Investigation of fibrotic factors during the exon-skipping therapy using antisense oligonucleotide for muscular dystrophy

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To enhance the effectiveness of antisense oligonucleotide (AO)-mediated exon skipping therapy for Duchenne muscular dystrophy (DMD), the relationship of fibrosis and inflammation to DMD was examined. At the beginning pharmacodynamics of the AO inducing the skipping of exon 45(AO85) was examined using cell-free splicing system, and the EC50 of AO85 was revealed to be 58.0 nM. Then, urinary tetranor PGDM which is major urinary metabolite of prostaglandin (PG) D2 were shown to be increased in DMD patients and became higher with advancing age. It was indicated that PGD2-mediated inflammation plays a role in the pathology of DMD. Furthermore, administration of AO85 to DMD cases resulted in the improvement of some inflammatory cytokines. These results indicated that fibrosis and inflammation were involved in the pathogenesis of DMD, and the modification of these factors was considered as one possible strategy for the enhancement of the effectiveness of AO-mediated exon skipping therapy.