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dc.contributor.authorDulla, Kalyanen
dc.contributor.authorAguila, Monicaen
dc.contributor.authorLane, Ameliaen
dc.contributor.authorJovanovic, Katarinaen
dc.contributor.authorParfitt, David Aen
dc.contributor.authorSchulkens, Irisen
dc.contributor.authorChan, Hee Lamen
dc.contributor.authorSchmidt, Irisen
dc.contributor.authorBeumer, Wouteren
dc.contributor.authorVorthoren, Larsen
dc.contributor.authorCollin, Rob WJen
dc.contributor.authorGaranto, Alejandroen
dc.contributor.authorDuijkers, Lonnekeen
dc.contributor.authorBrugulat-Panes, Annaen
dc.contributor.authorSemo, Ma'ayanen
dc.contributor.authorVugler, Anthony Aen
dc.contributor.authorBiasutto, Patriciaen
dc.contributor.authorAdamson, Peteren
dc.contributor.authorCheetham, Michael Een
dc.date.accessioned2019-08-07T23:30:41Z
dc.date.available2019-08-07T23:30:41Z
dc.date.issued2018-09-07en
dc.identifier.issn2162-2531
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/295404
dc.description.abstractLeber 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.
dc.description.sponsorshipThis 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.
dc.languageengen
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectQR-110en
dc.subjectoligonucleotideen
dc.subjectorganoiden
dc.subjectretinal dystrophyen
dc.subjectstem cellen
dc.subjecttherapyen
dc.titleSplice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models.en
dc.typeArticle
prism.endingPage740
prism.publicationDate2018en
prism.publicationNameMolecular Therapy: Nucleic Acidsen
prism.startingPage730
prism.volume12en
dc.identifier.doi10.17863/CAM.42459
dcterms.dateAccepted2018-07-18en
rioxxterms.versionofrecord10.1016/j.omtn.2018.07.010en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-09-07en
dc.identifier.eissn2162-2531
rioxxterms.typeJournal Article/Reviewen
cam.issuedOnline2018-07-23en


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International