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.

Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)

“…Furthermore, monoclonal antibodies are less costly to produce, easier to attain regulatory approval, and translate into clinical trials than other gene and cell therapy approaches . This strategy has the potential to be used as an adjuvant therapy of pharmacological treatments currently in preclinical and clinical development (i.e. trehalose) or gene therapy that target aggregate formation without addressing the issue of pre‐existing muscle atrophy or fibrosis.…”

Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age‐related muscle wasting

“…Although various gene‐based therapies (such as exon‐skipping, gene transfer, or gene editing) have been developed to restore a functional dystrophin in DMD muscles, the fibrosis induced by TGF‐β1 can severely compromise the efficacy of these therapies by limiting access of the therapeutic vectors to dystrophic muscles . To overcome this limitation, ‘combined therapies’ including both a therapy to correct the genetic defect and an additional one to improve the status of recipient muscle have been proposed recently . The protective effects of Hjv on dystrophic muscles indicate that pretreating dystrophic muscles with a HJV expression vector may maximize the efficacy of gene‐based approaches by reducing the fibrosis, thereby allowing the use of lower and safer vector doses to achieve a therapeutic expression level of dystrophin.…”

Prostaglandin EP2 receptor downstream of Notch signaling inhibits differentiation of human skeletal muscle progenitors in differentiation conditions

“…uchenne muscular dystrophy (DMD) is a devastating muscle disease caused by mutations of the DMD gene, which encodes dystrophin. Currently there is no effective treatment for DMD 1 . Transplantation of muscle progenitors/ precursors is a therapeutic strategy for DMD 2 .…”