Emerging chemotherapeutic strategies for Huntington's disease

Abstract

Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for the protein, huntingtin. There is no clinically proven 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 a cascade of pathogenic mechanisms associated with transcriptional dysfunction, oxidative stress, mitochondrial alterations, apoptosis, bioenergetic defects and subsequent excitotoxicity. Understanding how these processes interrelate has become important in identifying a pharmacotherapy in HD and in the design of clinical trials. A number of drug compounds that separately target these mechanisms have significantly improved the clinical and neuropathological phenotype of HD transgenic mice and, as such, are immediate candidates for human clinical trials in HD patients. These compounds are discussed herein.