DMD – ANIMAL MODELS & PRECLINICAL TREATMENT: P.218 A novel in-frame deletion of exons 52-55 DMD mouse model preserves muscle function

Abstract

Duchenne muscular dystrophy (DMD) is a life-limiting X-linked recessive neuromuscular disorder, affecting approximately 1 in 5000 boys. DMD is caused by mutations in the DMD gene encoding dystrophin, a member of the dystrophin glycoprotein complex (DGC) which protects muscle fibers from contraction-induced injury. DMD is marked by absent dystrophin expression, often caused by frame-shift mutations. Among the dystrophinopathies, Becker muscular dystrophy (BMD) is a milder disorder typically caused by in-frame DMD mutations, resulting in shortened yet partly functional dystrophin formation. Both the clinical presentation and prognosis of BMD patients are improved compared to those with DMD. Therefore, conversion of out-of-frame Dmd mutations into in-frame mutations by means of exon-skipping, is appealing as a potential therapeutic option. This study first created a DMD mouse model mirroring a patient deletion of exons 52-54 (Dmd Δ52-54). Such a mutation may be amenable to exon skipping to create a deletion of exons 52-55. We then generated a mouse model of the in-frame deletion mutation Dmd Δ52-55, recapitulating the result of exon skipping in our DMD mouse. To date, Dmd Δ52-55 is the first BMD mouse model generated. Both mouse models were subsequently subjected to histopathological and functional analysis. Dmd Δ52-54 mice lacked dystrophin expression, exhibited a muscular dystrophy phenotype, and had compromised motor and cardiac function. In contrast, the Dmd Δ52-55 mice showed expression of a truncated dystrophin which localized correctly to the sarcolemma and recruited DGC components, which were absent in Dmd Δ52-54. Furthermore, this shortened dystrophin maintained muscle integrity and protected from exercise-induced damage similar to wildtype dystrophin. Thus, our results indicate that therapies targeting the conversion of DMD-causing frameshift mutations into BMD-like in-frame mutations may restore shortened dystrophin expression and improve dystrophic phenotype.