Gene therapy and immunotherapy as promising strategies to combat Huntington’s disease-associated neurodegeneration: emphasis on recent updates and future perspectives

ABSTRACT

Introduction

Modulation of gene expression using gene therapy as well as modulation of immune activation using immunotherapy has attracted considerable attention as rapidly emerging potential therapeutic intervention for the treatment of HD. Several preclinical and clinical trials for gene-based therapy and immunotherapy/antibody-based have been conducted.

Areas covered

This review focused on the potential use of gene therapy and immuno-based therapies to treat HD, including the current status, the rationale for these approaches as well as preclinical and clinical data supporting it. Growing knowledge of HD pathogenesis has resulted in the discovery of new therapeutic targets, some of which are now in clinical trials. Focus has been allocated to RNA and DNA-based gene therapies for the reduction of mutant huntingtin (mHTT), using Immuno/antibody-based therapies.

Expert opinion

While safety and efficacy of gene therapy and immunotherapy has been well demonstrated for HD, therefore much focus has now been shifted to disease-modifying therapies. This review defines the current status and future directions of gene therapy and immunotherapies. The review summarizes by what means HD genetic root cause modification and functional restoration of mHtt protein could be achieved by using targeted multimodality gene therapy and immunotherapy to target intracellular and extracellular mHtt.

KEYWORDS:

• Huntington disease
• gene therapy
• antisense oligonucleotide
• rna interference
• zinc finger protein
• crispr/Cas9
• immuno/antibody therapy

Article highlights

• Current HD therapy HD aims at providing symptomatic relief whereas emerging approaches seek to modify HD at gene-level or inhibit mHtt protein by using antibody or combination of both.

• In preclinical studies, gene therapy-based Htt-lowering strategies (ASOs, RNAi, ZFP, and CRISPR-Cas9) showed promising impact in reducing HD at proximal level.

• Based on the ASO approach, some Gene modifiers has recently entered a phase I/II clinical trial aimed at nonselective huntingtin gene knockdown.

• The safety and efficacy issue of allele-specific approach (targeting only mHtt) and allele-specific nonspecific therapies (targeting both wtHtt and mHtt) is yet to be established.

• Nevertheless, immuno/antibody-based therapy hold promise to treat HD and positive results are expected from the clinical trial, investigating a monoclonal antibody (mAb67-2) against HD-associated neuroinflammation.

• The newest or young idea coming out is combination therapy, i.e. gene therapy along with immune/antibody-based therapy.

Declaration of interest

The authors have no 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

This paper was not funded.