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

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 ~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 a patient homozygous for the USH2A c.2299delG mutation. 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. ### Competing Interest Statement An international patent application has been filed by Stichting Katholieke Universiteit Nijmegen (WO/2016/005514) describing methods and means regarding oligonucleotide therapy for USH2A-associated retinitis pigmentosa. Stichting Katholieke Universiteit Nijmegen has licensed the exclusive rights of the patent to ProQR Therapeutics. As the inventor, E.W. is entitled to a share of any future royalties paid to Stichting Katholieke Universiteit Nijmegen, should the therapy eventually be brought to the market. H.D. and P.A. were employed by ProQR Therapeutics during this project.