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Co-expression of fibulin-5 and VEGF165 increases long-term patency of synthetic vascular grafts seeded with autologous endothelial cells

Gene Therapy volume 23, pages 237–246 (2016)Cite this article

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Abstract

Small caliber synthetic vascular grafts are commonly used for bypass surgery and dialysis access sites but have high failure rates because of neointima formation and thrombosis. Seeding synthetic grafts with endothelial cells (ECs) provides a biocompatible surface that may prevent graft failure. However, EC detachment following exposure to blood flow still remains a major obstacle in the development of biosynthetic grafts. We tested the hypothesis that induced expression by the seeded EC, of vascular endothelial growth factor165 (VEGF165) and of fibulin-5, an extracellular matrix glycoprotein that has a crucial role in elastin fiber organization and increase EC adherence to surfaces, may improve long-term graft patency. Autologous ECs were isolated from venous segments, and were transduced with retroviral vectors expressing fibulin-5 and VEGF165. The modified cells were seeded on expanded polytetrafluoroethylene (ePTFE) grafts and implanted in a large animal model. Three months after transplantation, all grafts seeded with modified EC were patent on a selective angiography, whereas only a third of the control grafts were patent. Similar results were shown at 6 months. Thus, seeding ePTFE vascular grafts with genetically modified EC improved long-term small caliber graft patency. The biosynthetic grafts may provide a novel therapeutic modality for patients with peripheral vascular disease and patients requiring vascular access for hemodialysis.

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Acknowledgements

This work was partially supported by a grant from the Israel Academy of Science.

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Authors and Affiliations

  1. Institute of Hematology, Lady Davis Carmel Medical Center, Haifa, Israel

    M Preis

  2. Department of Vascular Surgery, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    J Schneiderman

  3. Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, Haifa, Israel

    B Koren, Y Ben-Yosef, T Cohen, M Blich, M Israeli-Amit, Y Sarnatzki, D Gershtein, B S Lewis & M Y Flugelman

  4. MultiGene Vascular Systems Ltd, Haifa, Israel

    B Koren, Y Ben-Yosef, T Cohen, M Israeli-Amit, Y Sarnatzki, D Gershtein, B S Lewis & M Y Flugelman

  5. The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel

    D Levin-Ashkenazi, R Shofti, B S Lewis & M Y Flugelman

  6. Immunology Research Unit, Lady Davis Carmel Medical Center, Haifa, Israel

    S Shapiro

  7. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Y Shaul

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  1. M Preis
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Correspondence to M Y Flugelman.

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Competing interests

The following authors are or were employees of MGVS Ltd, Haifa, Israel: Belly Koren, Yaara Ben-Yosef, Dana Levin Ashkenazi, Tzafra Cohen, Mira Israeli-Amit, Yael Sarnatzki, Diana Gershtein. Basil S Lewis and Moshe Y Flugelman are the founders of MGVS Ltd. The following authors are or were supported or consultants to MGVS Ltd, Haifa, Israel: Meir Preis (until 2009), Jacob Schneiderman, Rona Shofti.

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This work was done in Haifa, Israel.

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Preis, M., Schneiderman, J., Koren, B. et al. Co-expression of fibulin-5 and VEGF165 increases long-term patency of synthetic vascular grafts seeded with autologous endothelial cells. Gene Ther 23, 237–246 (2016). https://doi.org/10.1038/gt.2015.104

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