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Published on: September 9, 2011
Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised,
M J Mann1, A D Whittemore, M C Donaldson
1Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Background:
Cell-cycle blockade by ex-vivo gene therapy of experimental vein grafts inhibits the neointimal hyperplasia and subsequent accelerated atherosclerosis that lead to human bypass-graft failure. In a prospective, randomised, controlled trial, we investigated the safety and biological efficacy of intraoperative gene therapy in patients receiving bypass vein grafts.
Methods:
We studied gene therapy that uses decoy oligodeoxynucleotide, which binds and inactivates the pivotal cell-cycle transcription factor E2F. 41 patients were randomly assigned untreated (16), E2F-decoy-treated (17), or scrambled-oligodeoxynucleotide-treated (eight) human infrainguinal vein grafts. Oligonucleotide was delivered to grafts intraoperatively by ex-vivo pressure-mediated transfection. The primary endpoints were safety and inhibition of target cell-cycle regulatory genes and of DNA synthesis in the grafts. Analysis was by intention to treat.
Findings:
Mean transfection efficiency was 89.0% (SD 1.9). Proliferating-cell nuclear antigen and c-myc mRNA concentrations and bromodeoxyuridine incorporation were decreased in the EF2-decoy group by medians of 73% [IQR 53-84], 70% [50-79], and 74% [56-83], respectively) but not in the scrambled-oligodeoxynucleotide group (p<0.0001). Groups did not differ for postoperative complication rates. At 12 months, fewer graft occlusions, revisions, or critical stenoses were seen in the E2F-decoy group than in the untreated group (hazard ratio 0.34 [95% CI 0.12-0.99]).
Interpretation:
Intraoperative transfection of human bypass vein grafts with E2F-decoy oligodeoxynucleotide is safe, feasible, and can achieve sequence-specific inhibition of cell-cycle gene expression and DNA replication. Application of this genetic-engineering strategy may lower failure rates of human primary bypass vein grafting.
Insights
Intraoperative gene therapy using E2F-decoy oligodeoxynucleotide safely inhibits cell-cycle progression in vein grafts. This novel approach shows promise in reducing bypass graft failure in patients.
Area of Science:
- Vascular Surgery
- Gene Therapy
- Molecular Biology
Background:
- Vein graft failure due to neointimal hyperplasia and atherosclerosis is a significant clinical challenge.
- Ex-vivo gene therapy targeting cell-cycle blockade has shown potential in experimental models.
- This study evaluates the safety and efficacy of intraoperative gene therapy in human bypass vein grafts.
Purpose of the Study:
- To assess the safety and biological efficacy of intraoperative gene therapy using E2F-decoy oligodeoxynucleotide in human infrainguinal vein grafts.
- To determine the ability of this gene therapy to inhibit target cell-cycle regulatory genes and DNA synthesis.
- To evaluate the impact on clinical outcomes such as graft occlusion and stenosis.
Main Methods:
- A prospective, randomized, controlled trial involving 41 patients undergoing infrainguinal vein bypass grafting.
- Patients were assigned to untreated, E2F-decoy-treated, or scrambled-oligodeoxynucleotide-treated groups.
- Oligonucleotide delivery was achieved via ex-vivo pressure-mediated transfection during surgery.
Main Results:
- High transfection efficiency (89.0%) was achieved with E2F-decoy oligodeoxynucleotide.
- Significant inhibition of cell-cycle markers (PCNA, c-myc mRNA) and DNA synthesis (BrdU incorporation) was observed in the E2F-decoy group (p<0.0001).
- The E2F-decoy group showed a reduced incidence of graft occlusion, revision, or critical stenosis at 12 months compared to the untreated group (HR 0.34).
Conclusions:
- Intraoperative E2F-decoy oligodeoxynucleotide transfection is a safe and feasible method for human bypass vein grafts.
- This gene therapy effectively achieves sequence-specific inhibition of cell-cycle gene expression and DNA replication.
- This genetic engineering strategy holds potential for improving the long-term patency rates of primary bypass vein grafts.
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