How much dystrophin is enough: the physiological consequences of different levels of dystrophin in themdxmouse

Abstract

Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model.

Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy

“…For example, a recent study in skeletal muscle by Godfrey et al suggests that protection against eccentric contraction-induced injury requires homogenous dystrophin expression at the 15% of wild-type level. However, reduction of skeletal muscle histopathology requires much more dystrophin [11]. …”

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

“…2 A and B), a dramatic increase for a pharmacological agent. In fact, this 40% increase in specific force with simvastatin is comparable to that provided by the most effective gene-based therapeutic approaches, including a minidystrophin gene therapy construct containing the neuronal NOS (nNOS) binding region (29) and antisense oligonucleotides (exon skipping), which led to homologous expression of a slightly truncated dystrophin protein throughout mdx TA muscle (30). Therefore, our data demonstrate that, as a nongenetic approach, simvastatin provides a substantial improvement in contractile performance of dystrophic muscle.…”

“…Loss of dystrophin causes widespread effects on muscle signaling and metabolic pathways, leading to cell death and progressive replacement of functional muscle fibers with fibrotic connective tissue. This process results in profound muscle weakness, usually leaving DMD boys wheelchair-bound by their early teenage years and leading to death from the consequences of respiratory and/or cardiac muscle failure by age [20][21][22][23][24][25][26][27][28][29][30]. Current treatments, such as corticosteroids, slow disease progression only marginally (1), whereas gene-based approaches, such as exonskipping, although promising in preclinical studies, will need to overcome many technical and regulatory hurdles, as well becoming affordable, before they are a widely available therapy for DMD patients (2).…”

Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy

“…It has been estimated that even low-level expression of dystrophin (4 to 15%) can partially ameliorate cardiomyopathy (24) and protect against eccentric contraction-induced injury in skeletal muscle (25). The efficiency of restoration of dystrophin expression observed after delivery of Myoediting components to mdx mice by AAV is therefore within the range expected to provide therapeutic benefit.…”