Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations

Mutations in USH2A, encoding usherin, are the most common cause of syndromic and non-syndromic retinitis pigmentosa (RP). The two founder mutations in exon 13 (c.2299delG and c.2276G>T) collectively account for approximately 34% of USH2A-associated RP cases. Skipping of exon 13 from the USH2A transcript during pre-mRNA splicing presents a potential treatment modality in which the resulting transcript is predicted to encode a slightly shortened usherin protein. Morpholino-induced skipping of ush2a exon 13 in larvae of the previously published ush2a exon 13 zebrafish mutant resulted in the production of usherinΔexon13 and completely restored retinal function. RNA antisense oligonucleotides were investigated for their potential to specifically induce human USH2A exon 13 skipping. Lead candidate QR 421a induced dose-dependent exon 13 skipping in iPSC-derived photoreceptor precursors from homozygous USH2A c.2299delG patients and healthy donors. Intravitreal delivery of QR-421a in non-human primates showed that QR-421a penetrates the retinal outer nuclear layer and induces detectable levels of exon 13 skipping until at least 3 months post injection. In conclusion, QR-421a-induced exon skipping proves to be a highly promising treatment for RP caused by mutations in exon 13 of the USH2A gene.