期刊
MOLECULAR THERAPY
卷 28, 期 6, 页码 1432-1441出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2020.04.017
关键词
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资金
- National Institutes of Health (NIH) [HL132840, U42OD026645, UG3HL151545]
- Cancer Prevention and Research Institute of Texas [RP180672, RR140081]
- American Heart Association [19PRE34380467, 19POST34430092]
- NIH [HL007676, GM08231, CA125123, RR024574]
- Cytometry and Cell Sorting Core at Baylor College of Medicine
Adeno-associated viral (AAV) vectors are a leading candidate for the delivery of CRISPR-Cas9 for therapeutic genome editing in vivo. However, AAV-based delivery involves persistent expression of the Cas9 nuclease, a bacterial protein. Recent studies indicate a high prevalence of neutralizing antibodies and T cells specific to the commonly used Cas9 orthologs from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9) in humans. We tested in a mouse model whether pre-existing immunity to SaCas9 would pose a barrier to liver genome editing with AAV packaging CRISPR-Cas9. Although efficient genome editing occurred in mouse liver with pre-existing SaCas9 immunity, this was accompanied by an increased proportion of CD8(+) T cells in the liver. This cytotoxic T cell response was characterized by hepatocyte apoptosis, loss of recombinant AAV genomes, and complete elimination of genome-edited cells, and was followed by compensatory liver regeneration. Our results raise important efficacy and safety concerns for CRISPR-Cas9-based in vivo genome editing in the liver.
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