Alzheimer's Disease

Coding Dimension ID: 
304
Coding Dimension path name: 
Neurological Disorders / Alzheimer's Disease
Funding Type: 
Tools and Technologies III
Grant Number: 
RT3-07893
Investigator: 
Institution: 
Type: 
Partner-PI
ICOC Funds Committed: 
$1 147 596
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Collaborative Funder: 
Australia
Stem Cell Use: 
Embryonic Stem Cell
Public Abstract: 

Microglia are a type of immune cell within the brain that profoundly influence the development and progression of many neurological disorders. Microglia also inherently migrate toward areas of brain injury, making them excellent candidates for use in cell transplantation therapies. Despite the widely accepted importance of microglia in neurological disease, methods to produce microglia from stem cells have yet to be reported. Our team has recently developed one of the first protocols to generate microglia from human pluripotent stem cells. We have used several approaches to confirm that the resulting cells are microglia including examination of gene expression and testing of key microglial functions. However, our current protocol uses cell culture supplements that preclude the use of these cells for any future clinical applications in people. The major goal of this proposal is to resolve this problem. We will generate pluripotent human stem cells that have special "reporter" genes that make the cells glow as they become microglia, allowing us to readily monitor and quantify the generation of these important cells. Using these reporter lines we can then streamline the differentiation process and develop improved protocols that could be translated toward eventual clinical use. As a proof-of-principle experiment we will then use the resulting human microglia to study some important questions about the genetic causes and potential treatment of Alzheimer’s disease.

Statement of Benefit to California: 

Recent estimates suggest that nearly 2 million Californian adults are currently living with a neurological disorder. While the causes of neurological disease vary widely from Alzheimer’s disease to Stroke to Traumatic Brain Injury, a type of brain cell called microglia has been strongly implicated in all of these disorders. Microglia are often considered the immune cell of the brain, but they play many additional roles in the development and function of the nervous system. In neurological disease, Microglia appear to be involved in a response to injury but they can also secrete factors that exacerbate neurological impairment. Unfortunately, it has been difficult to study human microglia and their role in these diseases because of challenges in producing these cells. Our group recently developed an approach to ‘differentiate’ microglia from human pluripotent stem cells. This enables researchers to now study the role of different genes in human microglial function and disease. Yet our current approach dose not allow these cells to be used for potential clinical testing in patients. Our proposal therefore aims to develop new tools and technology that will allow us to produce clinically-relevant human microglia. These cells will then be used to study the role of a specific microglial gene in Alzheimer’s disease, and may ultimately be useful for developing treatments for the many Californians suffering from neurological disease.

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

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

Statement of Benefit to California: 

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

Progress Report: 
  • We have developed new proteins that will stimulate immune responses to a major factor in Alzheimer's disease. Previous studies from our lab and others indicate that those responses can be improve memory deficits and brain pathology that occurs in Alzheimer's patients, and in Alzheimer's mice. To stimulate these immune responses the new proteins must be expressed by specific immune cells called, dendritic cells. Viruses have been made that carry the codes for these new proteins and we have confirmed that those viruses can deliver them into dendritic cells. To optimize these procedures we have made dendritic cells from human embryonic stem cells, and we developed methods to accomplish that step in our laboratory. At the end of year 2 we are nearing the completion of our preclinical studies and are poised to begin introducing the new proteins into immune cells that are derived from human blood, within the next year. The over-arching goal of this project is to develop method to trigger Alzheimer's-specific immune responses in a safe and reliable manner that could provide beneficial effects with minimal side-effects. This CIRM-funded project is on track to be completed within the 5 year time-frame.
Funding Type: 
Comprehensive Grant
Grant Number: 
RC1-00116
Investigator: 
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.
Funding Type: 
Preclinical Development Awards
Grant Number: 
PC1-08086
Investigator: 
ICOC Funds Committed: 
$1 737 271
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
Cell Line Generation: 
Embryonic Stem Cell
iPS Cell
Public Abstract: 

Over 6 million people in the US suffer from Alzheimer’s disease (AD). There are no drugs that prevent the death of nerve cells in AD, nor has any drug been identified that can stimulate nerve cell replacement in aged human brain. Importantly, even if nerve cells could be replaced, the toxic environment of the AD brain which caused the disease in the first place will likely kill any cells that are born into that environment unless they are resistant to those conditions or can be protected by a drug. Therefore, drugs that stimulate the generation of new neurons (neurogenesis) alone will not be effective. A drug with both neurogenic and neuroprotective properties is required. With the ability to use cells derived from human neural precursor cells (hNPCs) derived from human embryonic stem cells (hESCs) as a screen for neurogenic compounds, we have shown that it is possible to identify and tailor drugs for therapeutic use in AD. With the support of CIRM, we have recently made a very potent AD drug candidate that is exceptionally effective in promoting the making of new nerve cells from human embryonic stem cells. It is both neurogenic and has therapeutic efficacy in a rodent model of AD. However, this molecule needs more preclinical development work before it can start the formal FDA pre clinical toxicity screening protocols. This work will optimize the chances for its true therapeutic potential in AD, and presents a unique opportunity to expand the use of hESCs for the development of a therapeutic for a disease for which there is no cure.

Statement of Benefit to California: 

Over 6 million people in the US suffer from AD, and unless a viable therapeutic is identified it is estimated that this number will increase to at least 16 million by 2050, with a cost of well over $1 trillion per year, likely overwhelming both the California and national health care systems. There is no treatment to prevent, cure or slow down this condition. In this application we have used the new human stem cell technologies to develop an AD drug candidate that stimulates the multiplication of nerve precursor cells derived from human embryonic stem cells. This approach presents a unique opportunity to expand the use of human embryonic stems cells for the development of a therapeutic for a disease for which there is no cure, and could lead to a paradigm shift in the treatment of neurodegenerative disease. Since our AD drug discovery approach is fundamentally different from the unsuccessful approaches used by the pharmaceutical industry. It could also stimulate new biotech. The work in this proposal addresses one of the most important medical problems of California as well as the rest of the world, and if successful would benefit all.

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07011
Investigator: 
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.

Progress Report: 
  • The goal of this project has been to understand how neurons made from stem cells that are genetically engineered to develop Alzheimer's disease in a dish generate abnormal biochemistry that we can measure with simple assays. In the first year of this project we developed new probes for the pathway we are trying to measure. However, we encountered technical obstacles that interfere with our ability to evaluate the function of this pathway. We think we have identified the cause of the problems and in the second year of the project we will initiate experiments to solve these problems and rigorously evaluate how genetic mutations that cause abnormal Alzheimer's biochemistry generate the abnormal biochemistry in our human neural system made from stem cells.
Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
Investigator: 
ICOC Funds Committed: 
$9 999 834
Disease Focus: 
Developmental Disorders
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Liver Disease
Epilepsy
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 

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

Statement of Benefit to California: 

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

Progress Report: 
  • The California Institute for Regenerative Medicine (CIRM) Human Pluripotent Stem Cell Biorepository is operated by the Coriell Institute for Medical Research and is a critical component of the CIRM Human Stem Cell Initiative. The overall goal of this initiative is to generate, for world-wide use by non-profit and for-profit entities, high quality, disease-specific induced pluripotent stem cells (iPSCs). These cells are derived from existing tissues such as blood or skin, and are genetically manipulated in the laboratory to change into cells that resemble embryonic stem cells. iPSCs can be grown indefinitely in the Petri dish and have the remarkable capability to be converted into most of the major cell types in the body including neurons, heart cells, and liver cells. This ability makes iPSCs an exceptional resource for disease modeling as well as for drug screening. The expectation is that these cells will be a major benefit to the process for understanding prevalent, genetically complex diseases and in developing innovative therapeutics.
  • The Coriell CIRM iPSC Biorepository, located at the Buck Institute for Research on Aging in Novato, CA, is funded through a competitive grant award to Coriell from CIRM and is managed by Mr. Matt Self under the supervision of the Program Director, Dr. Steven Madore, Director of Molecular Biology at Coriell. The Biorepository will receive biospecimens consisting of peripheral blood mononuclear cells (PBMCs) and skin biopsies obtained from donors recruited by seven Tissue Collector grant awardees. These biospecimens will serve as the starting material for iPSC derivation by Cellular Dynamics, Inc (CDI). Under a contractual agreement with Coriell, CDI will expand each iPSC line to generate sufficient aliquots of high quality cryopreserved cells for distribution via the Coriell on-line catalogue. Aliquots of frozen cell lines and iPSCs will be stored in liquid nitrogen vapor in storage units at the Buck Institute with back-up aliquots stored in a safe off-site location.
  • Renovation and construction of the Biorepository began at the Buck Institute in late January. The Biorepository Manger was hired March 1 and after installation of cryogenic storage vessels and alarm validation, the first biospecimens were received on April 30, 2014. Additionally, Coriell has developed a Clinical Information Management System (CIMS) for storing all clinical and demographic data associated with enrolled subjects. Tissue Collectors utilize CIMS via a web interface to upload and edit the subject demographic and clinical information that will ultimately be made available, along with the iPSCs, via Coriell’s on-line catalogue
  • As of November 1 specimens representing a total of 725 unique individuals have been received at the Biorepository. These samples include PBMCs obtained from 550 unique individuals, skin biopsies from 72 unique individuals, and 103 primary dermal fibroblast cultures previously prepared in the laboratories of the CIRM Tissue Collectors. A total of 280 biospecimen samples have been delivered to CDI for the purpose of iPSC derivation. The Biorepository is anticipating delivery of the first batches of iPSCs for distribution in early 2015. These lines, along with the associated clinical data, will become available to scientists via the on-line Coriell catalogue. The CIRM Coriell iPSC Biorepository will ensure safe long-term storage and distribution of high quality iPSCs.
Funding Type: 
hiPSC Derivation
Grant Number: 
ID1-06557
Investigator: 
Type: 
PI
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
Liver Disease
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.

Progress Report: 
  • First year progress on grant ID1-06557, " Generation and Characterization of High-Quality, Footprint-Free Human Induced Pluripotent Stem Cell (iPSC) Lines From 3000 Donors to Investigate Multigenic Disease" has met all agreed-upon milestones. In particular, Cellular Dynamics International (CDI) has taken lease to approximately 5000 square feet of lab space at the Buck Institute for Research on Aging in Novato, CA. The majority of this space is located within the new CIRM-funded Stem Cell Research Building at the Buck Institute and was extensively reconfigured to meet the specific needs of this grant. All equipment, including tissue culture safety cabinets and incubators, liquid-handling robotics, and QC instrumentation have been installed and qualified. A total of 16 scientists have been hired and trained (13 in Production and 3 in Quality) and more than 20 Standard Operating Procedures (SOPs) have been developed and approved specifically for this project. These SOPs serve to govern the daily activities of the Production and Quality staff and help ensure consistency and quality throughout the iPSC derivation and characterization process. In addition, a Laboratory Information Management System (LIMS) had to be developed to handle the large amount of data generated by this project and to track all samples from start to finish. The first and most important phase of this LIMS project has been completed; additional functionalities will likely be added to the LIMS during the next year, but completion of phase 1 will allow us to enter full production mode on schedule in the first quarter of year 2. Procedures for the shipping, infectious disease testing, and processing of donor samples were successfully implemented with the seven Tissue Collectors. To date, over 700 samples have been received from these Tissue Collectors and derivation of the first 50 patient-derived iPSC lines has been completed on schedule. These cells have been banked in the Coriell BioRepository, also located at the Buck Institute. The first Distribution Banks will be available for commercial release during year 2.
Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06589
Investigator: 
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.

Progress Report: 
  • We have completed startup procedures, including obtaining approval for human subjects research, and making logistical arrangements for the study. We have carried out publicity efforts for the study, including giving presentations at health fairs and senior centers. We have recruited 4 subjects as of October 1, 2014. Now that procedures are in place, we are ready to accelerate recruitment. The goals of the study are to obtain blood or skin biopsy samples from well-characterized people with Alzheimer's disease and from healthy elderly controls, to have these samples reprogrammed into nerve cells, which will support research.
  • We have continued to collect blood samples from patients with Alzheimer's disease, of varying age at onset, as well as well-characterized elderly controls. These will be used for reprogramming into pluripotent stem cells. Those can then be reprogrammed into other types of mature cells such as nerve cells or neurons. these can be used for research to understand mechanisms of aging, Alzheimer's disease, and other disorders. The mechanisms of Alzheimer's disease are incompletely understood. It is not possible to study nerve cells from patients with Alzheimer's disease during life. Using stem cell technology enables such studies to occur.
Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
DR2A-05416
Investigator: 
Institution: 
Type: 
PI
Type: 
Co-PI
ICOC Funds Committed: 
$20 000 000
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Closed
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.
  • Alzheimer’s disease (AD), the leading cause of dementia, results in profound loss of memory and cognitive function, and ultimately death. In the United States, 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. Efforts to discover 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 urgent.
  • StemCells Inc., 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. 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 September 2012, the CIRM awarded a loan to StemCells Inc. to partially fund a program to test human neural stem cells in two animal models used by some researchers to study AD and the study was initiated in July of 2013. The goal of this study was chiefly to try to replicate earlier successful experiments with human neural stem cells in these mice in support of an IND filing with the U.S. FDA within four years.
  • In the first year of the study, the Disease Team actively worked on 5 important scientific milestones in our effort to develop human neural stem cells as a potential therapy for AD. We also held a pre-IND meeting with the FDA in which we shared our plans for the preclinical and clinical studies in AD; the meeting provided helpful guidance and assurances regarding our IND enabling activities.
  • As of the second year of the study, all of the first 5 scientific milestones have been completed. Specifically, the team conducted three animal studies believed necessary 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.
  • Despite seeing a very exciting increase in the number of connections between key hippocampal neurons within the brains of mice treated with human neural stem cells, this did not appear to robustly and consistently improve memory in the animals. Without seeing a significant change in memory performance, the preclinical results of the study did not satisfy one or more of the specific “No/No Go” scientific milestones agreed to with the CIRM. Given this, the loan was subsequently terminated in December 2014 as a consequence of the unanticipated preclinical results.
  • This study was 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. Although disappointing, the results of this study do not negate the potential of neural stem cell transplantation in AD; rather, having reviewed and discussed the data with our collaborators, we believe the data highlight the challenge of obtaining reliable and consistent behavior readouts of memory improvement in animals. Finally, the observed increases in the connections between hippocampal neurons are very interesting and may justify further efforts to improve pre-clinical development for this complex disorder.
Funding Type: 
Early Translational III
Grant Number: 
TR3-05669
Investigator: 
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.
  • 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.
  • 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. We harnessed the power of hESCs and medicinal chemistry to develop CAD-31. We completed extensive pharmacokinetic and safety studies on the six best of over 200 compounds that were synthesized. 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. Finally, it was determined that 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.
  • In summary, 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.

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