Emerging antibody-based therapies for Huntington’s disease: current status and perspectives for future development

ABSTRACT

Introduction

Being an inherited neurodegenerative disease with an identifiable genetic defect, Huntington’s disease (HD) is a suitable candidate for early intervention, possibly even in the pre-symptomatic stage. Our recent advances in elucidating the pathogenesis of HD have revealed a series of novel potential therapeutic targets, among which immunotherapies are actively pursued in preclinical experiments.

Areas covered

This review focuses on the potential of antibody-based treatments targeting various epitopes (of mutant huntingtin as well as phosphorylated tau) that are currently evaluated in vitro and in animal experiments. The references used in this review were retrieved from the PubMed database, searching for immunotherapies in HD, and clinical trial registries were reviewed for molecules already evaluated in clinical trials.

Expert opinion

Antibody-based therapies have raised considerable interest in a series of neurodegenerative diseases characterized by deposition of aggregated of aberrantly folded proteins, HD included. Intrabodies and nanobodies can interact with mutant huntingtin inside the nervous cells. However, the conflicting results obtained with some of these intrabodies highlight the need for proper choice of epitopes and for developing animal models more closely mimicking human disease. Approval of these strategies will require a considerable financial and logistic effort on behalf of healthcare systems.

KEYWORDS:

• Huntington’s disease
• mutant huntingtin
• intrabodies
• nanobodies
• immunization

Article highlights

• Although the genetic defect that causes Huntington’s disease (HD) is known and identifiable, current HD therapy provides only symptomatic relief.

• Our increasing knowledge on HD pathogenesis has identified a series of therapeutic targets amenable to antibody-based therapies, acting both on the intracellular mutant huntingtin protein (mHTT), as well as in the extracellular space. While intracellular mHTT can be lowered or its toxicity can be reduced with intrabodies or nanobodies, the spread of extracellular mHTT between neighboring neurons can be hindered with monoclonal antibodies.

• Other proteins, such as tau, have been shown to accumulate and aggregate in the brain of patients with HD, which can also be addressed with immunotherapies.

• Although antibody-based approaches show promise in cell lines and animal models of HD, a series of conflicting results obtained in different animal models with the same antibody, as well as several safety issues raised by preclinical trials points toward the need for more detailed research in the area of immunotherapies for HD before they can escalate to clinical trials.

• Nevertheless, a combination therapy (gene therapy along with antibody-based therapies) delivered in the pre-symptomatic stage of HD could prevent disease onset or halt progression in symptomatic patients. Given the rapid progress in research, healthcare systems should be prepared to support financially and logistically these novel therapeutic strategies.

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.