Early Translational I
$3 599 997
Statement of Benefit to California:
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.