Advances in Clinical Therapies for Huntington's Disease and the Promise of Multi‐Targeted/Functional Drugs Based on Clinicaltrials.gov

Abstract

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a triad of motor, cognitive, and psychiatric problems. Caused by CAG repeat expansion in the huntingtin gene (HTT), the disease involves a complex network of pathogenic mechanisms, including synaptic dysfunction, impaired autophagy, neuroinflammation, oxidative damage, mitochondrial dysfunction, and extrasynaptic excitotoxicity. Although current therapies targeting the pathogenesis of HD primarily aim to reduce mHTT levels by targeting HTT DNA, RNA, or proteins, these treatments only ameliorate downstream pathogenic effects. While gene therapies, such as antisense oligonucleotides, small interfering RNAs and gene editing, have emerged in the field of HD treatment, their safety and efficacy are still under debate. Therefore, pharmacological therapy remains the most promising breakthrough, especially multi‐target/functional drugs, which have diverse pharmacological effects. This review summarizes the latest progress in HD drug development based on clinicaltrials.gov search results (Search strategy: key word “Huntington's disease” in HD clinical investigational drugs registered as of December 31, 2023), and highlights the key role of multi‐target/functional drugs in HD treatment strategies.