Hunting in silencing delays onset and slows progression of Huntington's disease: a biomarker study
Hunting in silencing delays onset and slows progression of Huntington's disease: a biomarker study
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DOI：
10.1093/brain/awab190
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发表时间：
2021-10-20
期刊：
影响因子：
14.5
通讯作者：
Duan, Wenzhen
中科院分区：
文献类型：
--
作者：
Liu, Hongshuai;Zhang, Chuangchuang;Duan, Wenzhen
亨廷顿病是一种显性遗传的致命性神经退行性疾病，由编码病理性突变HTT蛋白（mHTT）的亨廷顿（HTT）基因中的CAG扩增引起。由于其功能获得性机制和单基因病因，降低HTT的策略正被积极研究作为疾病修饰疗法。大多数方法目前针对的是明显阶段，其中临床结果用于评估治疗的有效性。然而，由于几乎50%的纹状体体积在临床表现出现时已经丧失，因此最好在表现前期开始治疗。为了解决这个问题，我们的目标是开发非侵入性敏感的生物标志物，提供洞察亨廷顿病的前期表现阶段的治疗效果。在这项研究中，我们使用基于流入的血管空间占用（iVASO）MRI绘制了杂合zQ 175小鼠的小动脉脑血容量（CBVa）的时间轨迹，zQ 175小鼠是一种全长mHTT表达和缓慢进展的模型，具有与人类亨廷顿病相同的表现前期。在运动缺陷和纹状体萎缩之前，在人类表现前亨廷顿病中重现改变的CBVa。纹状体神经元中CRISPR/Cas9介导的非等位基因特异性HTT沉默恢复了预先表现的zQ 175小鼠中改变的CBVa，延迟了纹状体萎缩的发作，这项研究首次表明，一种非侵入性的功能性磁共振成像测量方法可以在表现前阶段检测治疗效果，并证明了非等位基因的长期益处，选择性HTT沉默治疗引入了预显亨廷顿病。
Huntington's disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, coding for pathological mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic aetiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, where clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period.An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we aim to develop non-invasive sensitive biomarkers that provide insight into therapeutic efficacy in the premanifest stage of Huntington's disease. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI in the heterozygous zQ175 mice, a full-length mHTT expressing and slowly progressing model with a premanifest period as in human Huntington's disease.Significantly elevated CBVa was evident in premanifest zQ175 mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest Huntington's disease. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology.This study-for the first time-shows that a non-invasive functional MRI measure detects therapeutic efficacy in the premanifest stage and demonstrates long-term benefits of a non-allele-selective HTT silencing treatment introduced in the premanifest Huntington's disease.