Cutting-edge therapeutic approaches for Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is the most common and severe type of muscular dystrophy and is an intractable X-linked genetic disorder characterized by progressive muscle atrophy and weakness including skeletal, cardiac, and respiratory muscles. DMD is caused by disruption of the reading frame with mutations of the dystrophin gene (DMD) and the loss of dystrophin protein. Approximately 1 in 5,000 boys are diagnosed with DMD. Various therapeutic approaches have been currently developed for the treatment of DMD patients. One of the most promising approaches is exon-skipping by antisense oligonucleotides. Four exon-skipping drugs, eteplirsen, viltolarsen, golodirsen, and casimersen, have been approved by the U.S. Food and Drug Administration (FDA). We have collaborated with Nippon Shinyaku Co., Ltd. to develop FDA-approved exon 53 skipping drug “NS-065/NCNP-01 (viltolarsen)”. Additionally, we have been developing other exon-skipping drugs, exon 44 skipping drug “NS-089/NCNP-02 (brogidirsen)”, exon 50 skipping drug “NS-050/NCNP-03”, and exon 51 skipping “NS-051/NCNP-04”, for patients not eligible for treatment with viltolarsen. In particular, brogidirsen was the first in the world to successfully restore the expression of dystrophin protein to more than 15% of normal in clinical trials. Notably, brogidirsen is the first exon-skipping drug to receive breakthrough therapy designation from the FDA. Vector-mediated therapy is also attractive approaches for DMD treatment. The review summarizes the latest therapeutic developments in exon-skipping and vector-mediated gene therapy for DMD.