Huntingtin-lowering strategies for Huntington’s disease

ABSTRACT

Introduction

Huntington’s disease (HD) is an incurable, autosomal dominant neurodegenerative disease caused by an abnormally long polyglutamine tract in the huntingtin protein. Because this mutation causes disease via gain-of-function, lowering huntingtin levels represents a rational therapeutic strategy.

Areas covered

We searched MEDLINE, CENTRAL, and other trial databases, and relevant company and HD funding websites for press releases until April 2020 to review strategies for huntingtin lowering, including autophagy and PROTACs, which have been studied in preclinical models. We focussed our analyses on oligonucleotide (ASOs) and miRNA approaches, which have entered or are about to enter clinical trials.

Expert opinion

ASO and mRNA approaches for lowering mutant huntingtin protein production and strategies for increasing mutant huntingtin clearance are attractive because they target the cause of disease. However, questions concerning the optimal mode of delivery and associated safety issues remain. It is unclear if the human CNS coverage with intrathecal or intraparenchymal delivery will be sufficient for efficacy. The extent that one must lower mutant huntingtin levels for it to be therapeutic is uncertain and the extent to which CNS lowering of wild-type huntingtin is safe is unclear. Polypharmacy may be an effective approach for ameliorating signs and symptoms and for preventing/delaying onset and progression.

KEYWORDS:

• Allele specific oligonucleotide
• autophagy
• huntingtin
• Huntington’s disease
• miRNA
• neurodegeneration
• polyglutamine
• PROTAC

Article highlights

• Huntington’s disease is an autosomal dominant disease caused by a gain-of-function mutation.

• Extensive data in preclinical models argue that lowering mutant huntingtin levels may ameliorate disease onset and progression.

• Huntingtin levels can be lowered by either enhancing degradation via autophagy of the ubiquitin-proteasome routes, strategies supported in preclinical models, or by reducing its formation via allele-specific oligonucleotides or mRNAs, strategies that are being tested in the clinic.

• Current data suggest that these approaches are not associated with overt liabilities in the short term and could in theory be combined.

• New technologies and approaches being developed will lead to refinement of approaches leading to huntingtin lowering and have the potential to bring strategies aiming to enhance huntingtin degradation into the clinic.

This box summarizes key points contained in the article.

Acknowledgments

We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) (DC Rubinsztein), Roger de Spoelberch Foundation, Alzheimer’s Research UK (DC. Rubinsztein), National Institute for Health Research Cambridge Biomedical Research Centre (DC Rubinsztein.; RA.Barker.), and Takeda Science Foundation (M Fujimaki). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

Declaration of interest

DC Rubinsztein is on the SABs of Aladdin Healthcare Technologies and Nido Biosciences.

RA Barker advises the following companies on some of their therapeutic developments – Living Cell Technologies; Fujifilm Cellular Dynamics Inc; Novo Nordisk; BlueRock Therapeutics; Aspen Neuroscience and UCB. M Fujimaki has received funding from Takeda Science Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The research of the authors was funded by the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) (D.C.R.), Roger de Spoelberch Foundation, Alzheimer’s Research UK (D.C.R.), National Institute for Health Research Cambridge Biomedical Research Centre (D.C.R.; R.A.B.), and Takeda Science Foundation (M.F.). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.