Huntingtin-Lowering Therapies for Huntington Disease: A Review of the Evidence of Potential Benefits and Risks.

Huntington disease (HD) is caused by a cytosine-adenine-guanine trinucleotide repeat expansion in the huntingtin gene, HTT, that results in expression of variant (mutant) huntingtin protein (HTT). Therapeutic strategies that reduce HTT levels are currently being pursued to slow or stop disease progression in people with HD. These approaches are supported by robust preclinical data indicating that reducing variant huntingtin protein is associated with decreased HD pathology. However, the risk-benefit profile of reducing either variant HTT or both variant and wild-type HTT is currently an open question that is being addressed in ongoing clinical trials. This review aims to examine the current data available regarding altered HTT in humans, normal animals, and animal models of HD. Studies indexed in PubMed were searched using the MeSH term Huntington disease or the text words huntington or huntingtin from August 31, 1999, to August 31, 2019, with no language restrictions. Additional studies were included from the reference lists of relevant studies and the authors' personal files. Articles describing at least 1 aspect of HTT reduction were included, prioritizing those published within the last 10 years. In vivo studies were also prioritized, with a focus on studies that examined the consequences of wild-type HTT reduction in adults. In a recently completed phase 1/2a study of RG6042 in 46 adults with early manifest HD, antisense oligonucleotide-mediated partial reduction of HTT was reported to be generally safe and well tolerated over the course of 4-monthly RG6042 doses. In case studies of people with rare genetic variations in huntingtin alleles, the loss of 1 wild-type allele was not associated with HD. People with homozygous cytosine-adenine-guanine expansions developed normally until the onset of HD, although they may have experienced a more aggressive disease course. In mouse models of HD, partial reduction of HTT was beneficial, with improvements in motor, cognitive, and behavioral phenotypes. The partial reduction of wild-type HTT in normal adult rodents and nonhuman primates was generally safe and well tolerated. The body of evidence reviewed in this article indicates a positive risk-benefit profile for the partial reduction of either variant HTT alone or both variant and wild-type HTT. These strategies target the underlying cause of HD and are currently being tested in several investigational clinical trials.