Latest advances on new promising molecular-based therapeutic approaches for Huntington's disease

Abstract

Huntington's disease (HD) is a devastating, autosomal-dominant inherited, neurodegenerative disorder characterized by progressive motor deficits, cognitive impairments, and neuropsychiatric symptoms. It is caused by excessive cytosine-adenine-guanine (CAG) trinucleotide repeats within the huntingtin gene (HTT). Presently, therapeutic interventions capable of altering the trajectory of HD are lacking, while medications for abnormal movement and psychiatric symptoms are limited. Numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. In this review, we update the latest advances on new promising molecular-based therapeutic strategies for this disorder, including DNA-targeting techniques such as zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9; post-transcriptional huntingtin-lowering approaches such as RNAi, antisense oligonucleotides, and small-molecule splicing modulators; and novel methods to clear the mHTT protein, such as proteolysis-targeting chimeras. We mainly focus on the ongoing clinical trials and the latest pre-clinical studies to explore the progress of emerging potential HD therapeutics.

Keywords: Huntington’s disease; preclinical and clinical studies; therapeutic strategy.

Figure 1

Molecular-based therapeutical approaches for HD. The orange boxes are therapeutic approaches. ASO: antisense oligonucleotide; CRISPR: clustered regularly interspaced short palindromic repeats; mHTT: mutant huntingtin; NMDAR: N-methyl-d-aspartate receptor; PROTACs: proteolysistargeting chimeras; RNAi: RNA interference; Sigma1R: sigma1 receptor; TALENs: transcription activator-like effector nucleases; VMT2R: vesicular monoamine transporter 2; WT-HTT: wildtype huntingtin; ZFP: zinc-finger protein.