Systemic Antisense Therapeutics for Dystrophin and Myostatin Exon Splice Modulation Improve Muscle Pathology of Adult mdx Mice.

Ngoc Lu-Nguyen,George Dickson,Gunnar Hanson,Fred Schnell,Linda Popplewell,Alberto Malerba

doi:10.1016/j.omtn.2016.11.009

Abstract

Antisense-mediated exon skipping is a promising approach for the treatment of Duchenne muscular dystrophy (DMD), a rare life-threatening genetic disease due to dystrophin deficiency. Such an approach can restore the disrupted reading frame of dystrophin pre-mRNA, generating a truncated form of the protein. Alternatively, antisense therapy can be used to induce destructive exon skipping of myostatin pre-mRNA, knocking down myostatin expression to enhance muscle strength and reduce fibrosis. We have reported previously that intramuscular or intraperitoneal antisense administration inducing dual exon skipping of dystrophin and myostatin pre-mRNAs was beneficial in mdx mice, a mouse model of DMD, although therapeutic effects were muscle type restricted, possibly due to the delivery routes used. Here, following systemic intravascular antisense treatment, muscle strength and body activity of treated adult mdx mice increased to the levels of healthy controls. Importantly, hallmarks of muscular dystrophy were greatly improved in mice receiving the combined exon-skipping therapy, as compared to those receiving dystrophin antisense therapy alone. Our results support the translation of antisense therapy for dystrophin restoration and myostatin inhibition into the clinical setting for DMD.

Highlights

Duchenne muscular dystrophy (DMD) is the most common fatal muscular disease in children, affecting approximately one in 3,500 male births.[1]
The dual treatment ameliorated the pathology of DMD and increased body activity and muscle strength of treated mdx mice, significantly improving the effect of the single dystrophin approach
While we expected to observe muscle hypertrophy following myostatin knockdown, the body mass and muscle mass of treated animals decreased toward the wild-type values

Summary

Introduction

Duchenne muscular dystrophy (DMD) is the most common fatal muscular disease in children, affecting approximately one in 3,500 male births.[1]. Current therapies are able to address several dystrophinopathy symptoms to improve the quality of life for DMD patients or delay the disease development, but they fail in halting the progression completely.[7,8,9,10] Gene- and cell-based approaches, on the other hand, provide promise for a cure, as they have shown abilities to correct the faulty DMD gene,[11,12] to add a modified form of the DMD gene,[13,14,15,16] or to generate myofibers from engrafted mesoangioblasts.[17] Among these, antisense therapy has been considered as one of the most promising approaches,[18,19] and so far it is the only genetic therapy to be conditionally approved by the FDA for DMD treatment (i.e., EXONDYS 51, Eteplirsen, Sarepta Therapeutics). One of the most promising strategies is targeting the myostatin signaling

Methods

Results

Conclusion