Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by mutations inUSH2Aexon 13

crossref(2020)

引用 0|浏览2
暂无评分
摘要
AbstractMutations inUSH2A, 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% ofUSH2A-associated RP cases. Skipping of exon 13 from theUSH2Atranscript 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 ofush2aexon 13 in larvae of the previously publishedush2aexon 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 humanUSH2Aexon 13 skipping. Lead candidate QR-421a induced dose-dependent exon 13 skipping in iPSC-derived photoreceptor precursors from a patient homozygous for theUSH2Ac.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 theUSH2Agene.
更多
查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要