Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models
dc.contributor.author | Hakim, Chady H. | |
dc.contributor.author | Kumar, Sandeep R. P. | |
dc.contributor.author | Pérez-López, Dennis O. | |
dc.contributor.author | Wasala, Nalinda B. | |
dc.contributor.author | Zhang, Dong | |
dc.contributor.author | Yue, Yongping | |
dc.contributor.author | Teixeira, James | |
dc.contributor.author | Zhang, Keqing | |
dc.contributor.author | Million, Emily D. | |
dc.contributor.author | Nelson, Christopher E. | |
dc.contributor.author | Metzger, Samantha | |
dc.contributor.author | Han, Jin | |
dc.contributor.author | Louderman, Jacqueline A. | |
dc.contributor.author | Schmidt, Florian | |
dc.contributor.author | Feng, Feng | |
dc.contributor.author | Grimm, Dirk | |
dc.contributor.author | Smith, Bruce F. | |
dc.contributor.author | Yao, Gang | |
dc.contributor.author | Yang, N. Nora | |
dc.contributor.author | Gersbach, Charles A. | |
dc.contributor.author | Chen, Shi-jie | |
dc.contributor.author | Herzog, Roland W. | |
dc.contributor.author | Duan, Dongsheng | |
dc.contributor.department | Pediatrics, School of Medicine | |
dc.date.accessioned | 2024-04-24T13:31:32Z | |
dc.date.available | 2024-04-24T13:31:32Z | |
dc.date.issued | 2021-11-24 | |
dc.description.abstract | Adeno-associated virus (AAV)-mediated CRISPR-Cas9 editing holds promise to treat many diseases. The immune response to bacterial-derived Cas9 has been speculated as a hurdle for AAV-CRISPR therapy. However, immunological consequences of AAV-mediated Cas9 expression have thus far not been thoroughly investigated in large mammals. We evaluate Cas9-specific immune responses in canine models of Duchenne muscular dystrophy (DMD) following intramuscular and intravenous AAV-CRISPR therapy. Treatment results initially in robust dystrophin restoration in affected dogs but also induces muscle inflammation, and Cas9-specific humoral and cytotoxic T-lymphocyte (CTL) responses that are not prevented by the muscle-specific promoter and transient prednisolone immune suppression. In normal dogs, AAV-mediated Cas9 expression induces similar, though milder, immune responses. In contrast, other therapeutic (micro-dystrophin and SERCA2a) and reporter (alkaline phosphatase, AP) vectors result in persistent expression without inducing muscle inflammation. Our results suggest Cas9 immunity may represent a critical barrier for AAV-CRISPR therapy in large mammals. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Hakim CH, Kumar SRP, Pérez-López DO, et al. Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models. Nat Commun. 2021;12(1):6769. Published 2021 Nov 24. doi:10.1038/s41467-021-26830-7 | |
dc.identifier.uri | https://hdl.handle.net/1805/40175 | |
dc.language.iso | en_US | |
dc.publisher | Springer Nature | |
dc.relation.isversionof | 10.1038/s41467-021-26830-7 | |
dc.relation.journal | Nature Communications | |
dc.rights | Attribution 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | PMC | |
dc.subject | Neuromuscular disease | |
dc.subject | CRISPR-Cas9 genome editing | |
dc.subject | Duchenne muscular dystrophy | |
dc.title | Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models | |
dc.type | Article |