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Stent-based delivery of AAV2 vectors encoding oxidation-resistant apoA1
Bahman Hooshdaran1, Benjamin B Pressly1, Ivan S Alferiev1,2
1Division of Cardiology, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, CHOP, ARC, Room 702 C, Philadelphia, PA, 19104, USA.
Scientific Reports
|April 1, 2022
Summary
This study explored using gene therapy with oxidation-resistant apolipoprotein A1 (apoA1) to prevent in-stent restenosis. While feasible, delivering apoA1 via gene delivery stents did not prevent restenosis in severe atherosclerotic pigs.
Area of Science:
- Cardiovascular Research
- Gene Therapy
- Atherosclerosis
Background:
- In-stent restenosis (ISR) is a complication following arterial revascularization.
- Oxidative modification of apolipoprotein A1 (apoA1) diminishes its protective functions.
- An oxidation-resistant apoA1 variant (4WF) was engineered to retain functionality under oxidative stress.
Purpose of the Study:
- To investigate the efficacy of adeno-associated viral (AAV) vector-mediated local delivery of oxidation-resistant apoA1 (4WF) in preventing ISR.
- To assess the functional preservation of apoA1(4WF) compared to wild-type apoA1 (WT) under oxidative conditions.
- To evaluate the feasibility and effectiveness of AAV gene delivery stents (GDS) for ISR mitigation.
Main Methods:
- In vitro studies assessed cholesterol efflux from macrophages and proliferation of smooth muscle cells (SMC) and endothelial cells (EC) transduced with apoA1(WT) or apoA1(4WF).
- Reactive oxygen species (ROS) production and monocyte attachment to activated endothelium were measured.
- AAV vectors were immobilized on stainless steel mesh to model stent-based delivery, and in vivo studies used gene delivery stents in pigs.
Main Results:
- ApoA1(4WF) enhanced cholesterol efflux from macrophages under oxidative stress compared to apoA1(WT).
- Both apoA1(WT) and apoA1(4WF) inhibited SMC proliferation but increased endothelial cell proliferation.
- Stent delivery of AAV2-apoA1(4WF) failed to prevent in-stent restenosis in hypercholesterolemic diabetic pigs.
Conclusions:
- Local delivery of AAV vectors expressing oxidation-resistant apoA1(4WF) preserves some apoA1 functions in vitro.
- Stent-based delivery of AAV2-apoA1(4WF) is technically feasible but ineffective in mitigating ISR in a severe atherosclerotic model.
- Further strategies are needed to overcome the limitations of gene therapy for ISR in advanced disease states.
