Leber congenital amaurosis type 10 (LCA10) is a severe inherited retinal dystrophy associated with mutations in CEP290. The deep intronic c.2991+1655A>G mutation in CEP290 is the most common mutation in LCA10 individuals and represents an ideal target for oligonucleotide therapeutics. Here, a panel of antisense oligonucleotides was designed to correct the splicing defect associated with the mutation and screened for efficacy and safety. This identified QR-110 as the best-performing molecule. QR-110 restored wild-type CEP290 mRNA and protein expression levels in CEP290 c.2991+1655A>G homozygous and compound heterozygous LCA10 primary fibroblasts. Furthermore, in homozygous three-dimensional iPSC-derived retinal organoids, QR-110 showed a dose-dependent restoration of mRNA and protein function, as measured by percentage and length of photoreceptor cilia, without off-target effects. Localization studies in wild-type mice and rabbits showed that QR-110 readily reached all retinal layers, with an estimated half-life of 58 days. It was well tolerated following intravitreal injection in monkeys. In conclusion, the pharmacodynamic, pharmacokinetic, and safety properties make QR-110 a promising candidate for treating LCA10, and clinical development is currently ongoing.

Leber 先天性黑蒙 10 型 (LCA10) 是一种与CEP290突变相关的严重遗传性视网膜营养不良。 CEP290中的深层内含子 c.2991+1655A>G 突变是 LCA10 个体中最常见的突变，是寡核苷酸治疗的理想靶点。在这里，设计了一组反义寡核苷酸来纠正与突变相关的剪接缺陷，并筛选其有效性和安全性。这表明 QR-110 是性能最好的分子。 QR-110恢复了CEP290 c.2991+1655A>G纯合子和复合杂合子LCA10原代成纤维细胞中野生型CEP290 mRNA和蛋白质的表达水平。此外，在纯合三维 iPSC 衍生的视网膜类器官中，通过光感受器纤毛的百分比和长度测量，QR-110 显示出剂量依赖性的 mRNA 和蛋白质功能恢复，且没有脱靶效应。对野生型小鼠和兔子的定位研究表明，QR-110 很容易到达视网膜的所有层，估计半衰期为 58 天。猴子玻璃体内注射后耐受性良好。总之，药效学、药代动力学和安全特性使 QR-110 成为治疗 LCA10 的有希望的候选药物，目前临床开发正在进行中。