An examination of the mechanisms driving the therapeutic effects of an AAV expressing a soluble variant of VEGF receptor-1.

Autor: Moon SY; Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul, Korea.; CdmoGen Co., Ltd., Cheongju, Korea., Kim HJ; Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul, Korea.; CdmoGen Co., Ltd., Cheongju, Korea., Kim JK; Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul, Korea.; CdmoGen Co., Ltd., Cheongju, Korea., Kim J; Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul, Korea.; CdmoGen Co., Ltd., Cheongju, Korea., Choi JS; Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul, Korea.; CdmoGen Co., Ltd., Cheongju, Korea., Won SY; Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul, Korea.; CdmoGen Co., Ltd., Cheongju, Korea., Park K; Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul, Korea.; CdmoGen Co., Ltd., Cheongju, Korea., Lee SHS; Institute of New Drug Development Research, CdmoGen Co., Ltd., Seoul, Korea.; CdmoGen Co., Ltd., Cheongju, Korea.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Jul 11; Vol. 19 (7), pp. e0305466. Date of Electronic Publication: 2024 Jul 11 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0305466
Abstrakt: In previous animal model studies, we demonstrated the potential of rAAV2-sVEGFRv-1, which encodes a truncated variant of the alternatively spliced soluble version of VEGF receptor-1 (VEGFR1), as a human gene therapy for age-related macular degeneration (AMD) and diabetic retinopathy (DR). Here, we elucidate in vitro some of the mechanisms by which rAAV2-sVEGFRv-1 exerts its therapeutic effects. Human umbilical vein endothelial cells (HUVECs) were infected with rAAV2-sVEGFRv-1 or a control virus vector in the presence of members of the VEGF family to identify potential binding partners via ELISA, which showed that VEGF-A, VEGF-B, and placental growth factor (PlGF) are all ligands of its transgene product. In order to determine the effects of rAAV2-sVEGFRv-1 on cell proliferation and permeability, processes that are important to the progression AMD and DR, HUVECs were infected with the therapeutic virus vector under the stimulation of VEGF-A, the major driver of the neovascularization that characterizes the forms of these conditions most associated with vision loss. rAAV2-sVEGFRv-1 treatment, as a result, markedly reduced the extent to which these processes occurred, with the latter determined by measuring zonula occludens 1 expression. Finally, the human microglial HMC3 cell line was used to show the effects of the therapeutic virus vector upon inflammatory processes, another major contributor to angiogenic eye disease pathophysiology, with rAAV2-sVEGFRv-1 reducing therein the secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-6. Combined with our previously published in vivo data, the in vitro activity of the expressed transgene here further demonstrates the great promise of rAAV2-sVEGFRv-1 as a potential human gene therapeutic for addressing angiogenic ocular conditions.
Competing Interests: S.Y.M., H.J.K., J.K.K., J.K., J.-S.C., S.-Y.W., K.P., and S.H.S.L. are employees of CdmoGen Co., Ltd., in which K.P. and S.H.S.L. have personal financial interests. No other potential conflicts of interest relevant to this article were reported. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2024 Moon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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