Duchenne Muscular Dystrophy (DMD) is a severe inherited muscle disorder with the highest incidence that is limited to male children. The onset of disease is due to dystrophin deficiency arising from mutation of the dystrophin gene, resulting in muscle degeneration and eventual death. Exon skipping is a therapeutic approach based on the use of a synthetic oligonucleotide, called an antisense oligonucleotide, to restore the amino acid reading frame by artificially skipping certain exons of the transcription product (mRNA) to be translated into protein. Applied to DMD, this approach produces a dystrophin protein that is shorter than normal but still functional, to improve muscle function. The exon to be skipped depends on the mutation type of the patient. The highest proportion of patients is targeted by exon 51 skipping, and some exon 51 skipping products have already been developed to the clinical stage. The number of patients who are targeted by exon 53 skipping is thought to be the second largest, or, in Japan, about the same as the number of patients targeted by exon 51 skipping. The development of an exon 53 skipping product is expected to provide an important treatment choice for DMD patients.
On the basis of the above background, NCNP and Nippon Shinyaku started a collaboration in 2009 aimed at the development of an exon 53 skipping product, and concluded a co-development agreement for NS-065/NCNP-01 in February of this year. NCNP is one of the best medical care and research centers for nerve and muscle disorders worldwide, and it has reported its research on exon-skipping therapy in DMD mice and dogs as well as in cells derived from DMD patients. Nippon Shinyaku has technologies for genomic drug discovery and oligonucleotide synthesis based on its research and development of nucleic acid products since the 1980s. During the collaboration, Nippon Shinyaku performed comprehensive synthesis of oligonucleotide sequences which induce exon 53 skipping. As a result of work by NCNP and Nippon Shinyaku, an optimized sequence for the treatment of DMD has been identified. The product is an antisense oligonucleotide with the optimized sequence synthesized from morpholino compounds, so that potent efficacy and high safety are expected. Non-clinical studies have confirmed its efficacy in cells from DMD patients with mutation types responding to exon 53 skipping, and disease progression is expected to be suppressed.
This is the first clinical study in Japan of an antisense oligonucleotide discovered in Japan, and it is the first clinical study of DMD targeting exon 53 skipping in the world. This investigator-initiated trial will start in July of this year after the Japanese authorities have approved the study schedule. Nippon Shinyaku will perform further clinical development of the product in collaboration with NCNP with a view to launching it in 2018. On the basis of the knowledge and experience gained from the development of this product, NCNP and Nippon Shinyaku will continue research and development efforts to create effective products for muscular dystrophy patients with other mutations in the dystrophin gene.