QR-110 is a single-stranded, fully phosphorothioated, and 2′ O-methyl-modified RNA oligonucleotide designed to correct the splicing defect resulting from the CEP290 c.2991+1655A>G mutation. In this study, we describe the development of QR-110, a clinical drug candidate oligonucleotide with potential to restore visual function, or slow vision loss, in patients with LCA10. In conclusion, the pharmacodynamic, pharmacokinetic, and safety properties make QR-110 a promising candidate for treating LCA10, and clinical development is currently ongoing. It was well tolerated following intravitreal injection in monkeys. 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. 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. QR-110 restored wild-type CEP290 mRNA and protein expression levels in CEP290 c.2991+1655A>G homozygous and compound heterozygous LCA10 primary fibroblasts. This identified QR-110 as the best-performing molecule. Here, a panel of antisense oligonucleotides was designed to correct the splicing defect associated with the mutation and screened for efficacy and safety.
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. Leber congenital amaurosis type 10 (LCA10) is a severe inherited retinal dystrophy associated with mutations in CEP290. Gene Editing: Technology & Applications.
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