Huntington's Disease (HD) is a hereditary autosomal dominant triplet-repeat disease with complete penetrance, manifest by progressive motor and cognitive deterioration. HD affects males and females in relatively equal numbers, typically presenting with symptoms in the 3rd-4th decade of life. The disorder occurs in various geographic and ethnic populations worldwide. The frequency of HD appears to vary among different populations, ranging from an estimated 4 to 10 individuals per 100,000. HD is a progressive neurological disorder usually leading to death 15-20 years after onset of neurological or psychological impairment. Recent discoveries made through the collaborative work of scientists at Encore Pharmaceuticals, Inc. and the Oklahoma Medical Research Foundation (OMRF) have demonstrated novel antioxidant, anti-inflammatory and neuroprotective activities for gamma-carboxyethyl hydroxychroman (gamma-CEHC), a natural metabolite of gamma-tocopherol. gamma-CEHC slows disease progression in a mouse model of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's Disease) even when gamma-CEHC is administered late in the disease. Because ALS and Huntington's Disease (HD) share common neuropathic features, we have begun to investigate whether gamma-CEHC might show protection in preclinical models of HD. We find that systemically administered gamma-CEHC completely protects mice against chronic 3NP-induced HD-like neurological damage, suggesting its therapeutic potential in Huntington's Disease. EncorePharma and the OMRF established complementary patent protection in the field of tocopherol analogs, specifically seven United States patents (and their foreign counterparts) in the area of gamma-tocopherol, its metabolites and derivatives, including composition of matter patents for gamma-CEHC. Recently our two entities have developed a strategic relationship in order to combine scientific and business acumen. Through this relationship we plan to capitalize on the commercial potential offered by the novel tocopherol metabolites. Expressly, through this partnership we wish to leverage our recent discoveries and initiate product commercialization efforts by further elucidating the in vivo therapeutic of gamma-CEHC. The targeted objectives of the research defined in this Phase I application are to conduct a complete evaluation of gamma-CEHC for the slowing of HD progression in an accepted mouse genetic model, the R6/2 mouse that expresses the first exon of mutant human huntingtin (Htt) containing a pathogenic polyglutamine expansion. We are uniquely positioned to perform mechanistic studies of gamma-CEHC in preclinical models of HD and to pursue translational research leading quickly to human clinical trials. Successful demonstration of gamma-CEHC efficacy in a mouse genetic model of HD will ultimately result in the filing of an investigational new drug (IND) application for gamma-CEHC for the treatment of HD, after performing the necessary preclinical safety studies, followed by initiation of clinical development activities with Orphan Drug Designation. Although early in the preclinical development process for this agent, few if any safety issues have been seen or are anticipated. The need to move this potential therapeutic forward for a disease that has very few treatment alternatives cannot be understated
