期刊
HUMAN MOLECULAR GENETICS
卷 25, 期 12, 页码 2552-2563出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw118
关键词
-
资金
- Netherlands Organisation for Scientific Research (NWO) [VENI 916.10.096]
- Foundation Fighting Blindness (FFB) USA [TA-GT-0912-0582-RAD]
- FP7-PEOPLE-ITN programme EyeTN, Brussels, Belgium [317472]
- JANIVO stichting
- Stichting August F. Deutman Researchfonds Oogheelkunde
- Rotterdamse Vereniging Blindenbelangen
- Algemene Nederlandse Vereniging ter Voorkoming van Blindheid
- Gelderse Blindenstichting
- Stichting Winckel-Sweep
- Stichting Nederlands Oogheelkundig Onderzoek
- FFB [C-GT-09130627-UPA02]
- NIH [DP1-OD008267]
- Curing Kids Fund, FFB [TA-GT-0611-0571]
- Grousbeck Family Foundation
Leber congenital amaurosis (LCA) is a severe disorder resulting in visual impairment usually starting in the first year of life. The most frequent genetic cause of LCA is an intronic mutation in CEP290 (c.2991+1655A>G) that creates a cryptic splice donor site resulting in the insertion of a pseudoexon (exon X) into CEP290 mRNA. Previously, we showed that naked antisense oligonucleotides (AONs) effectively restored normal CEP290 splicing in patient-derived lymphoblastoid cells. We here explore the therapeutic potential of naked and adeno-associated virus (AAV)-packaged AONs in vitro and in vivo. In both cases, AON delivery fully restored CEP290 pre-mRNA splicing, significantly increased CEP290 protein levels and rescued a ciliary phenotype present in patient-derived fibroblast cells. Moreover, administration of naked and AAV-packaged AONs to the retina of a humanized mutant Cep290 mouse model, carrying the intronic mutation, showed a statistically significant reduction of exon X-containing Cep290 transcripts, without compromising the retinal structure. Together, our data highlight the tremendous therapeutic prospective of AONs for the treatment of not only CEP290-associated LCA but potentially many other subtypes of retinal dystrophy caused by splicing mutations.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据