Hope for Huntington's disease patients: first clinical gene silencing study in progress

Abstract

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder, characterized by motor, psychiatric and cognitive symptoms for which as yet no causal treatment is available. It has a prevalence of 1 : 10 000 in Germany. Its cause is a mutation in the Huntington gene (CAG-repeat). The mutation induces a polyglutamine expansion in the huntingtin protein (HTT). Mutant HTT (mHTT) has cytotoxic properties, aggregates in the cell and leads to complex pathophysiological disturbances ending in cell death. This review explains the principles of gene silencing which suppresses transcription and translation of huntingtin. One way to achieve gene silencing is the use of antisense oligonucleotides (ASO) that bind to pre-mRNA. Since August 2015, a first clinical trial with ASO (study drug: IONIS-HTTRx) in early manifest HD patients is in progress (NCT02519036). Results from this study could lead to a first causal treatment option in HD.