Huntingtin silencing delays onset and slows progression of Huntington’s disease: a biomarker study

• DOI: 10.1093/brain/awab190
• Publication Date: 2021-05-26T19:21:09Z
• Authors: Hongshuai Liu; Chuangchuang Zhang; Jiadi Xu; Jing Jin; Liam Cheng; Xinyuan Miao; Qian Wu; Zhiliang Wei; Peiying Liu; Hanzhang Lu; Peter C M van Zijl; Christopher A Ross; Jun Hua; Wenzhen Duan
• Keywords: Male; 0301 basic medicine; Huntingtin Protein; Mice, Transgenic; Magnetic Resonance Imaging; 3. Good health; Mice; 03 medical and health sciences; Huntington Disease; Disease Progression; Animals; Female; Gene Silencing; Biomarkers

Abstract Huntington’s disease is a dominantly inherited, fatal neurodegenerative disorder caused by 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 are being actively investigated as disease-modifying therapies. Most approaches currently targeted at manifest stage, where clinical outcomes used evaluate effectiveness therapy. However, almost 50% striatal volume has been lost time onset manifest, it would be preferable begin therapy premanifest period. An unmet challenge how therapeutic efficacy before presence symptoms outcome measures. To address this, we aim develop non-invasive sensitive biomarkers that provide insight into stage disease. In this study, mapped temporal trajectories arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI heterozygous zQ175 mice, full-length mHTT expressing slowly progressing model with period human Significantly elevated CBVa was evident mice prior motor deficits atrophy, recapitulating altered CRISPR/Cas9-mediated non-allele-specific silencing neurons restored delayed slowed progression phenotype brain pathology. This study—for first time—shows functional measure detects demonstrates long-term benefits non-allele-selective treatment introduced