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Patricia Biasutto, Hee Lam Chan, Hester Boersma, Thomas Hoogenboezem, Jim Swildens, Kalyan Dulla, Ma'ayan Mary Semo, Anthony Alexander Vugler, Rob Collin, Peter Adamson; QR-110, an RNA oligonucleotide (AON) directing skipping of the cryptic exon in p.Cys998X CEP290 associated with Leber’s congenital amaurosis, shows increase in wild-type mRNA and an ability to reach the outer nuclear layer (ONL) in mice following intravitreal administration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):1123.
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The p.Cys998X mutation (known as c.2991+1655A>G) in the human CEP290 gene is associated with Leber’s congenital amaurosis type 10 (LCA10) when present in homozygosity or compound heterozygosity. These genotypes result in a childhood blindness associated with loss of photoreceptors. The p.Cys998X mutation results in a splicing defect which directs the mRNA to include an additional exon (exon X) between exon 26 and exon 27 in the mature mRNA that contains a premature stop codon which results in reduced protein production. QR-110 is a chemically modified antisense oligonucleotide designed to direct the skipping of exon X in the p.Cys998X sequence, increasing the amount of wild-type mRNA and restoration of CEP290 protein and function.
Fibroblasts derived from homozygous p.Cys998X CEP290 (LCA10) patients were transfected with QR-110 and CEP290 mRNA and protein levels were assessed. Labeled and unlabeled QR-110 was injected by intravitreal (IVT) injection into mouse eyes (10-100ug) to assess the retinal localization.
Restoration of the wild-type mRNA transcript profile in patient fibroblasts could be correlated with an increase in CEP290 protein levels. QR-110 shows intranuclear localization in the ONL of the retinae after a single IVT dose in mouse and was present in the ONL 21 days after injection.
QR-110 demonstrated an ability to direct a wild-type splicing pattern of CEP290 mRNA carrying the p.Cys998X mutation, leading to an increase in CEP290 protein, and reaching the ONL target tissue in mouse eyes following IVT administration.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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