Recent advances in Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD), an allelic X-linked progressive muscle-wasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene- and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene- and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.

Keywords: animal models; dystrophy; exon skipping; gene therapy; pharmacological; utrophin.

Figure 1

Current genetic and pharmacological targets of dystrophic pathology. Notes: Receptor or structural protein components at the skeletal muscle sarcolemma targeted for therapeutic purposes are represented in dark grey. Components of signaling pathways specifically targeted for intentional downregulation are represented in yellow boxes, with two key regulators of dystrophic pathology NFκB, and TNFα, highlighted in light blue. Associated white boxes contain the therapeutic compound(s) used to modulate either a positive (+) or negative (−) effect on a particular protein/receptor. Arrow-headed lines represent a simplified version of the signaling pathways involved in inflammatory, fibrotic, and hypertrophic responses, symbolizing only regulatory proteins that are covered in the text. The background-shaded section represents cellular process affected by calcium influx, with the red line representing the feedback mechanism with ROS, TNFα, and NFκB. The interactions delineated between and within signaling pathways are not an exhaustive representation and pharmacological compounds that act in a nonspecific or undetermined mode of action have been excluded. Red dots, representative mRNA sequence leading to translation stop codon; black dots, promoter elements; red squares, representative of gene modification by repair or insertion/deletion by zinc finger or meganucleases. Abbreviations: PA, polyaxamer 188; TGF-β, transforming growth factor beta; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B (PKB); IKK, IκB kinase; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; BMP, bone morphogenic protein; AngII, angiotensin II; RI/RII, receptor I/II; AT, angiotensin; ACE, angiotensin-converting enzyme; NBD, NEMO binding domain; IGF-1, insulin growth factor 1; LAM-III, laminin-111 protein; VPA, valproic acid; ALK-4, activin receptor-like kinase; ActRII, activin receptor type II; BCL/ABL, breakpoint cluster region/Abelson murine leukemia viral oncogene homologue 1; Akt, acutely transforming retrovirus AKT8 in rodent T-cell lymphoma; [Ca²⁺]i, intracellular calcium; L-Arg, L-arginine; NO, nitric oxide; nNOS, neural nitric oxide synthase; cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GC, guanylate cyclase; BGP-15, O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime; PDE5, cGMP-specific phosphodiesterase type 5; TNF-α, tumour necrosis factor alpha; CsA, cyclosporine A; ROS, reactive oxygen species; MPTP, mitochondrial permeability transition pore; cycD, cyclophilin D; HSP72, heat shock protein 72; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; SG, sarcoglycans; Src, sarcospan; syn, sytrophin; db, dystrobrevin; RDO, RNA/DNA oligonucleotide; AON, antisense oligonucleotide; 2′OMePS, 2′-O-methyl oligoribonucleotide; PMO, phosphorodiamidate morpholino oligomer; AICAR, 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide; UTRN/DMD/MSTN, utrophin/DMD/myostatin gene; DAPC, dystrophin-associated protein complex; LAM, laminin; Utr, utrophin minigene construct; cDNA, complementary DNA.