Huntingtin-lowering strategies for Huntington's disease

Area of Science:

• Neurodegenerative Diseases
• Genetics
• Pharmacology

Background:

• Huntington's disease (HD) is an incurable, autosomal dominant neurodegenerative disorder.
• It is caused by an expanded polyglutamine tract in the huntingtin protein, leading to a toxic gain-of-function.
• Lowering huntingtin protein levels is a rational therapeutic approach for HD.

Purpose of the Study:

• To review current strategies for lowering huntingtin protein in Huntington's disease.
• To focus on oligonucleotide (ASO) and miRNA approaches entering clinical trials.
• To assess the potential of autophagy and PROTACs in preclinical models.

Main Methods:

• Searched MEDLINE, CENTRAL, and trial databases for huntingtin-lowering strategies.
• Reviewed company and HD funding websites for relevant press releases up to April 2020.
• Focused analysis on oligonucleotide (ASO) and miRNA approaches.

Main Results:

• Oligonucleotide (ASO) and mRNA approaches target the root cause of Huntington's disease by reducing mutant huntingtin production.
• Strategies for increasing mutant huntingtin clearance are also being investigated.
• Preclinical studies have explored autophagy and PROTACs for huntingtin lowering.

Conclusions:

• ASO and mRNA therapies are attractive for Huntington's disease due to their disease-targeting mechanism.
• Key challenges include determining optimal delivery methods (intrathecal, intraparenchymal) and ensuring central nervous system (CNS) coverage.
• Safety concerns regarding the necessary reduction of mutant huntingtin and potential lowering of wild-type huntingtin require further investigation. Polypharmacy may also be beneficial.