The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, United States of America.
PLoS One. 2022 Aug 29;17(8):e0273710. doi: 10.1371/journal.pone.0273710. eCollection 2022.
Huntington's Disease (HD) is a dominantly inherited neurodegenerative disease for which the major causes of mortality are neurodegeneration-associated aspiration pneumonia followed by cardiac failure. mTORC1 pathway perturbations are present in HD models and human tissues. Amelioration of mTORC1 deficits by genetic modulation improves disease phenotypes in HD models, is not a viable therapeutic strategy. Here, we assessed a novel small molecule mTORC1 pathway activator, NV-5297, for its improvement of the disease phenotypes in the N171-82Q HD mouse model. Oral dosing of NV-5297 over 6 weeks activated mTORC1, increased striatal volume, improved motor learning and heart contractility. Further, the heart contractility, heart fibrosis, and survival were improved in response to the cardiac stressor isoprenaline when compared to vehicle-treated mice. Cummulatively, these data support mTORC1 activation as a therapeutic target in HD and consolidates NV-5297 as a promising drug candidate for treating central and peripheral HD phenotypes and, more generally, mTORC1-deficit related diseases.
亨廷顿病（HD）是一种显性遗传的神经退行性疾病，其主要死亡原因是与神经退行性相关的吸入性肺炎，其次是心力衰竭。mTORC1 通路异常在 HD 模型和人类组织中都存在。通过遗传调节改善 mTORC1 缺陷可改善 HD 模型的疾病表型，但不是一种可行的治疗策略。在这里，我们评估了一种新型小分子 mTORC1 通路激活剂 NV-5297，以评估其对 N171-82Q HD 小鼠模型疾病表型的改善作用。NV-5297 口服给药 6 周可激活 mTORC1，增加纹状体体积，改善运动学习和心脏收缩力。与接受载体治疗的小鼠相比，NV-5297 还可改善异丙肾上腺素引起的心脏收缩力、心脏纤维化和存活率。综上所述，这些数据支持 mTORC1 激活作为 HD 的治疗靶点，并巩固了 NV-5297 作为治疗中枢和外周 HD 表型以及更普遍的 mTORC1 缺陷相关疾病的有前途的药物候选物。
