Huntington’s disease (HD) is a monogenic neurodegenerative disorder that presents with progressive motor, behavior, and cognitive symptoms leading to early disability and mortality. HD is caused by an expanded CAG repeats in exon 1 of the huntingtin (HTT) gene. The corresponding genetic test allows a clinical, definite diagnosis in life and the identification of a fully penetrant mutation carrier in a premanifest stage. In addition to the development of symptomatic treatments that attempt to address unmet care needs such as apathy, irritability, and cognition, novel therapies that target pathways specific to HD biology are being developed with the intent of slowing disease progression. Among these approaches, HTT protein lowering therapies hold great promise. There are currently active programs using antisense oligonucleotides (ASOs), RNA interference, small-molecule splicing modulators, and zinc-finger protein transcription factor. Except for ASOs and RNA interference approaches, the remaining therapeutic strategies are at a preclinical stage of development. While the current therapeutic landscape in HD may bring an unparalleled change in the lives of people with HD and their families with the first-ever disease-modifying therapy, the evaluation of these therapies requires novel tools that enable a more efficient and expedited discovery and evaluative process. Examples are biomarkers targeting the HTT protein to measure target engagement or disease progression and rating scales more sensitive to the earliest clinical changes. These tools will be instrumental in the next phase of disease-modifying clinical trials in HD likely to target the phenoconversion period of the disease, including the prodromal HD stage.

亨廷顿病 (HD) 是一种单基因神经退行性疾病，表现为进行性运动、行为和认知症状，导致早期残疾和死亡。 HD 是由亨廷顿蛋白 (HTT) 基因外显子 1 中的 CAG 重复序列扩展引起的。相应的基因测试可以在生活中进行临床明确的诊断，并在显性前期识别出完全渗透性突变携带者。除了开发试图解决冷漠、易怒和认知等未满足的护理需求的对症治疗外，还开发了针对 HD 生物学特有途径的新疗法，旨在减缓疾病进展。在这些方法中，HTT 蛋白降低疗法前景广阔。目前有一些活跃的项目使用反义寡核苷酸（ASO）、RNA干扰、小分子剪接调节剂和锌指蛋白转录因子。除 ASO 和 RNA 干扰方法外，其余治疗策略均处于临床前开发阶段。虽然当前 HD 的治疗前景可能会通过首个疾病缓解疗法给 HD 患者及其家人的生活带来前所未有的变化，但对这些疗法的评估需要新的工具，以实现更高效、更快速的发现和评估。过程。例如，针对 HTT 蛋白的生物标志物可测量靶标参与度或疾病进展，以及对最早的临床变化更敏感的评级量表。这些工具将有助于下一阶段的 HD 疾病修饰临床试验，可能针对疾病的表型转变期，包括 HD 前驱阶段。