Combined Therapies for Duchenne Muscular Dystrophy to Optimize Treatment Efficacy

Abstract

Duchene Muscular Dystrophy (DMD) is the most frequent muscular dystrophy and one of the most severe due to the absence of the dystrophin protein. Typical pathological features include muscle weakness, muscle wasting, degeneration, and inflammation. At advanced stages DMD muscles present exacerbated extracellular matrix and fat accumulation. Recent progress in therapeutic approaches has allowed new strategies to be investigated, including pharmacological, gene-based and cell-based therapies. Gene and cell-based therapies are still limited by poor targeting and low efficiency in fibrotic dystrophic muscle, therefore it is increasingly evident that future treatments will have to include "combined therapies" to reach maximal efficiency. The scope of this mini-review is to provide an overview of the current literature on such combined therapies for DMD. By "combined therapies" we mean those that include both a therapy to correct the genetic defect and an additional one to address one of the secondary pathological features of the disease. In this mini-review, we will not provide a comprehensive view of the literature on therapies for DMD, since many such reviews already exist, but we will focus on the characteristics, efficiency, and potential of such combined therapeutic strategies that have been described so far for DMD.

Keywords: Duchenne muscular dystrophy; atrophy; cell therapy; dystrophin; fibrosis; gene therapy; inflammation; muscle.

Figure 1

(A) Muscular dystrophies fibers, including loss of mass, weakness, fat, and extracellular matrix accumulation. Gene and cell based therapies will have to overcome the progressive degeneration of muscle fibers. When these histological changes become prominent, combined strategies are needed. (B) Muscle pre- or co-treatment may target inflammation, atrophy, membrane fragility, muscle weakness, and/or atrophy to pre-condition the tissue to increase efficiency of gene and cell therapy.