Therapeutic homology-independent targeted integration in retina and liver.

Autor: Tornabene P; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy.; Medical Genetics, Department of Translational Medicine, Federico II University, 80131, Naples, Italy., Ferla R; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy.; Medical Genetics, Department of Translational Medicine, Federico II University, 80131, Naples, Italy., Llado-Santaeularia M; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Centrulo M; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Dell'Anno M; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy.; Medical Genetics, Department of Translational Medicine, Federico II University, 80131, Naples, Italy., Esposito F; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Marrocco E; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Pone E; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy.; Medical Genetics, Department of Translational Medicine, Federico II University, 80131, Naples, Italy., Minopoli R; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Iodice C; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Nusco E; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Rossi S; Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania L. Vanvitelli, 80131, Naples, Italy., Lyubenova H; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Manfredi A; Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics, 80078, Pozzuoli, Italy.; Next Generation Diagnostic Srl, 80078, Pozzuoli, Italy., Di Filippo L; Next Generation Diagnostic Srl, 80078, Pozzuoli, Italy., Iuliano A; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Torella A; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy.; Department of Precision Medicine, University of Campania L. Vanvitelli, 80138, Naples, Italy., Piluso G; Department of Precision Medicine, University of Campania L. Vanvitelli, 80138, Naples, Italy., Musacchia F; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy., Surace EM; Medical Genetics, Department of Translational Medicine, Federico II University, 80131, Naples, Italy., Cacchiarelli D; Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics, 80078, Pozzuoli, Italy.; Department of Translational Medicine, Federico II University, 80131, Naples, Italy., Nigro V; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy.; Department of Precision Medicine, University of Campania L. Vanvitelli, 80138, Naples, Italy., Auricchio A; Telethon Institute of Genetics and Medicine (TIGEM), 80078, Pozzuoli, Italy. auricchio@tigem.it.; Medical Genetics, Department of Advanced Biomedical Sciences, Federico II University, 80131, Naples, Italy. auricchio@tigem.it.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Apr 12; Vol. 13 (1), pp. 1963. Date of Electronic Publication: 2022 Apr 12.
DOI: 10.1038/s41467-022-29550-8
Abstrakt: Challenges to the widespread application of gene therapy with adeno-associated viral (AAV) vectors include dominant conditions due to gain-of-function mutations which require allele-specific knockout, as well as long-term transgene expression from proliferating tissues, which is hampered by AAV DNA episomal status. To overcome these challenges, we used CRISPR/Cas9-mediated homology-independent targeted integration (HITI) in retina and liver as paradigmatic target tissues. We show that AAV-HITI targets photoreceptors of both mouse and pig retina, and this results in significant improvements to retinal morphology and function in mice with autosomal dominant retinitis pigmentosa. In addition, we show that neonatal systemic AAV-HITI delivery achieves stable liver transgene expression and phenotypic improvement in a mouse model of a severe lysosomal storage disease. We also show that HITI applications predominantly result in on-target editing. These results lay the groundwork for the application of AAV-HITI for the treatment of diseases affecting various organs.
(© 2022. The Author(s).)
Databáze: MEDLINE
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