乌特罗芬
肌营养不良蛋白
杜氏肌营养不良
肌营养不良
遗传增强
免疫原性
医学
腺相关病毒
mdx鼠标
免疫学
生物
免疫系统
内科学
基因
遗传学
载体(分子生物学)
重组DNA
作者
Yafeng Song,Lupe Morales,Alock Malik,Andrew Mead,Christopher Greer,Matthew D. Mitchell,M. Petrov,Leonard T. Su,Margaret E Choi,Shira Rosenblum,Xiangping Lu,D. Jake VanBelzen,Ranjith K Krishnankutty,Frederick J. Balzer,Emanuele Loro,Robert A. French,Kathleen J. Propert,Shangzhen Zhou,Benjamin W Kozyak,Peter P. Nghiem,Tejvir S. Khurana,Joe N. Kornegay,Hansell H. Stedman
出处
期刊:Nature Medicine
[Springer Nature]
日期:2019-10-01
卷期号:25 (10): 1505-1511
被引量:64
标识
DOI:10.1038/s41591-019-0594-0
摘要
The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin1, a rod-like protein2 that protects striated myocytes from contraction-induced injury3,4. Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin5. Importantly, normal thymic expression in DMD patients6 should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (µUtro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that µUtro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-µUtro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, µUtro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of µUtro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed µDystrophin (µDystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization. A gene therapy vector expressing micro-utrophin provides functional replacement of lost dystrophin, and lacks the adverse immunogenicity associated with direct dystrophin therapy, in rodent and canine models of Duchenne muscular dystrophy.
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