肌营养不良蛋白
杜氏肌营养不良
医学
心肌病
胞苷脱氨酶
外显子
骨骼肌
肌营养不良
外显子跳跃
mdx鼠标
心力衰竭
内科学
病理
生物
遗传学
免疫学
基因
选择性拼接
抗体
作者
Jia Li,Kaiying Wang,Yuchen Zhang,Tuan Qi,Jing Yuan,Lei Zhang,Qian Han,Jinxi Wang,Huang‐Tian Yang,Yi Dai,Yan Song,Xing Chang
出处
期刊:Circulation
[Ovid Technologies (Wolters Kluwer)]
日期:2021-11-30
卷期号:144 (22): 1760-1776
被引量:25
标识
DOI:10.1161/circulationaha.121.054628
摘要
Loss of dystrophin protein causes Duchenne muscular dystrophy (DMD), characterized by progressive degeneration of cardiac and skeletal muscles, and mortality in adolescence or young adulthood. Although cardiac failure has risen as the leading cause of mortality in patients with DMD, effective therapeutic interventions remain underdeveloped, in part, because of the lack of a suitable preclinical model.We analyzed a novel murine model of DMD created by introducing a 4-bp deletion into exon 4, one of the exons encoding the actin-binding domain 1 of dystrophin (referred to as DmdE4* mice). Echocardiography, microcomputed tomography, muscle force measurement, and histological analysis were performed to determine cardiac and skeletal muscle defects in these mice. Using this model, we examined the feasibility of using a cytidine base editor to install exon skipping and rescue dystrophic cardiomyopathy in vivo. AAV9-based CRISPR/Cas9-AID (eTAM) together with AAV9-sgRNA was injected into neonatal DmdE4* mice, which were analyzed 2 or 12 months after treatment to evaluate the extent of exon skipping, dystrophin restoration, and phenotypic improvements of cardiac and skeletal muscles.DmdE4* mice recapitulated many aspects of human DMD, including shortened life span (by ≈50%), progressive cardiomyopathy, kyphosis, profound loss of muscle strength, and myocyte degeneration. A single-dose administration of AAV9-eTAM instituted >50% targeted exon skipping in the Dmd transcripts and restored up to 90% dystrophin in the heart. As a result, early ventricular remodeling was prevented and cardiac and skeletal muscle functions were improved, leading to an increased life span of the DmdE4* mice. Despite gradual decline of AAV vector and base editor expression, dystrophin restoration and pathophysiological rescue of muscular dystrophy were long lasted for at least 1 year.Our study demonstrates the feasibility and efficacy to institute exon skipping through an enhanced TAM (eTAM) for therapeutic application(s).
科研通智能强力驱动
Strongly Powered by AbleSci AI