Cas9-specific immune responses compromise local and systemic AAV CRISPR therapy in multiple dystrophic canine models

Chady H. Hakim, Sandeep R. P. Kumar, Dennis O. Pérez-López, Nalinda B. Wasala, Dong Zhang, Yongping Yue, James Teixeira, Xiufang Pan, Keqing Zhang, Emily D. Million, Christopher E. Nelson, Samantha Metzger, Jin Han, Jacqueline A. Louderman, Florian Schmidt, Feng Feng, Dirk Grimm, Bruce F. Smith, Gang Yao, N. Nora Yang, Charles A. Gersbach, Shi-jie Chen, Roland W. Herzog and Dongsheng Duan ()
Additional contact information
Chady H. Hakim: The University of Missouri
Sandeep R. P. Kumar: Indiana University
Dennis O. Pérez-López: The University of Missouri
Nalinda B. Wasala: The University of Missouri
Dong Zhang: The University of Missouri
Yongping Yue: The University of Missouri
James Teixeira: The University of Missouri
Xiufang Pan: The University of Missouri
Keqing Zhang: The University of Missouri
Emily D. Million: The University of Missouri
Christopher E. Nelson: Duke University
Samantha Metzger: The University of Missouri
Jin Han: The University of Missouri
Jacqueline A. Louderman: The University of Missouri
Florian Schmidt: University of Heidelberg
Feng Feng: The University of Missouri
Dirk Grimm: University of Heidelberg
Bruce F. Smith: Auburn University
Gang Yao: The University of Missouri
N. Nora Yang: National Center for Advancing Translational Sciences, NIH
Charles A. Gersbach: Duke University
Shi-jie Chen: The University of Missouri
Roland W. Herzog: Indiana University
Dongsheng Duan: The University of Missouri

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26830-7

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