From Preclinical to Clinical Trials: An Update on Potential Therapies for Huntington’s Disease

Patricia   S.   Brocardo; Joana   M.   Gil-Mohapel

doi:10.2174/2211556011302020003

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene that codifies the protein huntingtin and characterized by neurodegeneration of certain areas of the brain, particularly the striatum and the cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. The disease is invariable fatal and there is currently no cure for individuals affected with this disorder. In a search to find a cure for this devastating neurodegenerative disorder, numerous pharmacological compounds have now been tested through preclinical trials that have heavily relied on the various transgenic mouse models that are currently available to study HD. Unfortunately however, to date the benefits observed in the clinical setting have been somewhat limited. We have recently published a review article comparing the results of these preclinical studies with the outcomes of the corresponding clinical trials involving HD afflicted individuals (Brocardo and Gil- Mohapel, 2012, Current Psychopharmacology 1:137-154). In the present article we present an update to our previous review, where the new preclinical and clinical studies that have been performed over the past year have been also discussed with the goal of further elucidating the efficacy of the pharmacological treatments that have been attempted in both transgenic HD mouse models and human HD patients. By providing and maintaining an up-to-date overview of the most current literature, we hope that patterns will emerge that will guide the design of more effective preclinical and clinical studies, such as the use of combination therapies that utilize different cocktails of pharmacological compounds to simultaneously target different intracellular pathways that are affected in HD.

Keywords: Behavioural deficits, clinical trial, Huntington’s disease, neuropathology, preclinical study, transgenic model, therapeutic strategy.