Correction of a splicing defect in a mouse model of congenital muscular dystrophy type 1A using a homology-directed-repair-independent mechanism
Nature Medicine 23, 984 (2017).
doi:10.1038/nm.4367
Authors: Dwi U Kemaladewi, Eleonora Maino, Elzbieta Hyatt, Huayun Hou, Maylynn Ding, Kara M Place, Xinyi Zhu, Prabhpreet Bassi, Zahra Baghestani, Amit G Deshwar, Daniele Merico, Hui Y Xiong, Brendan J Frey, Michael D Wilson, Evgueni A Ivakine & Ronald D Cohn
Splice-site defects account for about 10% of pathogenic mutations that cause Mendelian diseases. Prevalence is higher in neuromuscular disorders (NMDs), owing to the unusually large size and multi-exonic nature of genes encoding muscle structural proteins. Therapeutic genome editing to correct disease-causing splice-site mutations has been accomplished only through the homology-directed repair pathway, which is extremely inefficient in postmitotic tissues such as skeletal muscle. Here we describe a strategy using nonhomologous end-joining (NHEJ) to correct a pathogenic splice-site mutation. As a proof of principle, we focus on congenital muscular dystrophy type 1A (MDC1A), which is characterized by severe muscle wasting and paralysis. Specifically, we correct a splice-site mutation that causes the exclusion of exon 2 from Lama2 mRNA and the truncation of Lama2 protein in the dy2J/dy2J mouse model of MDC1A. Through systemic delivery of adeno-associated virus (AAV) carrying clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 genome-editing components, we simultaneously excise an intronic region containing the mutation and create a func...
Source: Nature Medicine - Category: General Medicine Authors: Dwi U Kemaladewi Eleonora Maino Elzbieta Hyatt Huayun Hou Maylynn Ding Kara M Place Xinyi Zhu Prabhpreet Bassi Zahra Baghestani Amit G Deshwar Daniele Merico Hui Y Xiong Brendan J Frey Michael D Wilson Evgueni A Ivakine Ronald D Cohn Tags: Letter Source Type: research
More News: Adenoviruses | Brain | Gastroschisis Repair | General Medicine | Genetics | Men | Muscular Dystrophy | Neurology | Reflex Sympathetic Dystrophy