Myotonic dystrophy type 1 (DM1) causes muscle weakness and a difficulty of muscles to relax after contraction. DM1 is the most frequent muscular dystrophy in adults, with an estimated prevalence of 1/8000; there is currently no cure.
The use of antisense oligonucleotides for muscular disease is challenging due to the lack of drug delivery to skeletal muscle. To overcome this limitation, we used an arginine-rich Pip6a cell-penetrating peptide and showed that these compounds dramatically enhanced ASO delivery into striated muscles of DM1 mice following systemic administration in comparison with unconjugated PMO and other ASO strategies. Thus, low-dose treatment with Pip6a-PMO-CAG targeting pathologic expansions (responsible for the DM1 muscle pathology) was sufficient to induce long-lasting myotonic dystrophy correction in patient-derived cells and mice. Moreover, we show that our Pip6a-PMO-CAG compound and normalizes the overall disease transcriptome to healthy levels supporting the therapeutic use of peptide conjugates for systemic corrective therapy in DM1.
Several rare genetic diseases may be also treated using antisense oligonucleotides (synthesised RNA fragments) acting on the mutated RNA. Now, the we are working to finalize the preclinical development of advanced peptide-PMOs with wide therapeutic index to initiate a clinical trial with DM1 patients.
The restoration of dystrophin protein in the muscles of Duchenne muscular dystrophy (DMD) boys is a major technical challenge, and the focus of many investigational drugs developed by our group and others. Effective dystrophin resuce is dependent on the amount, quality, and correct localization of dystrophin protein. In this study we investigated the effects of variable levels of dystrophin expression on the levels of serum microRNA biomarkers (which reflect the response to therapy). Using various models (e.g. mdx-Xist mouse whcih expresses patchy dystrophin, and exon skipping-treated mdx mice which re-express uniform dystrophin) we found that a uniform pattern of dystrophin expression is required to both influence serum microRNA levels, and to ameliorate muscle pathology. This study is important because it highlights the importance of dystrophin uniformity in the effective correction of the DMD phenotype. In contrast, therapies which result in patchy patterns of dystrophin expression may be insufficient to effectively treat DMD.
Exosomes A Clinical Compendium
Chapter by Imre Mager Eduard Willms Scott Bonner and Matthew Wood