Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models.
Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models.
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DOI：
10.1016/j.omtn.2018.07.010
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发表时间：
2018-09-07
期刊：
影响因子：
--
通讯作者：
Cheetham ME
中科院分区：
文献类型：
--
作者：
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
Leber先天性黑朦10型（LCA10）是一种与CEP290基因突变相关的严重遗传性视网膜营养不良。CEP290中的深层内含子c.2991+1655A>G突变是LCA10个体中最常见的突变，是寡核苷酸治疗的理想靶点。在这里，设计了一组反义寡核苷酸来纠正与突变相关的剪接缺陷，并对其有效性和安全性进行了筛选。这表明QR-110是性能最好的分子。QR-110恢复了野生型CEP290 mRNA和蛋白在CEP290 c.2991+1655A>G纯合子和复合杂合子LCA10原代成纤维细胞中的表达水平。此外，在纯合子三维ipsc衍生的视网膜类器官中，通过测量光感受器纤毛的百分比和长度，QR-110显示出mRNA和蛋白质功能的剂量依赖性恢复，没有脱靶效应。在野生型小鼠和兔子中进行的定位研究表明，QR-110很容易到达视网膜的所有层，估计半衰期为58天。在猴体内玻璃体内注射后耐受性良好。总之，QR-110的药效学、药代动力学和安全性使其成为治疗LCA10的有希望的候选药物，目前正在进行临床开发。
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.
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影响因子：
17.8
作者：
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通讯作者：
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