Emerging therapies in Huntington’s disease

ABSTRACT

Introduction: Huntington’s disease (HD) is an inherited neurodegenerative condition for which there are no disease-modifying treatments. The availability of early genetic diagnosis makes HD an ideal candidate for early intervention. Growing understanding of pathogenesis has led to the identification of new therapeutic targets for which some compounds are now in clinical trials.

Areas covered: A detailed review of medical databases and clinical trial registries was performed. Recent clinical trials aimed to establish disease-modification were included. Focus was assigned to RNA and DNA-based therapies aimed at lowering mutant huntingtin (mHTT) including antisense oligonucleotides (ASOs), RNA interference (RNAi), zinc finger proteins (ZFPs) and the CRISPR-Cas9 system. Modulation of mHTT and immunotherapies is also covered.

Expert opinion: Targeting HD pathogenesis at its most proximal level is under intense investigation. ASOs are the only HTT-lowering strategy in clinical trials of manifest HD. Safety and efficacy of an allele specific vs. allele non-specific approach has yet to be established. Success will extend to premanifest carriers for which development of clinical and imaging biomarkers will be necessary. Scientific and technological advancement will bolster new methods of treatment delivery. Cumulative experience, collaborative research, and platforms such as ENROLL-HD will facilitate efficient and effective clinical trials.

KEYWORDS:

• Anti-sense oligonucleotides
• deep brain stimulation
• disease-modifying therapy
• CRISPR-Cas9
• gene therapy
• Huntington’s disease
• Huntingtin
• immunotherapy
• RNA interference
• stem cells

Article highlights

• Huntington’s disease (HD) is an inherited neurodegenerative condition for which there are no disease-modifying treatments. The availability of early genetic diagnosis makes HD an ideal candidate for early intervention in order to slow or halt progression.

• Emerging therapeutic approaches aimed at disease-modification include huntingtin-lowering strategies, huntingtin modulation, immunotherapy to reduce neuroinflammation, synaptic modulation and stem cell transplantation.

• Huntingtin-lowering strategies have garnered particular interest as they address the most proximal level of pathogenesis. Of these, only anti-sense oligonucleotides have reached clinical trials. The IONIS-HTT_Rx (RG6042) allele non-specific compound is now being tested in phase III clinical trial to determine safety and efficacy. RNA interference, zinc finger motif proteins, and the CRISPR-Cas9 system are other potential huntingtin-lowering therapies still in preclinical studies.

• The safety of allele specific vs. allele non-specific therapies has yet to be established. There is a potential risk of harmful effects when both wild-type and mutant huntingtin are reduced.

• Several other disease-modifying clinical trials have delivered negative results. Immunotherapies still hold promise and results are expected from the SIGNAL trial, investigating a monoclonal antibody (mAb67-2) against semaphorin 4AD, a transmembrane signaling protein that modulates pathways of neuroinflammation.

• International patient registries such as ENROLL-HD will help collect standardized data to map natural history of the disease and provide valuable information for the design of future clinical trials.

• This box summarizes the key points contained in the article.

Declaration of interest

The author has 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.