Ex vivo gene therapy with adenovirus-mediated transforming growth factor β1 expression for endovascular treatment of aneurysm: Results in a canine bilateral aneurysm model

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Abstract

Objective: Endovascular treatment of cerebral aneurysm is safe and effective, but recurrence of disease is frequent compared with results with surgery. The purpose of this study was to determine the effects of recombinant transforming growth factor β1 (rTGFβ1) secreted by transplanted autologous vascular smooth muscle cells (VSMC) on results of endovascular treatment. Methods: VSMC from canine femoral arteries were infected with adenovirus vector encoding rTGFβ1/green fluorescent protein (rTGFβ1/GFP) or GFP only. rTGFβ1 production was measured with an enzyme-linked immunosorbent assay, and autocrine and paracrine effects of rTGFβ1 on cell functions were quantified with a proliferation assay and collagen synthesis. A bilateral carotid aneurysm model was used to compare angiographic and pathologic results after embolization with sponges seeded (n = 14) or not seeded (n = 34) with VSMC expressing TGFβ1 or GFP (n = 7 each). Transgene retention was confirmed with Western blot analysis. Results: In vitro, TGFβ1 production varied from 0.9 to 180 ng/mL/d with increasing multiplicity of infection (MOI). Collagen synthesis was doubled at low (<300) MOI and increased by one and a half times at high (≥300) MOI. rTGFβ1 was biologically active, as shown with the mink lung epithelial cell proliferation assay. VSMC grafts showed effective GFP expression up to 3 weeks after transplantation. Angiographic results were improved and neointima thickness was increased with cellular grafts, as compared with controls, but there was no significant difference between aneurysms treated with VSMC encoding rTGFβ1/GFP or GFP vectors. Conclusion: Cellular grafts can promote healing of aneurysms, but overexpression of rTGFβ1/GFP did not demonstrate added benefits in this model. Copyright © 2003 by The Society for Vascular Surgery.

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Ribourtout, E., Desfaits, A. C., Salazkin, I., & Raymond, J. (2003). Ex vivo gene therapy with adenovirus-mediated transforming growth factor β1 expression for endovascular treatment of aneurysm: Results in a canine bilateral aneurysm model. Journal of Vascular Surgery, 38(3), 576–583. https://doi.org/10.1016/S0741-5214(03)00333-1

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