2024 年 41 巻 3 号 p. 425-430
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. Although anti–inflammatory steroid therapy is the only treatment to delay disease progression, various therapeutic approaches, including exon–skipping therapy, vector–mediated gene therapy and cell transplantation, have been currently developed for the treatment of DMD patients. One of the most promising approaches is exon–skipping mediated by antisense oligonucleotides. Four exon–skipping drugs, eteprilsen, viltolarsen, gorodirsen, and casimersen, have been approved by the FDA. We have evaluated the efficacy and safety of exon–skipping drugs in DMD model mdx52 mice and urine–derived cells, and based on these data, 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. Vector–mediated therapy and stem cell transplantation are also attractive approaches for DMD treatment. In 2023, Sarepta Therapeutics announced FDA approval of ELEVIDYS, the first gene therapy to treat DMD. ELEVIDYS microdystrophin uses AAVrh74 as the vector, a muscle–specific MHCK7 promotor, and a microdystrophin transgene. The review summarizes the latest therapeutic developments in exon–skipping, vector–mediated gene therapy and cell transplantation for DMD.
