Low dystrophin levels in heart can delay heart failure in mdx mice

Abstract

Duchenne muscular dystrophy is caused by mutations that prevent synthesis of functional dystrophin. All patients develop dilated cardiomyopathy. Promising therapeutic approaches are underway that successfully restore dystrophin expression in skeletal muscle. However, their efficiency in the heart is limited. Improved quality and function of only skeletal muscle potentially accelerate the development of cardiomyopathy. Our study aimed to elucidate which dystrophin levels in the heart are required to prevent or delay cardiomyopathy in mice. Heart function and pathology assessed with magnetic resonance imaging and histopathological analysis were compared between 2, 6 and 10-month-old female mdx-Xist(Δhs) mice, expressing low dystrophin levels (3-15%) in a mosaic manner based on skewed X-inactivation, dystrophin-negative mdx mice, and wild type mice of corresponding genetic backgrounds and gender. With age mdx mice developed dilated cardiomyopathy and hypertrophy, whereas the onset of heart pathology was delayed and function improved in mdx-Xist(Δhs) mice. The ejection fraction, the most severely affected parameter for both ventricles, correlated to dystrophin expression and the percentage of fibrosis. Fibrosis was partly reduced from 9.8% in mdx to 5.4% in 10 month old mdx-Xist(Δhs) mice. These data suggest that mosaic expression of 4-15% dystrophin in the heart is sufficient to delay the onset and ameliorate cardiomyopathy in mice.

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

“…A study in genetically modified mice suggests that expression in 3 to 5% of cardiomyocytes at the wild-type level (in every dystrophin positive cell) may delay the onset of heart disease [21]. In a different study, Wu et al found that 5% dystrophin positive cells in the heart of adult mdx mice did not improve cardiac histology/baseline function although mice tolerated dobutamine stress better [22].…”

In vivo gene editing in dystrophic mouse muscle and muscle stem cells

“…We show that programmable CRISPR complexes can be delivered locally and systemically to terminally differentiated skeletal muscle fibers and cardiomyocytes, as well as muscle satellite cells, in neonatal and adult mice, where they mediate targeted gene modification, restore DYSTROPHIN expression and partially recover functional deficiencies of dystrophic muscle. As prior studies in mice and humans indicate that DYSTROPHIN levels as low as 3–15% of wild-type are sufficient to ameliorate pathologic symptoms in the heart and skeletal muscle (23–26), and levels as low as 30% can suppress the dystrophic phenotype altogether (27) and protect dystrophic muscle from damage (28), the restoration of DYSTROPHIN achieved here by one-time administration of AAV- Dmd CRISPR clearly encourages further evaluation and optimization of this system as a new candidate modality for the treatment of DMD (see Supplementary Text). …”

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.…”