Gall-Duncan Terence, Ko Sangyoon Y, Quick Isabelle K, Khan Mahreen, Feng Kristie, Kelley Chase P, Coleman Annabelle, Touze Alexiane, Tang Shuqian, Mehkary Mustafa, Yokoi Katsuyuki, Herrington Casey R, You Justin, Lambie Scott C, Prasolava Tanya K, Panigrahi Gagan B, Park Jeehye, Nakatani Kazuhiko, Byrne Lauren M, Wang Peixiang, Schneekloth John S, Nakamori Masayuki, Frankland Paul W, Wang Eric T, Pearson Christopher E
Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, M5G 0A4, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1X8, Canada.
bioRxiv. 2025 Apr 28:2025.04.25.650652. doi: 10.1101/2025.04.25.650652.
Huntington disease (HD) is caused by inherited CAG expansions, which continue expanding somatically in affected brain regions to hasten disease onset and progression. Therapeutically diminishing somatic expansions is expected to be clinically beneficial. However, it is not known if interventionally modifying somatic CAG expansions will actually modify clinically-relevant phenotypes, what the therapeutic window is, or which phenotypes will be altered. Here we show that acute (6-week) delivery of the contraction-inducing slipped-CAG DNA ligand naphthyridine-azaquinolone to young (4-week-old) (CAG)120 HD mice, induces contractions throughout brain regions, improves motor function (locomotion, balance, coordination, muscle strength), molecular disease landmarks (mHTT aggregates, nuclear envelope morphology, nucleocytoplasmic mRNA transport, transcriptomic dysregulation, neuroinflammation), and neurodegeneration. Beneficial effects of modifying somatic expansions were also evident in muscle and blood, where blood CAG instability correlated with brain instability and blood serum had diminished levels of neurofilament light (a biomarker for neurodegeneration) - offering blood as having elements of target engagement and efficacy. These data support that targeting somatic repeat expansions can be a rapid disease-modifying therapeutic avenue for HD and possibly other repeat expansion diseases. Our findings support an etiologic pathway interconnected to somatic CAG expansions that will inform the design of clinical trials expecting clinical benefit by modulating somatic expansions.
亨廷顿舞蹈症（HD）由遗传性CAG重复序列扩增引起，这些重复序列在受影响的脑区会进行体细胞扩增，从而加速疾病的发作和进展。从治疗角度减少体细胞扩增有望带来临床益处。然而，目前尚不清楚通过干预改变体细胞CAG扩增是否真的会改变临床相关表型、治疗窗口期是多久，或者哪些表型会发生改变。在此，我们表明，向年轻（4周龄）的（CAG）120 HD小鼠急性（6周）递送诱导收缩的滑链CAG DNA配体萘啶氮杂喹啉，可诱导全脑各区域的收缩，改善运动功能（运动、平衡、协调、肌肉力量）、分子疾病标志物（突变型亨廷顿蛋白聚集体、核膜形态、核质mRNA转运、转录组失调、神经炎症）以及神经退行性变。改变体细胞扩增的有益效果在肌肉和血液中也很明显，血液中CAG的不稳定性与大脑的不稳定性相关，且血清中神经丝轻链（一种神经退行性变的生物标志物）水平降低——这表明血液具有靶点参与和疗效的要素。这些数据支持，靶向体细胞重复序列扩增可能是HD以及其他可能的重复序列扩增疾病的一种快速疾病修饰治疗途径。我们的研究结果支持了一条与体细胞CAG扩增相互关联的病因学途径，这将为期望通过调节体细胞扩增获得临床益处的临床试验设计提供信息。
