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. 2019 Feb;25(2):229-233.
doi: 10.1038/s41591-018-0327-9. Epub 2019 Jan 21.

Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10

Morgan L Maeder  1 , Michael Stefanidakis  2 , Christopher J Wilson  2 , Reshica Baral  2 , Luis Alberto Barrera  2 , George S Bounoutas  2 , David Bumcrot  2 , Hoson Chao  2 , Dawn M Ciulla  2 , Jennifer A DaSilva  2 , Abhishek Dass  2 , Vidya Dhanapal  2 , Tim J Fennell  3 , Ari E Friedland  2 , Georgia Giannoukos  2 , Sebastian W Gloskowski  2 , Alexandra Glucksmann  2 , Gregory M Gotta  2 , Hariharan Jayaram  2 , Scott J Haskett  2 , Bei Hopkins  2 , Joy E Horng  2 , Shivangi Joshi  2 , Eugenio Marco  2 , Rina Mepani  2 , Deepak Reyon  2 , Terence Ta  2 , Diana G Tabbaa  2 , Steven J Samuelsson  2 , Shen Shen  2 , Maxwell N Skor  2 , Pam Stetkiewicz  2 , Tongyao Wang  2 , Clifford Yudkoff  2 , Vic E Myer  2 , Charles F Albright  2 , Haiyan Jiang  2
Affiliations

Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10

Morgan L Maeder et al. Nat Med. 2019 Feb.

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.

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Comment in

  • Gene therapy for retinal dystrophy.
    Sahel JA, Dalkara D. Sahel JA, et al. Nat Med. 2019 Feb;25(2):198-199. doi: 10.1038/s41591-019-0346-1. Nat Med. 2019. PMID: 30718907 No abstract available.

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