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Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial.

Publication ,  Journal Article
Mann, MJ; Whittemore, AD; Donaldson, MC; Belkin, M; Conte, MS; Polak, JF; Orav, EJ; Ehsan, A; Dell'Acqua, G; Dzau, VJ
Published in: Lancet
October 30, 1999

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.

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Published In

Lancet

DOI

ISSN

0140-6736

Publication Date

October 30, 1999

Volume

354

Issue

9189

Start / End Page

1493 / 1498

Location

England

Related Subject Headings

  • Transfection
  • Transcription Factors
  • Transcription Factor DP1
  • Statistics, Nonparametric
  • Retinoblastoma-Binding Protein 1
  • Proto-Oncogene Proteins c-myc
  • Proliferating Cell Nuclear Antigen
  • Oligonucleotides
  • Middle Aged
  • Male
 

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Mann, M. J., Whittemore, A. D., Donaldson, M. C., Belkin, M., Conte, M. S., Polak, J. F., … Dzau, V. J. (1999). Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial. Lancet, 354(9189), 1493–1498. https://doi.org/10.1016/S0140-6736(99)09405-2
Mann, M. J., A. D. Whittemore, M. C. Donaldson, M. Belkin, M. S. Conte, J. F. Polak, E. J. Orav, A. Ehsan, G. Dell’Acqua, and V. J. Dzau. “Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial.Lancet 354, no. 9189 (October 30, 1999): 1493–98. https://doi.org/10.1016/S0140-6736(99)09405-2.
Mann MJ, Whittemore AD, Donaldson MC, Belkin M, Conte MS, Polak JF, et al. Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial. Lancet. 1999 Oct 30;354(9189):1493–8.
Mann, M. J., et al. “Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial.Lancet, vol. 354, no. 9189, Oct. 1999, pp. 1493–98. Pubmed, doi:10.1016/S0140-6736(99)09405-2.
Mann MJ, Whittemore AD, Donaldson MC, Belkin M, Conte MS, Polak JF, Orav EJ, Ehsan A, Dell’Acqua G, Dzau VJ. Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial. Lancet. 1999 Oct 30;354(9189):1493–1498.
Journal cover image

Published In

Lancet

DOI

ISSN

0140-6736

Publication Date

October 30, 1999

Volume

354

Issue

9189

Start / End Page

1493 / 1498

Location

England

Related Subject Headings

  • Transfection
  • Transcription Factors
  • Transcription Factor DP1
  • Statistics, Nonparametric
  • Retinoblastoma-Binding Protein 1
  • Proto-Oncogene Proteins c-myc
  • Proliferating Cell Nuclear Antigen
  • Oligonucleotides
  • Middle Aged
  • Male