmatory work needs to be done, our data raise the possibility that AD can be modeled in human neurons made from hIPS cells. The methods we developed are moving us closer to having sources of normal and AD human neurons generated in the laboratory for drug-testing and development.

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.

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.
Progress Report: 
  • 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 have proposed 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 previous 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.
  • In the first year of the loan, the Disease Team actively worked on 5 important milestones in our effort to develop the use of human neural stem cells for AD. Of those, 2 milestones have been completed and 3 are ongoing. Specifically, the team has initiated three animal studies believed necessary to seek authorization by the FDA to start testing this therapeutic approach in human patients; these studies were designed to confirm that transplantation of the neural stem cells leads to improved memory in animal models relevant for AD. We are currently collecting and analyzing the data generated in these mouse studies. We have also identified the neural stem cell line that will be used in patients and have made considerable progress in its manufacturing and banking. Finally, we have held a pre-IND meeting with the FDA in which we shared our plans for the preclinical and clinical studies; the meeting provided helpful guidance and assurances regarding our IND enabling activities.
  • This project is 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. Together with expert clinicians and scientists throughout California, we continue to work towards a successful IND submission to permit human testing of a novel and unique approach for the treatment of AD.

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