Alzheimer's Disease

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

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.

ES-Derived Cells for the Treatment of Alzheimer's Disease

Funding Type: 
New Faculty I
Grant Number: 
RN1-00538-A
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.

ES-Derived Cells for the Treatment of Alzheimer's Disease

Funding Type: 
New Faculty I
Grant Number: 
RN1-00538-B
ICOC Funds Committed: 
$2 120 833
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Alzheimer’s disease is the most common cause of dementia in the elderly, affecting over 5 million people in the US alone. Boosting immune responses to beta-Amyloid (Aβ) has proven beneficial in mouse models and Alzheimer’s disease (AD) patients. Vaccinating Alzheimer’s mice with Aβ improves cognitive performance and lessens pathological features within the brain, such as Aβ plaque loads. However, human trials with direct Aβ vaccination had to be halted to brain inflammation in some patients. We have demonstrated that T cell immunotherapy also provides cognitive benefits in a mouse model for Alzheimer’s disease, and without any detectable brain inflammation. Translating this approach into a clinical setting requires that we first develop a method to stimulate the proliferation of Aβ-specific T cells without triggering generalized inflammatory response, as happens with vaccinations. Adaptive immune responses are provided by T cells and B cells, which are regulated by the innate immune system through antigen presenting cells, such as mature dendritic cells. We propose to leverage the power of embryonic stem (ES) cells by engineering dendritic cells that express a recombinant transgene that will specifically activate Aβ-specific T cells. We will test the effectiveness of this targeted stimulation strategy using real human T cells. If successful, this approach could provide a direct method to activate beneficial immune responses that may improve cognitive decline in Alzheimer’s disease.
Statement of Benefit to California: 
Alzheimer’s disease is the most common cause of dementia in the elderly, affecting more than 5 million people in the US. In addition to being home to more than 1 in 8 Americans, California is a retirement destination so a proportionately higher percentage of our residents are afflicted with Alzheimer’s disease. It has been estimated that the number of Alzheimer’s patients in the US will grow to 13 million by 2050, so Alzheimer’s disease is a pending health care crisis. Greater still is the emotional toll that Alzheimer’s disease takes on it’s patients, their families and loved one. Currently, there is no effective treatment or cure for Alzheimer’s disease. The research proposed here builds on more than 7 years of work showing that the body’s own immune responses keep Alzheimer’s in check in young and unaffected individuals, but deficiencies in T cell responses to beta-amyloid peptide facilitate disease progression. We have shown that boosting a very specific T cell immune response can provide cognitive and other benefits in mouse models for Alzheimer’s disease. Here we propose to use stem cell research to propel these findings into the clinical domain. This research may provide an effective therapeutic approach to treating and/or preventing Alzheimer’s disease, which will alleviate some of the financial burden caused by this disease and free those health care dollars to be spent for the well-being of all Californians.
Progress Report: 
  • Alzheimer’s disease remains the most common cause of dementia in California and the US with more than 5 million cases nationwide, a number that is expected to exceed 13 million by 2050 if treatments are not developed. We, and others, showed that T cells responses to beta-amyloid can provide beneficial effects in mouse models of this disease. However, a clinical trial of Abeta vaccination was halted due to immune cell infiltration of the meninges and consequent brain swelling. Most of the other patients seemed to benefit from the vaccination, but the uncontrolled robustness of the immune response to vaccination makes those trials unfeasible. This project aims to refine and control Abeta-specific T cell responses using antigen presenting cells derived from human embryonic stem cells (hESC). If we are successful, then we would be able to deliver only the beneficial cells responsible for the beneficial effects, and do so in a controlled manner so as to avoid encephalitogenic complications.
  • During the first 4 years of this CIRM grant, my lab developed novel methods to assess adaptive immune responses to the Alzheimer’s-linked peptide, amyloid-beta/Abeta, in human blood samples. This technique relies on the use of pluripotent stem cells to produce specific immune-modulating cells in a complicated differentiation process that takes ~50 days. Over the past year we have found that this technology can employ both human embryonic stem cells and induced-pluripotent stem cells (iPSC), the latter of which were developed in my lab through other funding sources. We have now confirmed that this method provides consistent and robust readouts. Over the past year we have moved into the clinical phase of this project and assessed these responses in over 60 human subjects. Control subjects (not affected by Alzheimer’s disease) were recruited from the university community. Initially, we looked for age-dependent changes in these responses with a cohort of >50 research subjects who ranged in age from 20-88 years. Interesting patterns emerged from that study, which are currently being prepared for publication, and will remain confidential until publication; further details are not provided in this report as it will become public record. Several Alzheimer’s patients have also been assessed. We recently entered into an agreement with a local Alzheimer’s assessment center that will allow us to expand our study by including subjects with a presumptive diagnosis of Alzheimer’s disease, as well as individuals with mild cognitive impairment (MCI) and other causes of dementia such as Fronto-temporal Dementia, Dementia with Lewy bodies and Vascular Dementia. It will be interesting to determine if the assay we have developed will be able to distinguish subjects with developing Alzheimer's pathology from those with other causes of dementia, using a small blood sample. Overall, our progress is on-track for this project to be completed at the end of year 5, with many more subject samples analyzed than were originally proposed. In the approved grant it was proposed that spleen samples from 6-8 organ donors would be assessed, but as we developed this technology it became clear that we can detect these responses using 20 mL whole blood samples from living human subjects. At present, we have used our assay to assess more than 60 human subjects – 10 times what was proposed - and by this time next year we estimate that number will double. Information gained from this research is providing exciting new insights into immune changes associated with Alzheimer’s disease. The Western University of Health Sciences is engaged in patent processes to secure intellectual property and commercialize this technology.
  • Alzheimer’s disease affects more than 5.5 million people in the USA. Problems with memory correspond with the appearance of insoluble plaques in certain brain regions, and these plaques large consist of a peptide called, amyloid-beta. For more than a decade it has known that certain immune responses to amyloid-beta improve memory in mouse models of Alzheimer’s disease, yet in humans little is known about how those responses normally occur or if they may a beneficial therapeutic strategy. In this grant we have used stem cell technology to pioneer a new method to isolate and characterize those cells using only 20 cc of whole blood from a variety of human subjects. We have found that these immune responses increase dramatically in when high-risk people are in their late 40’s and early 50’s. Those responses may provide protection against Alzheimer’s disease progression as they diminish as memory problems begin to develop. This technology will be developed as an early diagnostic test for Alzheimer's disease with private equity partners. A patent application covering this technology was submitted by the Western University of Health Sciences.
  • This CIRM grant allowed my group to translate findings from our Alzheimer’s research from mouse to man. Over several years my group, an others, showed that boosting T cell responses to a peptide found in the plaques of Alzheimer’s patients could reduce disease pathology and memory problems in mouse models of this disease. Interestingly, at least some people carry T cells in their immune system, but it was unknown who has them or if they are lost over the course of Alzheimer’s disease. In this CIRM-funded project we used stem cells to develop a new technology, called CD4see, to identify and quantify those T cells using a small sample of human blood, roughly the same amount taken for a standard blood panel. After years of development and testing of CD4see, we used it to look for and quantify those plaque-specific T cells in over 70 human subjects. We found an age-dependent decline of Aβ-specific CD4+ T cells that occurred earlier in women than in men. Men showed a 50% decline around the age of 70, but women reached the same level before the age of 60. Notably, women who carried the AD risk marker apolipoproteinE-ε4 (ApoE4) showed the earliest decline, with a precipitous drop that coincided with an age when menopause usually begins. This assay requires a sample of whole blood that is similar to standard blood panels, making it suitable as a routine test to evaluate adaptive immunity to Aβ in at-risk individuals as an early diagnostic test for Alzheimer’s disease. In future applications CD4see can be used to isolate those cells in the lab, expand them to millions of cells, and then return them back to the same person--our earlier mouse studies showed those T cells counter Alzheimer’s pathology and memory impairment, so this technology may lead to a new therapeutic approach. I am grateful to CIRM and California taxpayers for supporting young scientists and funding innovative research.

Neural Stem Cells as a Developmental Candidate to Treat Alzheimer Disease

Funding Type: 
Early Translational I
Grant Number: 
TR1-01245
ICOC Funds Committed: 
$3 599 997
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Collaborative Funder: 
Victoria, Australia
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Alzheimer disease (AD), the most common cause of dementia among the elderly and the third leading cause of death, presently afflicts over 5 million people in the USA, including over 500,000 in California. Age is the major risk factor, with 5% of the population over age 65 affected, with the incidence doubling every 5 years thereafter, such that 40-50% of those over age 85 are afflicted. Being told that one suffers from AD is one of the most devastating diagnoses a patient (and their family/caregivers) can ever receive, dooming the patient to a decade or more of progressive cognitive decline and eventual loss of all memory. At the terminal stages, the patients have lost all reasoning ability and are usually bed-ridden and unable to care for themselves. As the elderly represent the fastest growing segment of our society, there is an urgent need to develop therapies to delay, prevent or treat AD. If the present trend continues and no therapy is developed, over 16 million Americans will suffer from AD by 2050, placing staggering demands on our healthcare and economic systems. Thus, supporting AD research is a wise and prudent investment, particularly focusing on the power that stem cell biology offers. Currently, there is no cure or means of preventing AD. Existing treatments provide minor symptomatic relief– often associated with severe side effects. Multiple strategies are likely needed to prevent or treat AD, including the utilization of cell based approaches. In fact, our preliminary studies indicate that focusing on the promise of human stem cell biology could provide a meaningful therapy for a disease for which more traditional pharmaceutical approaches have failed. We aim to test the hypothesis that neural stem cells represent a novel therapeutic strategy for the treatment of AD. Our broad goal is to determine whether neural stem cells can be translated from the bench to the clinic as a therapy for AD. This proposal builds on extensive preliminary data that support the feasibility of neural stem cell-based therapies for the treatment of AD. Thus, this proposal focuses on a development candidate for treating Alzheimer disease. To translate our initial stem cell findings into a future clinical application for treating AD, we assembled a world class multi-disciplinary team of scientific leaders from the fields of stem cell biology, animal modeling, neurodegeneration, immunology, genomics, and AD clinical trials to collaborate in this early translational study aimed at developing a novel treatment for AD. Our broad goal is to examine the efficacy of human neural stem cells to rescue the cognitive phenotype in animal models of AD. Our studies aim to identify a clear developmental candidate and generate sufficient data to warrant Investigational New Drug (IND) enabling activity. The proposed studies represent a novel and promising strategy for treating AD, a major human disorder for which there is currently no effective therapy.
Statement of Benefit to California: 
Neurological disorders have devastating consequences for the quality of life, and among these, perhaps none is as dire as Alzheimer disease. Alzheimer disease robs individuals of their memory and cognitive abilities, such that they are no longer able to function in society or even interact with their family. Alzheimer disease is the most common cause of dementia among the elderly and the most significant and costly neurological disorder. Currently, 5.2 million individuals are afflicted with this insidious disorder, including over 588,000 in the State of California. Hence, over 10% of the nation's Alzheimer patients reside in California. Moreover, California has the dubious distinction of ranking first in terms of states with the largest number of deaths due to this disorder. Age is the major risk factor for Alzheimer disease, with 5% of the population over age 65 afflicted, with the incidence doubling every 5 years such that 40-50% of the population over age 85 is afflicted. As the elderly represent the fastest growing segment of our society, there is an urgent need to develop therapies to prevent or treat Alzheimer disease. By 2030, the number of Alzheimer patients living in California will double to over 1.1 million. All ethnic groups will be affected, although the number of Latinos and Asians living with Alzheimer will triple by 2030, and it will double among African-Americans within this timeframe. To further highlight the direness, at present, one person develops Alzheimer disease every 72 seconds, and it is estimated that by 2050, one person will develop the disease every 33 seconds! Clearly, the sheer volume of new cases will create unprecedented burdens on our healthcare system and have a major impact on our economic system. As the most populous state, California will be disproportionately affected, stretching our public finances to their limits. To illustrate the economic impact of Alzheimer disease, studies show that an estimated $8.5 billion of care were provided in one year in the state of California alone (this value does not include other economic aspects of Alzheimer disease). Therefore, it is prudent and necessary to invest resources to try and develop strategies to delay, prevent, or treat Alzheimer disease now. California has taken the national lead in conducting stem cell research. Despite this, there has not been a significant effort to utilize the power of stem cell biology for Alzheimer disease. This proposal seeks to reverse this trend, as we have assembled a world class group of investigators throughout the State of California and in [REDACTED] to tackle the most significant and critical questions that arise in translating basic research on human stem cells into a clinical application for the treatment of Alzheimer disease. This proposal is based on an extensive body of preliminary data that attest to the feasibility of further exploring human stem cells as a treatment for Alzheimer disease.
Progress Report: 
  • Over the past decade, the potential for using stem cell transplantation as a therapy to treat neurological disorders and injury has been increasingly explored in animal models. Studies from our lab have shown that neural stem cell transplantation can improve cognitive deficits in mice resulting from extensive neuronal loss and protein aggregation, both hallmarks of Alzheimer’s Disease pathology. Our results support the justification for exploring the use of human derived stem cells for the treatment of Alzheimer’s patients.
  • During the past few months, we have begun studies aimed at taking human derived stem cells from the bench top to the bed side. To identify the best possible human stem cells to use in our future studies, we have conducted comparisons between a wide array of human stem cells and a mouse neural stem cell line (the same mouse stem cells used in the studies mentioned above). Using these results, we have selected a cohort of human stem cell candidates to which we will continue to study in upcoming experiments involving our AD model mice.
  • In addition to identifying the best human stem cells to conduct further studies, we have also performed experiments to determine the optimal immune suppression regimen to use in our human stem cell engraftment studies. Similar to organ transplants in humans, we will need to administer immune suppressants to mice which receive our candidate human stem cells. Our group has identified a potential suppressant, also found to work in humans, which we will use in future studies.
  • Over the past decade, the potential for using stem cell transplantation as a therapy to treat neurological disorders and injury has been increasingly explored in animal models. Studies from our lab have shown that neural stem cell transplantation can improve cognitive deficits in mice resulting from extensive neuronal loss and protein aggregation, both hallmarks of Alzheimer’s Disease pathology. Our results support the justification for exploring the use of human derived stem cells for the treatment of Alzheimer’s patients.
  • During the past few months, we have begun studies aimed at taking human derived stem cells from the bench top to the bed side. To identify the best possible human stem cells to use in our future studies, we have conducted comparisons between a wide array of human stem cells and a mouse neural stem cell line (the same mouse stem cells used in the studies mentioned above). Using these results, we have selected a cohort of human stem cell candidates to which we will continue to study in upcoming experiments involving our AD model mice.
  • In addition to identifying the best human stem cells to conduct further studies, we have also performed experiments to determine the optimal immune suppression regimen to use in our human stem cell engraftment studies. Similar to organ transplants in humans, we will need to administer immune suppressants to mice which receive our candidate human stem cells. Our group has identified a potential suppressant, also found to work in humans, which we will use in future studies.
  • During the last reporting period the lab has made substantial advancements in determining the effects of long term human neural stem cells engraftment on pathologies associated with the advancement of Alzheimer's disease. In addition, data obtained by our lab has may provide additional insight on ways to target the immune system as a means of prolonging neural stem cell survival and effectiveness.

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.

Development of human ES cell lines as a model system for Alzheimer disease drug discovery

Funding Type: 
SEED Grant
Grant Number: 
RS1-00247
ICOC Funds Committed: 
$492 750
Disease Focus: 
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Alzheimer disease (AD) is a progressive neurodegenerative disorder that currently affects over 4.5 million Americans. By the middle of the century, the prevalence of AD in the USA is projected to almost quadruple. As current therapies do not abate the underlying disease process, it is very likely that AD will continue to be a clinical, social, and economic burden. Progress has been made in our understanding of AD pathogenesis by studying transgenic mouse models of the disease and by utilizing primary neuronal cell cultures derived from rodents. However, key proteins that are critical to the pathogenesis of this disease exhibit many species-specific differences at both a biophysical and functional level. Additional species differences in other as yet unidentified AD-related proteins are likely to also exist. Thus, there is an urgent need to develop novel models of AD that recapitulate the complex array of human proteins involved in this disease. Cell culture-based models that allow for rapid high-throughput screening and the identification of novel compounds and drug targets are also critically needed. To that end we propose to model both sporadic and familial forms of AD by generating two novel human embryonic stem cell lines (hES cells). Differentiation of these lines along a neuronal lineage will provide researchers with an easily accessible and reproducible neuronal cell culture model of AD. These cells will also allow high-throughput screening and experimentation in neuronal cells with a species-relevant complement of human proteins. In Aim 1 we will develop and characterize hES cell lines designed to model both sporadic and familial forms of AD. To model sporadic AD we will stably transfect HUES7 hES cells (developed by Douglas Melton) with lentiviral constructs coding for human wild type amyloid precursor protein (APP-695) under control of the human APP promoter. APP is well expressed within hES cells and upregulated upon neuronal differentiation. To model familial AD and generate cells that exhibit a more aggressive formation of oligomeric A species we will also develop a second hES cell line stably transfected with human APP that includes the Arctic (E693G) mutation.In Aim 2 we will utilize our wild-type APP hES cells to perform a high-throughput siRNA screen. We will utilize AMAXA reverse-nucleofection in conjunction with a human druggable genome siRNA array (Dharmacon) that targets 7309 genes considered to be potential therapeutic targets. Following transfection conditioned media will be examined by a sensitive ELISA to identify novel targets that modulate A levels. In addition a Thioflavin S assay will determine any effects on A aggregation. Follow-up experiments will confirm promising candidates identified in the high-throughput screen. Taken together these studies aim to establish novel AD-specific hES cell lines and identify promising new therapeutic targets for this devastating disease.
Statement of Benefit to California: 
Alzheimer disease (AD) is a progressive neurodegenerative disorder that currently affects over 500 thousand Californians. As the baby-boomer generation ages the prevalence of AD in California is projected to almost quadruple such that 1 in every 45 individuals will be afflicted. As current therapies do not abate the underlying disease process, it is very likely that AD will continue to be a major clinical, social, and economic burden. Some estimates have even suggested that AD alone may bankrupt the current Californian health care system. Progress has been made in our understanding of AD by studying rodent-based models of the disease. However, key proteins that are critical to the disease exhibit many species-specific differences at both a biophysical and functional level. Thus, there is an urgent need to develop novel models of AD that exhibit the complex array of human proteins involved in this disease. Cell culture-based models that also allow for rapid high-throughput screening and the identification of novel compounds and drug targets are also in critical need. The proposed studies aim to utilize human embryonic stem (hES) cells to establish a novel cell culture based model of Alzheimer’s disease. Once developed these cells will provide Californian researchers with a unique tool to investigate genes and proteins that influence the progress of AD. In this proposal we will also utilize these hES cells to perform a high-throughput screen of over 7300 genes to identify multiple novel drug targets that may critically regulate the development of this disease. Taken together these studies aim to establish novel AD-specific hES cell lines that can be utilized by multiple Californian researchers to identify promising new therapeutic targets for this devastating disease.
Progress Report: 
  • Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. It is characterized by an irreversible loss of neurons accompanied by the accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Currently, 5.3 million Americans are afflicted with this insidious disorder, including over 588,000 in the State of California alone. Mouse models of AD have contributed significantly to our understanding of the proteins and factors involved in the pathology of AD. However, there are critical differences between mouse and human cell physiology that likely dramatically influence the development of AD-related pathologies. Hence, there is an urgent need to develop novel human neuronal cell-based models of AD.
  • To achieve this goal, we have generated stable human embryonic stem cell (hES) lines over-expressing the gene for human amyloid precursor protein (APP). We succeeded in creating several lines of hES cells that stably express either wild-type (unaltered) APP or APP that includes rare familial mutations known to cause early-onset cases of AD. In each line, transgene expression is driven under control of the human APP proximal promoter. Mutant versions of APP utilized include the “Swedish” mutation which increases production of Aß and the “Arctic” mutation which increases the assembly and accumulation of synaptotoxic Aß oligomers and protofibrils. The generation of lines that harbor familial mutations in APP both provides an aggressive model of AD, to facilitate the identification of targets that modulate not only Aß production but also the assembly of toxic oligomeric species.
  • In addition to generating stable HUES7 and H9 cell lines over-expressing mutant and wild type forms of APP, we also succeeded in establishing a neuronal differentiation protocol which results in 80% of cells adopting a mature neuronal fate. Importantly, we have also verified by biochemical measures that APP-overexpressing cells produce significantly elevated levels of Aß. As a result we are now preparing to utilize these novel cell lines to identify and examine genes that regulate Aß production and hence the development of AD.
  • Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder. Currently, 5.3 million individuals are afflicted with this insidious disorder, including over 588,000 in the State of California alone. Unfortunately, existing therapies provide only palliative relief. Although transgenic mouse models and cell culture experiments have contributed significantly to our understanding of the proteins and factors involved in the pathology of AD, these approaches are beset by certain critical limitations. Most notably, mouse models by definition are not based on human cells and cell culture models have been limited to non-human or non-neuronal cells. Hence, there is an urgent need to develop a human neuronal cell-based model of AD. To address this need, we have engineered human embryonic stem cell lines to overexpress mutant human genes that cause early-onset familial AD. These novel stem cell lines will provide a valuable system to test therapies and enhance our understanding of the mechanisms that mediate this devastating disease. Interestingly, we have found that overexpression of these AD-related genes can trigger the rapid differentiation of human embryonic stem cells into neuronal cells. We have examined the mechanisms involved and anticipate that our findings may provide a novel and rapid method to generate neurons from embryonic stem cells.

Generation of forebrain neurons from human embryonic stem cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00205
ICOC Funds Committed: 
$612 075
Disease Focus: 
Aging
Alzheimer's Disease
Neurological Disorders
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
The goal of this proposal is to generate forebrain neurons from human embryonic stem cells. Our general strategy is to sequentially expose ES cells to signals that lead to differentiation along a neuronal lineage, and to select for cells that display characteristics of forebrain neurons. These cells would then be used in transplantation experiments to determine if they are able to make synaptic connections with host neurons. If successful these experiments would provide a therapeutic strategy for the treatment of Alzheimer’s disease and other disorders that are characterized by loss of forebrain neurons. Currently there is no effective treatments for Alzheimer’s disease, and with an aging baby-boomer population, the incidence of this disease is likely to increase sharply. One of the few promising avenues to treat Alzheimer’s is the possibility of cell replacement therapy in which the neurons lost could be replaced by transplanted neurons. Embryonic stem cells, which have the ability to differentiate into various cells of the body, could be a key component of such a therapy if we can successfully differentiate them into forebrain neurons.
Statement of Benefit to California: 
Alzheimer’s disease is a devastating sporadic neurological disorder that places all of us at risk. As the California population ages, there will be a significant increase in the incidence of Alzheimer’s disease, and the medical and financial cost on the state will be severe. There are currently no effective treatments for this disorder, and one of the few promises is the possibility of transplantation therapy to replace the neurons that are lost in the disease. Being able to generate forebrain neurons from human embryonic stem cells would provide a key tool in the fight against this disease. Needless to say, the development of an effective cell replacement therapy would not only be of immense medical significance as we care for our senior population, it will also greatly relieve the financial burden associated with the care of Alzheimer’s patients, which is often borne by the state.
Progress Report: 
  • The goal of this proposal was to generate forebrain neurons from human embryonic stem cells. Our general strategy was to sequentially expose ES cells to signals that would lead the cells to acquire characteristics typical of differentiated brain cells that are lost in disorders such as Alzheimer's Disease. The most important advance of the research was our ability to achieve this goal. We now have a well-developed protocol that can be used to generate forebrain cells in culture. We have found that these cells not only express genes typical of these cells, they extend axons and dendrites and can make synaptic connections. These cells could be very useful for transplantation studies, as well as for developing cell culture models of Alzheimer's disease. Finally, we have discovered that the same protocol is effective in generating forebrain neurons from iPS cells, attesting to the general usefulness of this strategy.

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: 
Neurological Disorders
Alzheimer's Disease
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.

Pages

Subscribe to RSS - Alzheimer's Disease

© 2013 California Institute for Regenerative Medicine