Early Translational I
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.
This proposal is focused on the development of a cell-based therapy for Alzheimer’s disease (AD). The applicant first proposes to transplant human neural stem cells (hNSCs) into mice and assess survival and engraftment using several different immunosuppressive strategies. The applicant will then use array-based genomic analysis to identify a candidate human embryonic stem cell (hESC) line with similar characteristics to a mouse NSC (mNSC) line capable of improving function in a mouse model of AD. This candidate hESC line will be differentiated into hNSCs and transplanted into the mouse model for behavioral, histological and biochemical analyses. The applicant will compare the efficacy of hNSC transplantation to that of other strategies, including viral delivery of brain-derived neurotrophic factor (BDNF) and transplantation of cells genetically modified to express either an enzyme that degrades amyloid beta protein or a transcription factor that promotes neuronal differentiation. Finally the applicant proposes to determine whether transplantation of hNSCs into a preclinical model of AD can reverse cognitive deficits and synaptic loss. Reviewers agreed that this proposal could have significant impact. AD is an age-related neurodegenerative disease of unknown etiology that results in profound cognitive impairment and subsequent dementia. Current treatment options are lacking and there is a clear need for novel therapeutic approaches to provide either neuroprotective support to neurons at risk or repopulation of affected brain regions. Reviewers felt that the applicant’s robust preliminary data were a strength of the proposal and provided an excellent scientific rationale for further investigation. These data demonstrate that transplantation of mNSCs into one of the better mouse models of AD both improves cognitive function and increases synaptic density in aged mice, at least in part through the release of BDNF. Reviewers commented that it is logical to extend this work into hNSCs and ultimately preclinical models. Reviewers praised the research plan as well-designed and carefully articulated. One reviewer appreciated that the applicant has considered several approaches for establishing immune tolerance and promoting survival of transplanted hNSCs in mice. This reviewer also commented that an important feature of the proposal is that it does not rely on a preconceived notion of the mechanism of action of the cell therapy. This is evident in Aim 3 in which the applicant proposes to compare hNSC transplant to viral delivery of BNDF as well as transplant of genetically modified cells. Reviewers did raise a few concerns about the research plan. One reviewer felt that Aim 2 has all the hallmarks of a “fishing expedition” and called it the riskiest part of the proposal. This reviewer and another were not sure that relevant similarities between mNSCs and hESCs would be found. A reviewer raised several questions about the preclinical studies, noting that a major problem in the field of AD research is a lack of an appropriate preclinical model. This reviewer suggested that an aged model may be a better model than the proposed lesion model and was concerned that the letter of support from the investigator in charge of these studies mentions the former but not the latter. The reviewer was worried about this discrepancy, cautioning that proposed model may be difficult to implement. The applicant should have clarified these issues by describing the rationale for the proposed model, the experience of the team with this model and some preliminary data on the appropriateness of the model. Another reviewer suggested that the applicant follow post-engraftment survival for longer than six months. Despite these issues the reviewers judged the proposal to be feasible and felt it crucial to demonstrate safety and efficacy of hNSCs in the preclinical model prior to clinical trials. Reviewers agreed that the applicant is a well-established and highly productive neuroscientist with the experience to lead this research effort. They praised the assembled research team, noting the presence of several experts in their respective fields, some with considerable expertise in translational research. One reviewer noted that the team is world-class and exemplary of CIRM’s goal to bring together the best and brightest in stem cell research. One reviewer raised concerns about the budget, describing it as very expensive and specifically citing high indirect costs for consultants and the large budget for preclinical studies. The reviewers recommended further breakdown and justification of these budget items. Overall reviewers were enthusiastic about this proposal and felt that its impact could be profound. They praised the strong preliminary data, logical progression of the research plan and thorough consideration of alternative approaches.