Current Gene Therapy

Title:Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

Volume: 12Issue: 3

Author(s):Rebecca J. Fairclough, Kelly J. Perkins and Kay E. Davies

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Keywords:Cardiac, duchenne, dystrophy, fibrosis, inflammation, muscular, pharmacological, utrophin, DMD, mdx

Abstract: DMD is a devastatingly progressive muscle wasting disorder of childhood that significantly shortens life expectancy.Despite efforts to develop an effective therapy that dates back over a century, clinical interventions are still restrictedto management of symptoms rather than a cure. The rationale to develop effective therapies changed in 1986 withthe discovery of the dystrophin gene. Since then extensive research into both the molecular basis and pathophysiology ofDMD has paved the way not only for development of strategies which aim to correct the primary defect, but also towardsthe identification of countless therapeutic targets with the potential to alleviate the downstream pathology. In addition togene and cell-based therapies, which aim to deliver the missing gene and/or protein, an exciting spectrum of pharmacologicalapproaches aimed at modulating therapeutic targets within DMD muscle cells through the use of small drugs arealso being developed. This review presents promising pharmacological approaches aimed at targeting the primary defect,including suppression of nonsense mutations and functional compensation by upregulation of the dystrophin homologue,utrophin. Downstream of the primary membrane fragility, inflammation and fibrosis are reduced by blocking NF-κB,TGF-α and TGF-β, and free radical damage has been targeted using antioxidants and dietary/nutritional supplements.There are new hopes that ACE and PDE5 inhibitors can protect against skeletal as well as cardiac pathology, and modulatingCa2+ influx, NO, BMP, protein degradation and the mitochondrial permeability pore hold further promise in tacklingthe complex pathogenesis of this multifaceted disorder.

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J. Fairclough Rebecca, J. Perkins Kelly and E. Davies Kay, Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy, Current Gene Therapy 2012; 12 (3) .https://dx.doi.org/10.2174/156652312800840595