The dystrophin-deficient mdx mouse has historically been used as the primary model of DMD, although this mouse does not experience the severe, body-wide dystrophy that considerably shortens lifespan in humans. Therefore, double-knockout (dKO) mice, which present a much more severe and progressive dystrophic phenotype than mdx mice, could represent a more appropriate model to test the therapeutic potential of the antisense approach.
"In a very challenging model of severe DMD, this study confirms our belief that PPMO, a next generation of AVI drug candidates under development, holds great promise as a treatment for incurable muscle wasting in DMD patients," said Ryszard Kole, PhD, Senior Vice President of Discovery Research at AVI BioPharma and co-author of the study.
AVI BioPharma is developing AVI-4658 for the treatment of DMD. This first generation PMO drug candidate is designed to skip exon 51 of the dystrophin gene, allowing for restoration of the reading frame in the dystrophin mRNA sequence. Results from a Phase 1 proof-of-concept trial showed that injection of the drug into the muscles of a series of boys with DMD successfully induced dystrophin production in a dose-responsive manner. Further, the drug was well tolerated, with no significant drug-related adverse events detected. AVI is currently conducting an ongoing Phase 1b/2 dose-finding clinical trial evaluating the systemic delivery of AVI-4658 for treatment of DMD. This is an open label, 12-week safety trial, which includes measures of drug efficacy and pharmacokinetics and is being conducted in London, UK at the UCL Institute of Child Health / Great Ormond Street Hospital NHS Trust facilities and at the Royal Victoria Infirmary, Newcastle-Upon-Tyne, UK which is the coordinating center for the European Treat Neuromuscular Diseases (Treat-NMD) initiative.
AVI BioPharma is also developing a second generation chemistry exon skipping drugs, with a PPMO, AVI-5038, nearing IND submission for the treatment of DMD by skipping exon 50.
Source: RATHBUN COMMUNICATIONS, INC.