Therapeutic homology-independent targeted integration in retina and liver

Patrizia Tornabene, Rita Ferla, Manel Llado-Santaeularia, Miriam Centrulo, Margherita Dell’Anno, Federica Esposito, Elena Marrocco, Emanuela Pone, Renato Minopoli, Carolina Iodice, Edoardo Nusco, Settimio Rossi, Hristiana Lyubenova, Anna Manfredi, Lucio Filippo, Antonella Iuliano, Annalaura Torella, Giulio Piluso, Francesco Musacchia, Enrico Maria Surace, Davide Cacchiarelli, Vincenzo Nigro and Alberto Auricchio ()
Additional contact information
Patrizia Tornabene: Telethon Institute of Genetics and Medicine (TIGEM)
Rita Ferla: Telethon Institute of Genetics and Medicine (TIGEM)
Manel Llado-Santaeularia: Telethon Institute of Genetics and Medicine (TIGEM)
Miriam Centrulo: Telethon Institute of Genetics and Medicine (TIGEM)
Margherita Dell’Anno: Telethon Institute of Genetics and Medicine (TIGEM)
Federica Esposito: Telethon Institute of Genetics and Medicine (TIGEM)
Elena Marrocco: Telethon Institute of Genetics and Medicine (TIGEM)
Emanuela Pone: Telethon Institute of Genetics and Medicine (TIGEM)
Renato Minopoli: Telethon Institute of Genetics and Medicine (TIGEM)
Carolina Iodice: Telethon Institute of Genetics and Medicine (TIGEM)
Edoardo Nusco: Telethon Institute of Genetics and Medicine (TIGEM)
Settimio Rossi: University of Campania L. Vanvitelli
Hristiana Lyubenova: Telethon Institute of Genetics and Medicine (TIGEM)
Anna Manfredi: Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics
Lucio Filippo: Next Generation Diagnostic Srl
Antonella Iuliano: Telethon Institute of Genetics and Medicine (TIGEM)
Annalaura Torella: Telethon Institute of Genetics and Medicine (TIGEM)
Giulio Piluso: University of Campania L. Vanvitelli
Francesco Musacchia: Telethon Institute of Genetics and Medicine (TIGEM)
Enrico Maria Surace: Federico II University
Davide Cacchiarelli: Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics
Vincenzo Nigro: Telethon Institute of Genetics and Medicine (TIGEM)
Alberto Auricchio: Telethon Institute of Genetics and Medicine (TIGEM)

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29550-8

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