Therapies targeting DNA and RNA in Huntington's disease

Abstract

No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA. An intrathecally delivered antisense oligonucleotide that aims to lower huntingtin is now well into its first human clinical trial, with other antisense oligonucleotides expected to enter trials in the next 1-2 years and virally delivered RNA interference and zinc finger transcriptional repressors in advanced testing in animal models. Recent advances in the design and delivery of therapies to target HTT RNA and DNA are expected to improve their efficacy, safety, tolerability, and duration of effect in future studies.

Figure 1

The production of huntingtin protein, and targeted molecular therapies in development to reduce it. Yellow marks the pathogenic expanded CAG tract and its polyglutamine product. Therapeutic approaches are highlighted with pink boxes. Yellow boxes indicate the most widely accepted toxic species. Dotted arrows and grey boxes indicate proposed non-traditional mechanisms for the production of toxic species. The chief mechanisms of action of ASOs and RNAi compounds are shown at the bottom. The image of huntingtin protein is adapted from reference under a creative commons licence (CC-BY-4.0).

Figure 2

First, second and third generation ASOs and native DNA. Each generation may contain numerous variations around the altered characteristic. HTT_Rx combines a phosphorothioate backbone (1^st generation) with 2’-O-MOE modification (2^nd generation) and is considered a 2^nd generation ASO overall.