Micro-utrophin Improves Cardiac and Skeletal Muscle Function of Severely Affected D2/mdx Mice

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked muscle-wasting disease caused by mutations in the dystrophin gene. DMD boys are wheelchair-bound around 12 years and generally survive into their twenties. There is currently no effective treatment except palliative care, although personalized treatments such as exon skipping, stop codon read-through, and viral-based gene therapies are making progress. Patients present with skeletal muscle pathology, but most also show cardiomyopathy by the age of 10. A systemic therapeutic approach is needed that treats the heart and skeletal muscle defects in all patients. The dystrophin-related protein utrophin has been shown to compensate for the lack of dystrophin in the mildly affected BL10/mdx mouse. The purpose of this investigation was to demonstrate that AAV9-mediated micro-utrophin transgene delivery can not only functionally replace dystrophin in the heart, but also attenuate the skeletal muscle phenotype in severely affected D2/mdx mice. The data presented here show that utrophin can indeed alleviate the pathology in skeletal and cardiac muscle in D2/mdx mice. These results endorse the view that utrophin modulation has the potential to increase the quality life of all DMD patients whatever their mutation.

Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models

“…Serum creatine kinase (CK), a biomarker that reflects sarcolemmal permeability, was statistically indistinguishable from that of wildtype mice (Fig. 1e), suggestin g that codon optimization and recombinant protein overexpression early in development improved the response relative to administration of alternative transgenes via tail vein injection after the onset of myopathology 10,22,24 .…”

PMO-based let-7c site blocking oligonucleotide (SBO) mediated utrophin upregulation in mdx mice, a therapeutic approach for Duchenne muscular dystrophy (DMD)

“…Here, we tested the efficacy of five different let-7c PMO-based SBOs for utrophin upregulation in vitro and studied the most efficient PMO (S56 PMO) in mdx mice to demonstrate improvement in dystrophic pathophysiology. AAV mediated μ-utrophin delivery [52][53][54] and artificial transcriptional factor mediated transcriptional upregulation of full length utrophin 24,55 respectively, have been shown to improve dystrophic pathophysiology in the mdx model. Notably, μ-utrophin expression does not induce significant immune responses compared to μ-dystrophin expression in deletional animal models of DMD 54 .…”

Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy

“…All these therapeutic methods must face the problem of immune rejection of either the restored or delivered dystrophin, as well as other foreign proteins, including viral capsids. Alternative strategies that bypass the problem of potential immune rejection consist of (1) genetically corrected autologous pluripotent stem cells differentiated ex vivo into dedicated muscle stem cells [58,59] and (2) therapies grounded on either pharmacological induction of the UTRN gene [57] or delivery of vectors encoding micro-and miniutrophins [40,60]. Importantly, the Davies and Chamberlain groups revealed the therapeutic potential of full-length [61] and truncated utrophins in the muscles of dystrophic mice [62,63].…”