Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models

被引：128

作者：

Dulla, Kalyan ^{[1
]}

Aguila, Monica ^{[2
]}

Lane, Amelia ^{[2
]}

Jovanovic, Katarina ^{[2
]}

Parfitt, David A. ^{[2
]}

Schulkens, Iris ^{[1
]}

Chan, Hee Lam ^{[1
]}

Schmidt, Iris ^{[1
]}

Beumer, Wouter ^{[1
]}

Vorthoren, Lars ^{[1
]}

Collin, Rob W. J. ^{[3
]}

Garanto, Alejandro ^{[3
]}

Duijkers, Lonneke ^{[3
]}

Brugulat-Panes, Anna ^{[2
]}

Semo, Ma'ayan ^{[2
]}

Vugler, Anthony A. ^{[2
]}

Biasutto, Patricia ^{[1
]}

Adamson, Peter ^{[1
,2
]}

Cheetham, Michael E. ^{[2
]}

机构：

[1] ProQR Therapeut, Zernikedreef 9, NL-2333 CK Leiden, Netherlands

[2] UCL Inst Ophthalmol, 11-43 Bath St, London EC1V 9EL, England

[3] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, Nijmegen, Netherlands

来源：

MOLECULAR THERAPY-NUCLEIC ACIDS | 2018年 / 12卷

基金：

英国惠康基金;

关键词：

LEBER CONGENITAL AMAUROSIS; ANTISENSE OLIGONUCLEOTIDES; RETINAL DEGENERATION; DISEASE MECHANISMS; PRIMARY CILIA; GENE-THERAPY; OPTIC CUPS; IN-VITRO; MUTATION; CELLS;

D O I：

10.1016/j.omtn.2018.07.010

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：730 / 740

页数：11

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Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A&gt;G LCA10 Models

Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models