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Investigation of Cas9 antibodies in the human eye.

TitleInvestigation of Cas9 antibodies in the human eye.
Publication TypeJournal Article
Year of Publication2022
AuthorsToral, Marcus A., Charlesworth Carsten T., Ng Benjamin, Chemudupati Teja, Homma Shota, Nakauchi Hiromitsu, Bassuk Alexander G., Porteus Matthew H., and Mahajan Vinit B.
JournalNat Commun
Date Published2022 02 25
KeywordsAnimals, Antibodies, CRISPR-Associated Protein 9, CRISPR-Cas Systems, Humans, Mice, Streptococcus pyogenes, T-Lymphocytes

Preexisting immunity against Cas9 proteins in humans represents a safety risk for CRISPR-Cas9 technologies. However, it is unclear to what extent preexisting Cas9 immunity is relevant to the eye as it is targeted for early in vivo CRISPR-Cas9 clinical trials. While the eye lacks T-cells, it contains antibodies, cytokines, and resident immune cells. Although precise mechanisms are unclear, intraocular inflammation remains a major cause of vision loss. Here, we used immunoglobulin isotyping and ELISA platforms to profile antibodies in serum and vitreous fluid biopsies from human adult subjects and Cas9-immunized mice. We observed high prevalence of preexisting Cas9-reactive antibodies in serum but not in the eye. However, we detected intraocular antibodies reactive to S. pyogenes-derived Cas9 after S. pyogenes intraocular infection. Our data suggest that serum antibody concentration may determine whether specific intraocular antibodies develop, but preexisting immunity to Cas9 may represent a lower risk in human eyes than systemically.

Alternate JournalNat Commun
PubMed ID35217666
PubMed Central IDPMC8881612
Grant ListP30 EY026877 / EY / NEI NIH HHS / United States
T32 GM139776 / GM / NIGMS NIH HHS / United States
R01 EY030151 / EY / NEI NIH HHS / United States
R01 EY024698 / EY / NEI NIH HHS / United States
T32 GM007337 / GM / NIGMS NIH HHS / United States
R01 EY031952 / EY / NEI NIH HHS / United States
R01 EY025225 / EY / NEI NIH HHS / United States