Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for a protein of unknown function, huntingtin (htt). There is no known treatment for HD. Although the exact cause of neuronal death in HD remains unknown, it has been postulated that the abnormal aggregation of the mutant huntingtin protein may cause toxic effects in neurons, leading to pathogenic mechanisms of oxidative stress, mitochondrial dysfunction, apoptosis, energy metabolism defects, and subsequent excitotoxicity. We have identified a number of drug compounds that separately target these mechanisms and have shown that they significantly ameliorate the phenotype of HD transgenic mice. These compounds or their analogs are available for human use and represent the immediate pipeline of candidate neuroprotective agents for clinical trials in HD. We have shown that these drugs have great potential for combined use to maximize neuroprotection. Much as treatment for cancer and AIDS has evolved, the most effective neuroprotection for HD will likely come from a cocktail of medications. Such combination therapies in HD mouse models would provide critical pre-clinical data to pilot combined therapies in humans. We propose a logical series of combination therapeutic trials in both HD transgenic mice and HD knock-in mice with proven drug compound regimens, using phenotype analysis, histopathology, toxicology, biochemistry, and pharmacokinetics as outcome measures. We will begin with two-drug trails using creatine and coenzyme Q10. These compounds are under trial in HD patients and will serve as a foundation to build further two-drug combinations. We will continue to add compounds to both creatine and coenzyme Q10 that we have already shown to be efficacious in transgenic HD mice. Because planning is underway for cysteamine to enter early phase clinical testing, a high priority will be to combine it with creatine and coenzyme Q10. Once the best combinations with creatine and coenzyme Q10 are determined, we will select additional compound pairs based on their potential for the greatest efficacy and least toxicity in humans (ie. inhibitors of htt aggregation, histone deacetylase inhibition, and transcription dysregulation). To model medication trials in presymptomatic individuals, as well as symptomatic individuals, we will perform studies in R6/2 mice initiating treatment upon weaning and repeated with treatment initiated once symptoms are present (6 weeks, analogous to early stages of human HD). We will confirm the most efficacious single and combination drug strategies identified in the transgenic HD mice within the full-length HD knock-in mice. By modeling combination therapeutic trials in both transgenic and knock-in HD mice we expect to emerge knowing which combinations have the most promise for prospective clinical drug-trials in HD patients and will initiate treatment strategies.
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