ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands.
Department of Otorhinolaryngology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
Mol Ther. 2021 Aug 4;29(8):2441-2455. doi: 10.1016/j.ymthe.2021.04.024. Epub 2021 Apr 23.
Mutations in USH2A are among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). The two most recurrent mutations in USH2A, c.2299delG and c.2276G > T, both reside in exon 13. Skipping exon 13 from the USH2A transcript 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 zebrafish ush2a mutants resulted in the production of usherinΔexon 13 protein and a completely restored retinal function. Antisense oligonucleotides were investigated for their potential to selectively induce human USH2A exon 13 skipping. Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an Usher syndrome patient homozygous for the c.2299delG mutation. Mouse surrogate mQR-421a reached the retinal outer nuclear layer after a single intravitreal injection and induced a detectable level of exon skipping until at least 6 months post-injection. In conclusion, QR-421a-induced exon skipping proves to be a highly promising treatment option for RP caused by mutations in USH2A exon 13.
USH2A 基因突变是综合征性和非综合征性色素性视网膜炎 (RP) 的最常见原因之一。USH2A 中最常见的两种突变，c.2299delG 和 c.2276G>T，均位于外显子 13 中。从 USH2A 转录本中跳过外显子 13 提供了一种潜在的治疗方式，预计产生的转录本将编码稍微缩短的 usherin 蛋白。在 zebrafish ush2a 突变体中，通过 morpholino 诱导 exon 13 的跳过导致产生 usherinΔexon 13 蛋白，并完全恢复视网膜功能。人们研究了反义寡核苷酸在选择性诱导人 USH2A exon 13 跳跃方面的潜力。候选药物 QR-421a 在诱导多能干细胞 (iPSC) 衍生的感光细胞前体中诱导了一个 Usher 综合征患者纯合 c.2299delG 突变的 exon 13 依赖性跳跃。单剂量玻璃体内注射后，小鼠替代物 mQR-421a 到达视网膜外核层，并在至少 6 个月的注射后诱导可检测水平的 exon 跳跃。总之，QR-421a 诱导的 exon 跳跃被证明是治疗由 USH2A exon 13 突变引起的 RP 的一种很有前途的治疗选择。
