Immune-orthogonal orthologues of AAV capsids and of Cas9 circumvent the immune response to the administration of gene therapy

Protein-based therapeutics can activate the adaptive immune system, leading to the production of neutralizing antibodies and the clearance of the treated cells mediated by cytotoxic T cells. Here, we show that the sequential use of immune-orthogonal orthologues of CRISPR-associated protein 9 (Cas9)...

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Bibliographic Details
Published in:Nature biomedical engineering, Vol. 3, No. 10 (2019), p. 806-816
Main Author: Moreno, Ana M
Other Involved Persons: Palmer, Nathan ; Alemán, Fernando ; Chen, Genghao ; Pla, Andrew ; Jiang, Ning ; Leong Chew, Wei ; Law, Mansun ; Mali, Prashant
Format: electronic Article
Language:English
ISSN:2157-846X
Item Description:Date Revised 23.10.2019
published: Print-Electronic
ErratumIn: Nat Biomed Eng. 2019 Aug 27;:. - PMID 31455920
Citation Status In-Data-Review
Copyright: From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Physical Description:Online-Ressource
DOI:10.1038/s41551-019-0431-2
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  • Protein-based therapeutics can activate the adaptive immune system, leading to the production of neutralizing antibodies and the clearance of the treated cells mediated by cytotoxic T cells. Here, we show that the sequential use of immune-orthogonal orthologues of CRISPR-associated protein 9 (Cas9) and adeno-associated viruses (AAVs) evades adaptive immune responses and enables effective gene editing using repeated dosing. We compared total sequence similarities and predicted binding strengths to class-I and class-II major histocompatibility complex (MHC) proteins for 284 DNA-targeting and 84 RNA-targeting CRISPR effectors and 167 AAV VP1-capsid-protein orthologues. We predict the absence of cross-reactive immune responses for 79% of the DNA-targeting Cas orthologues-which we validated for three Cas9 orthologues in mice-yet we anticipate broad immune cross-reactivity among the AAV serotypes. We also show that efficacious in vivo gene editing is uncompromised when using multiple dosing with orthologues of AAVs and Cas9 in mice that were previously immunized against the AAV vector and the Cas9 cargo. Multiple dosing with protein orthologues may allow for sequential regimens of protein therapeutics that circumvent pre-existing immunity or induced immunity