| Title: |
Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models |
| Authors: |
Dulla, K; Aguila, M; Lane, A; Jovanovic, K; Parfitt, DA; Schulkens, I; Chan, HL; Schmidt, I; Beumer, W; Vorthoren, L; Collin, RWJ; Garanto, A; Duijkers, L; Brugulat-Panes, A; Semo, M; Vugler, AA; Biasutto, P; Adamson, P; Cheetham, ME |
| Source: |
Molecular Therapy - Nucleic Acids , 12 pp. 730-740. (2018) |
| Publication Year: |
2018 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
QR-110; oligonucleotide; organoid; retinal dystrophy; stem cell; therapy |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10055210/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10055210/1/1-s2.0-S2162253118301513-main.pdf; https://discovery.ucl.ac.uk/id/eprint/10055210/ |
| Rights: |
open |
| Accession Number: |
edsbas.BB7C2DC6 |
| Database: |
BASE |