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RN1-00547-1: Stem cell regeneration of neural circuits in murine Huntington's disease models
Recommendation: Not recommended for funding
Public Abstract (provided by applicant)
Discovery of embryonic and tissue stem cells has provided renewed hope for the development of cell replacement therapies to treat neurodegenerative disorders. Currently, a number of stem cell-related strategies require preclinical evaluation in order to move such treatments to clinical trial. The present proposal will examine the therapeutic potential of endogenous and transplanted neural stem cells (NSCs) in a transgenic model of Huntington’s Disease (HD).
HD is an adult-onset disorder involving specific loss of striatal and cortical neurons that is accompanied by progressive motor system abnormalities (e.g. uncontrollable ballistic movements or “chorea”) and an array of cognitive impairments. HD is caused by a dominant mutation in a single gene, huntingtin (htn), containing expanded CAG repeats and genomic insertion of the mutant htn induces pathology in animals similar (or identical) to that observed clinically. Importantly, transgenic mice exhibit nearly identical abnormalities to HD patients in terms of motor and cognitive deficits and neuronal loss in the striatum and cerebral cortex. Further, as the pathology of transgenic HD mice develops, adult NSCs undergo population expansion and their progeny are redirected toward the striatum and a parallel increase in adult NSCs occurs in HD patients. Thus, stem cell function is influenced in a similar fashion by the presence of mutant huntingtin in mouse and human brain. These factors make transgenic HD mouse models an ideal system for cell replacement experimentation, particularly for strategies using stem cells.
Alternatives in cell replacement strategies has expanded immensely with the discovery and characterization of embryonic and adult stem cells. Our proposal provides a comparison of activation of endogenous NSCs and transplanted NSCs. Specificaly,endogenous NSCs will be stimulated in situ with factors that induce proliferation and survival of precursors. NSCs for transplantation will be derived from adult brain or from “neuralization” of embryonic stem stems, including human cells. Our laboratory is particularly well suited to conduct research of this nature because our combined cellular, systems neuroscience, and behavioral expertise will facilitate a thorough evaluation of stem cell therapeutics at the organism level necessary to move from preclinical studies to clinical trials.
Statement of Benefit to California (provided by applicant)
Nervous system disorders, ranging from idiopathic neurodegeration to trauma and stroke, account for an ever increasing portion of medical costs and for most of these syndromes there are few treatments and no cures. Cell replacement therapies offer a avenue of tremendous potential for the future of regenerative medicine. Clinical trials employing fetal tissue grafts for potential treatment of Parkinson’s and Huntington’s disease are under way and have yielded promising results. However, such potential treatments currently require aborted fetal tissue which provides both a moral obstacle and a limitation on the widespread employment of these approaches because of insufficient tissue sources. Discovery and characterization of embryonic and adult stem cells provide the potential opportunity for generating the large amounts of cells for widespred grafting because these cells (by definition) have extensive self-renewal capacity. Currently, many strategies for the use of stem cells require preclinical evaluation prior to the initiation of clinical trials. Our proposal will conduct preclinical trials using a mouse model of Huntington’s disease to compare the therapeutic potential of activating endogenous neural stem cells, transplanting neural stem cells, and transplanting neuralized embryonic stem cells. The findings of these studies will have direct relevance to developing clinical trials employing stem cells in the treatment of Huntington’s disease, as well as, other neurodegenerative disorders and traumatic brain injury. Accordingly, the proposed research will initiate steps towards fulfilling the hope that stem cells will be able to treat neurodegenerative disorders. Specifically, Huntington’s disease afflicts several thousand individuals in California and there is no cure or treatment for this disease. It is a progressive disorder that robs the individual of motor, cognitive, and emotional control that produces tremendous distress for the afflicted and their families. As such, creating therapeutic avenues for the management of this condition will be of direct benefit to the citizens of California as well as reducing long-term health costs associated with Huntington’s disease. Further, the proposed research will increase the diversity of stem cell research in the state and provide training and employment to future researchers.
Review
SYNOPSIS: This proposal seeks to identify the optimal cell source and conditions for cell replacement treatment of a Huntington’s Disease (HD) transgenic mouse. The PI will address the potential therapeutic value of neural stem cells (NSCs) and embryonic stem cells (ESCs) in HD in several ways. First, the PI will characterize the impact of growth factors and neurotrophic factors on long-term NSC function in normal and HD mouse brain. The PI will also determine the effectiveness of endogenous NSC and transplanted NSCs (including those derived from ESCs) with and without additional trophic factors on repairing circuits damaged in HD disease.
STRENGTHS AND WEAKNESSES OF THE RESEARCH PLAN: This proposal will explore the feasibility of restoring neurons and neuronal circuitry in a mouse model of Huntington’s disease (HD). The hypothesis that is tested in this proposal is that cell replacement strategies will lead to behavioral recovery and an increase in lifespan in HD transgenic mice. Preliminary data in a previous mouse model suggest that a population of proliferative and undifferentiated cells are available for recruitment and would be stimulated to replace degenerating neurons given the proper conditions. This application builds on the PI’s experience in a previous mouse model of HD. The current proposed mouse model in this application has a more comparable time course and pathology to HD in humans
The PI proposes to explore both endogenous and exogenous repair in the mouse model of HD. The results could have important implications for HD, and possibly to other neurodegenerative diseases and injury. However, the focus is rather narrow, since it is mainly applicable to one disease.
There were several strengths to this proposal. Overall, the experimental plan appears thorough and complete. Only occasional parts of the description are “dropped” in an unannounced manner, e.g. the use of a specific antibiotic. In many ways, this proposal builds and is based on previous studies and findings of others.
One major question with this proposal is what will the PI do if there is no increase in NSC in this mouse model of HD? There were also concerns with the second aim of the proposal. One reviewer recommended that the PI use a genetic approach to mark and follow cells to the striatum. Also, the small molecule studies, which will be in collaboration with another investigator, were not detailed and no letter from the collaborator is provided. In the third aim, one reviewer questioned how the transplanted cells will be identified since expression of the reporter is not being controlled by an independent promoter? In the fourth aim, one reviewer commented that the PI likely needs to sort neural cells so no tumors form. One reviewer’s enthusiasm for the project would have been bolstered with more innovative ideas and more risk-taking. Finally, a minor criticism of the proposal was that there were a number of typographical errors.
QUALIFICATIONS AND POTENTIAL OF THE PRINCIPAL INVESTIGATOR: The applicant received a PhD in 2000 and completed two post-doctoral fellowships (2000-2004) and then (2004-2005). The applicant has been an Assistant Professor since 2005. The applicant states s/he has 14 years of experience in behavioral neuroscience and one year in cell and molecular biology. The PI has training in HD and behavioral and molecular studies, some with relevance to this project. The PI has experience in culturing adult NSCs. The work with ESCs will take advantage of guidance from the core facility at the applicant’s institution.
The applicant’s publication record is quite good. Since 2003, the applicant has published more than ten papers as first author, shared first author, or last author. Five of these publications were in the last 2 years. One reviewer commented that these publications are largely descriptive. The PI is presently the recipient of two grants.
In reading the career developmental plan, one might get the impression that the PI is primarily interested in behavioral aspects of neuroscience and in the systems s/he studies, and that the neural stem cell component is somewhat secondary. The PI did not detail any plan in regard to mentoring.
INSTITUTIONAL COMMITMENT TO PRINCIPAL INVESTIGATOR: The applicant has apparently been very successful in his/her faculty position since starting at the applicant institution in 2005. The Department Chair states in a letter that the PI is to be tenured in one to two years. The applicant is said to have received a “generous start-up package,” although details are not provided.
A senior mentor has been assigned to assist the PI in his/her career development. The PI presently has 750 sq. ft. of wetbench and behavioral testing space. It appears as if they have many of the resources needed to do the work and has the appropriate equipment in the lab. Core facilities for FACS, confocal microscopy, animal care, genomics and proteomics are available.
The applicant’s institution has a growing interest in stem cell research, which should help the applicant. There is a shared laboratory for stem cell biology used by more than 10 PIs. Recruitment of additional stem cell PIs is planned.
DISCUSSION: Comments from the reviewers centered on the fact that the proposal is not very risk-taking, and might move the field forward only a little bit. The reviewers sensed a strong commitment to and self-described identity of the PI in behavioral neuroscience. There was some debate about the commitment of the investigator to stem-cell science, citing the following: the only component of the research plan to involve stem cells was via collaboration, and there was no mentoring plan in place for stem cell biology.
The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:
- None