Current and Possible Future Therapeutic Options for Huntington’s Disease

Abstract

Huntington’s disease (HD) is an autosomal neurodegenerative disease that is characterized by an excessive number of CAG trinucleotide repeats within the huntingtin gene ( HTT). HD patients can present with a variety of symptoms including chorea, behavioural and psychiatric abnormalities and cognitive decline. Each patient has a unique combination of symptoms, and although these can be managed using a range of medications and non-drug treatments there is currently no cure for the disease. Current therapies prescribed for HD can be categorized by the symptom they treat. These categories include chorea medication, antipsychotic medication, antidepressants, mood stabilizing medication as well as non-drug therapies. Fortunately, there are also many new HD therapeutics currently undergoing clinical trials that target the disease at its origin; lowering the levels of mutant huntingtin protein (mHTT). Currently, much attention is being directed to antisense oligonucleotide (ASO) therapies, which bind to pre-RNA or mRNA and can alter protein expression via RNA degradation, blocking translation or splice modulation. Other potential therapies in clinical development include RNA interference (RNAi) therapies, RNA targeting small molecule therapies, stem cell therapies, antibody therapies, non-RNA targeting small molecule therapies and neuroinflammation targeted therapies. Potential therapies in pre-clinical development include Zinc-Finger Protein (ZFP) therapies, transcription activator-like effector nuclease (TALEN) therapies and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas) therapies. This comprehensive review aims to discuss the efficacy of current HD treatments and explore the clinical trial progress of emerging potential HD therapeutics.

Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy

“…A randomized open-label extension trial (NCT 03342053) continued the assessment of adverse effects. It concluded in 2019, but the results have not yet been published [ 153 ]. Another randomized, double-blinded, phase 3 clinical trial aimed at evaluating the efficiency of tominersen (GENERATION HD1 (NCT03761849).…”

“…Another randomized, double-blinded, phase 3 clinical trial aimed at evaluating the efficiency of tominersen (GENERATION HD1 (NCT03761849). Although it was expected to be finished in 2022, it was discontinued due to concerns regarding the benefit-to-risk ratio raised by the review of data by an independent data monitoring Committee, as was the open-label extension phase, GEN-EXTEND, NCT03842969 [ 153 , 154 ]. Because tominersen is non-allele-selective, it reduces the expression of both normal and mutant huntingtin, a situation in which long-term use in symptom-free carriers of the genetic defect may raise safety concerns.…”

“…Although preliminary data from the PRECISION-HD2 study suggested a dose-dependent reduction in mHtt, in 2021, both trials were stopped by the sponsor due to a lack of significant change in mHtt levels, as were the 2 open-label extension studies (NCT04617847 and NCT04617860) [ 160 ]. Another allele-specific ASO, targeting an undisclosed SNP (SNP3), showed promising results in preclinical studies [ 161 ], leading the manufacturing company to submit an application for a clinical trial in 2020 [ 153 ].…”

“…Mutant Htt impairs the non-homologous end-joining (NHEJ)-mediated DNA DSB repair mechanism in neurons [ 166 , 167 ], suggesting that alterations of the DNA repair mechanism could have important contributions to the prominent cell loss. Targeting the mutS homolog 3 (MSH3) with TTX-3360 with ASOs, developed by Triplet Therapeutics, proved safe and efficient in mouse models of HD [ 153 ].…”

Current Knowledge and Future Directions in Huntington’s Disease

“…Psychotherapy aims to address behavioral problems, contributes to the development of coping strategies, and helps to establish effective communication between family members(71). Speech therapy is also performed to manage speech alterations and eating/swallowing difficulties and to instruct patients in the use of communication devices(72) (60). , and the identification of polymorphisms associated with disease features, a lack remains regarding the effect of the genetic variations on other relevant aspects of…”