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:
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.