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

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.

Combined Therapies for Duchenne Muscular Dystrophy to Optimize Treatment Efficacy

“…They showed a potent synergistic effect of the combined therapy on muscle force and architecture. This was also demonstrated with an AON triggering exon skipping of dystrophin and another one targeting myostatin to improve muscle weakness (Kemaladewi et al, 2011 ; Lu-Nguyen et al, 2017 ) with promising results. Similar approaches to interfere with the myostatin pathways have also been used in combined therapies: RNA interference for the Activin Receptor type IIb (AcvRIIB) (Dumonceaux et al, 2010 )—the receptor for Myostatin—or a soluble version of AcvRIIB (Hoogaars et al, 2012 ) have been used in combination with AAV-U7 based exon skipping resulting in a beneficial effect increasing both muscle mass and strength.…”

Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy

“…The economic loss, food security threats and impact of loss and treatment costs make the condition important to both breeders and owners, the veterinary medicine community, healthcare insurance, pharmaceutical companies, and those involved in the food industry. Advances in genetic testing and more recently gene therapy proof of concept advances are now making mutation detection more accessible and treatment development more promising even in the large dystrophin gene [ 146 , 147 , 148 ]. In addition, finding causative mutations enables testing for at risk breeds and species prior to clinical detection and/or symptoms.…”

Cell-Penetrating Peptides to Enhance Delivery of Oligonucleotide-Based Therapeutics

“…Thus, PMOs conjugated to B peptide were utilized in an exemplar study for targeting myostatin, a negative regulator of skeletal muscle growth and differentiation, in combination with Dmd exon skipping as a complementary strategy for DMD [ 53 ]. Combinatorial treatment improved some, but not all, functional measures of muscle pathology in the mdx model to a greater extent than dystrophin expression alone, demonstrating the potential of destructive exon skipping as an alternative to more widely used siRNA and RNaseH gene knockdown strategies [ 54 ]. This combinatorial approach has also been utilized to simultaneously target two genes using a single CPP-PMO construct.…”