Open Access
CC BY 4.0 · Aorta (Stamford) 2022; 10(S 01): A1-A56
DOI: 10.1055/s-0042-1750930
Presentation Abstracts

The Cell Strikes Back: Disease Responsive Gene Therapy for Aortic Aneurysms

Natalija Bogunovic
1   LUMC, Leiden, The Netherlands
2   Amsterdam UMC, Amsterdam, The Netherlands
,
Cindy I. Bart
1   LUMC, Leiden, The Netherlands
,
Juan Zhang
1   LUMC, Leiden, The Netherlands
,
Kak K. Yeung
2   Amsterdam UMC, Amsterdam, The Netherlands
,
Antoine A.F. de Vries
1   LUMC, Leiden, The Netherlands
› Author Affiliations
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    Introduction and Aim: Aortic aneurysms (AA) are pathological dilations of the aorta, associated with high mortality in case of rupture. No pharmacological therapy is available due to the lack of understanding of the molecular mechanisms, leaving surgery as the only option. Infiltration of white blood cells into the aortic wall and secretion of proinflammatory cytokines (e.g., TNFa), as well as increased TGFb signaling are known processes that contribute to AA formation and dysfunction of aortic smooth muscle cells (SMC). The aim of this project is to develop a gene therapy that prevents aortic wall dilation by targeting SMC dysfunction and demonstrating proof-of-principle.

    Work Summary and Results: Lentiviral vectors with promoters responsive to TNFa or TGFb were developed. Healthy control SMC isolated from the aorta of heart-beating kidney donors were transduced with these vectors. Upon stimulation with TNFa or TGFb1, to mimic AA disease signaling, SMC produced green fluorescent protein (GFP) for easy detection. After obtaining proof of concept, GFP will be replaced with a therapeutic gene, e.g., Survivin to prevent inflammation driven apoptosis induced by TNF. Pilot data ([Fig. 1]) demonstrate SMC transduced with lentiviral vector stimulated with 100ng/ml TNFa or 2ng/ml TGFb1 expressing GFP. An increase in the expression of GFP was noticed over time, simulating the increased expression of the therapeutic gene of interest.

    Conclusions: We have demonstrated proof of concept of ?disease responsive? gene therapy for AA related signaling pathways in SMC. After obtaining pilot data in control cells, the gene therapy will be used on AA patients? cells to demonstrate functionality and test the effects of different therapeutic genes. This conceptually new gene therapy can later be tested in animal models of AA to refine the concept for potential therapeutic applications in patients.

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    Fig. 1 Smooth muscle cells transduced with disease responsive viral vectors express GFP upon stimulation. Smooth muscle cells transduced with a disease responsive vector exhibit GFP upon stimulation with 100ng/ml TNFa or 2ng/ml TGFb1. Images are taken after four days.

    Funding

    The study was funded by the Dutch Heart foundation, Dekkerbeurs 2019T065 Senior clinical scientist grant.


     

    No conflict of interest has been declared by the author(s).

    Publication History

    Article published online:
    10 June 2022

    © 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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    Zoom
    Fig. 1 Smooth muscle cells transduced with disease responsive viral vectors express GFP upon stimulation. Smooth muscle cells transduced with a disease responsive vector exhibit GFP upon stimulation with 100ng/ml TNFa or 2ng/ml TGFb1. Images are taken after four days.