Dystrophin pre-messenger RNA exon 50 splicing regulatory sequence (DMD exon 50 SRS)

The dystrophin pre-messenger RNA (pre-mRNA) exon 50 splicing regulatory sequence is a specific region within the DMD gene transcript that contains motifs, such as exonic splicing enhancers (ESEs), required for the correct identification and inclusion of exon 50 during pre-mRNA splicing (1). In the context of Duchenne Muscular Dystrophy (DMD), this sequence serves as a therapeutic target for antisense oligonucleotides (ASOs) designed to induce exon skipping (2). By binding to these regulatory elements, ASOs sterically hinder the spliceosome, causing exon 50 to be excluded from the mature mRNA (3). This strategy is employed for patients with specific mutations, such as deletions of exon 51 or 49-51, where skipping exon 50 can restore the reading frame and lead to the synthesis of a truncated but functional dystrophin protein (4). This conversion from an out-of-frame to an in-frame transcript aims to slow disease progression and improve muscle function, mimicking the milder Becker Muscular Dystrophy phenotype (5). Drugs like NS-050 (NCNP-03) are currently under investigation to bind specifically to this regulatory sequence to facilitate this process (6). (1) Bladen CL, et al. (2015). Human Mutation. (2) Aartsma-Rus A, et al. (2017). Expert Opinion on Biological Therapy. (3) Kole R, et al. (2012). Nature Reviews Drug Discovery. (4) Hoffman EP, et al. (1987). Cell. (5) Lim KR, et al. (2017). Genetic Medicine. (6) Nippon Shinyaku Co., Ltd. (2023). Pipeline: NS-050 for DMD.

Other names

DMD exon 50Dystrophin exon 50 exonic splicing enhancerExon 50 of the DMD geneDMD pre-mRNA exon 50

Antisense oligonucleotide-mediated exon skipping by sterically blocking splicing regulatory elements (e.g., exonic splicing enhancers) to prevent exon inclusion during pre-mRNA processing, thereby restoring the reading frame.