The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration.

Autor: Glenn JD; REGENXBIO Inc., 9804 Medical Center Drive, Rockville, MD 20850, USA. Electronic address: jglenn@regenxbio.com., Negash H; REGENXBIO Inc., 9804 Medical Center Drive, Rockville, MD 20850, USA., Henry W; REGENXBIO Inc., 9804 Medical Center Drive, Rockville, MD 20850, USA., Qian R; REGENXBIO Inc., 9804 Medical Center Drive, Rockville, MD 20850, USA., Liu Y; REGENXBIO Inc., 9804 Medical Center Drive, Rockville, MD 20850, USA., Danos O; REGENXBIO Inc., 9804 Medical Center Drive, Rockville, MD 20850, USA., Bruder JT; REGENXBIO Inc., 9804 Medical Center Drive, Rockville, MD 20850, USA., Karumuthil-Melethil S; REGENXBIO Inc., 9804 Medical Center Drive, Rockville, MD 20850, USA.
Jazyk: angličtina
Zdroj: Cellular immunology [Cell Immunol] 2024 May-Jun; Vol. 399-400, pp. 104823. Date of Electronic Publication: 2024 Mar 19.
DOI: 10.1016/j.cellimm.2024.104823
Abstrakt: AAV-mediated gene transfer is a promising platform still plagued by potential host-derived, antagonistic immune responses to therapeutic components. CpG-mediated TLR9 stimulation activates innate immune cells and leads to cognate T cell activation and suppression of transgene expression. Here, we demonstrate that CpG depletion increased expression of an antibody transgene product by 2-3-fold as early as 24 h post-vector administration in mice. No significant differences were noted in anti-transgene product/ anti-AAV capsid antibody production or cytotoxic gene induction. Instead, CpG depletion significantly reduced the presence of a pDC-like myeloid cell population, which was able to directly bind the antibody transgene product via Fc-FcγR interactions. Thus, we extend the mechanisms of TLR9-mediated antagonism of transgene expression in AAV gene therapy to include the actions of a previously unreported pDC-like cell population.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All REGENXBIO employees earn salary and own stock in REGENXBIO Inc.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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