Emerging therapies in Huntington's disease

Abstract

Introduction: Huntington's disease (HD) is an inherited neurodegenerative condition for which there are no disease-modifying treatments. The availability of early genetic diagnosis makes HD an ideal candidate for early intervention. Growing understanding of pathogenesis has led to the identification of new therapeutic targets for which some compounds are now in clinical trials. Areas covered: A detailed review of medical databases and clinical trial registries was performed. Recent clinical trials aimed to establish disease-modification were included. Focus was assigned to RNA and DNA-based therapies aimed at lowering mutant huntingtin (mHTT) including antisense oligonucleotides (ASOs), RNA interference (RNAi), zinc finger proteins (ZFPs) and the CRISPR-Cas9 system. Modulation of mHTT and immunotherapies is also covered. Expert opinion: Targeting HD pathogenesis at its most proximal level is under intense investigation. ASOs are the only HTT-lowering strategy in clinical trials of manifest HD. Safety and efficacy of an allele specific vs. allele non-specific approach has yet to be established. Success will extend to premanifest carriers for which development of clinical and imaging biomarkers will be necessary. Scientific and technological advancement will bolster new methods of treatment delivery. Cumulative experience, collaborative research, and platforms such as ENROLL-HD will facilitate efficient and effective clinical trials.

Keywords: Anti-sense oligonucleotides; CRISPR-Cas9; Huntingtin; Huntington’s disease; RNA interference; deep brain stimulation; disease-modifying therapy; gene therapy; immunotherapy; stem cells.