| Literature DB >> 30664785 |
Morgan L Maeder1, Michael Stefanidakis2, Christopher J Wilson2, Reshica Baral2, Luis Alberto Barrera2, George S Bounoutas2, David Bumcrot2, Hoson Chao2, Dawn M Ciulla2, Jennifer A DaSilva2, Abhishek Dass2, Vidya Dhanapal2, Tim J Fennell3, Ari E Friedland2, Georgia Giannoukos2, Sebastian W Gloskowski2, Alexandra Glucksmann2, Gregory M Gotta2, Hariharan Jayaram2, Scott J Haskett2, Bei Hopkins2, Joy E Horng2, Shivangi Joshi2, Eugenio Marco2, Rina Mepani2, Deepak Reyon2, Terence Ta2, Diana G Tabbaa2, Steven J Samuelsson2, Shen Shen2, Maxwell N Skor2, Pam Stetkiewicz2, Tongyao Wang2, Clifford Yudkoff2, Vic E Myer2, Charles F Albright2, Haiyan Jiang2.
Abstract
Leber congenital amaurosis type 10 is a severe retinal dystrophy caused by mutations in the CEP290 gene1,2. We developed EDIT-101, a candidate genome-editing therapeutic, to remove the aberrant splice donor created by the IVS26 mutation in the CEP290 gene and restore normal CEP290 expression. Key to this therapeutic, we identified a pair of Staphylococcus aureus Cas9 guide RNAs that were highly active and specific to the human CEP290 target sequence. In vitro experiments in human cells and retinal explants demonstrated the molecular mechanism of action and nuclease specificity. Subretinal delivery of EDIT-101 in humanized CEP290 mice showed rapid and sustained CEP290 gene editing. A comparable surrogate non-human primate (NHP) vector also achieved productive editing of the NHP CEP290 gene at levels that met the target therapeutic threshold, and demonstrated the ability of CRISPR/Cas9 to edit somatic primate cells in vivo. These results support further development of EDIT-101 for LCA10 and additional CRISPR-based medicines for other inherited retinal disorders.Entities:
Mesh：
Year: 2019 PMID： 30664785 DOI： 10.1038/s41591-018-0327-9
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440