Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models.
Parfitt, David A
Chan, Hee Lam
Collin, Rob WJ
Vugler, Anthony A
Cheetham, Michael E
Molecular Therapy: Nucleic Acids
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Dulla, K., Aguila, M., Lane, A., Jovanovic, K., Parfitt, D. A., Schulkens, I., Chan, H. L., et al. (2018). Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models.. Molecular Therapy: Nucleic Acids, 12 730-740. https://doi.org/10.1016/j.omtn.2018.07.010
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.
QR-110, oligonucleotide, organoid, retinal dystrophy, stem cell, therapy
This study was funded by ProQR. iPSC work in the Cheetham lab is also supported by the Wellcome Trust, Fight for Sight, RP Fighting Blindness, and Moorfields Eye Charity.
External DOI: https://doi.org/10.1016/j.omtn.2018.07.010
This record's URL: https://www.repository.cam.ac.uk/handle/1810/295404
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/