Endograft technology: a delivery vehicle for intravascular gene therapy.

Abstract

PURPOSE:

The purpose of this study was to determine whether vascular smooth muscle cells (SMCs) suffused into a bilayered stent graft retain and express a retrovirally transduced gene for 7 months in vivo.

METHODS:

SMCs harvested from dog jugular vein were retrovirally transduced to introduce genes for tissue plasminogen activator (t-PA) and beta-galactosidase. These cells were then suffused into a novel dual-layered Dacron graft and cultured for 36 to 48 hours. The grafts were mounted on a Palmaz stent and balloon- expanded in the infrarenal aorta of the SMC donor dogs (n = 6). Grafts were recovered at 1, 2, 3, 4, 5, and 7 months. A control endograft suffused with SMCs transduced with only the beta-galactosidase gene was placed in the dogs with grafts recovered at 2, 3, and 4 months. t-PA antigen concentration and expression were analyzed with an enzyme-linked immunosorbent assay.

RESULTS:

Retained engineered SMCs (blue nuclei) were identified in the explanted grafts, neointima, and underlying aorta with X-gal staining. The t-PA antigen concentration and t-PA activity from the SMCs recovered from the grafts remained elevated for the duration of the experiment (7 months) at levels significantly higher (3.7 +/- 0.2 ng/mL per 10(5) cells per 24 hours and 1.4 +/- 0.1 IU/mL per 10(5) cells per 24 hours) than in control endografts (0.5 +/- 0.03 ng/mL per 10(5) cells per 24 hours and 0.07 +/- 0.00 IU/mL per 10(5) cells per 24 hours; P <.001). No graft stenosis was observed.

CONCLUSION:

Retrovirally engineered vascular SMCs survived the implantation trauma, repopulated each graft, migrated into the underlying aorta, and expressed the transduced genes for the 7-month duration of the experiment. This bilayered Dacron endograft model provides a platform to study direct intravascular gene therapy.

• Authors: Darwin Eton, Hong Yu, Yingcai Wang, Jeffrey Raines, Gary Striker, Alan Livingstone
• Journal: Journal of vascular surgery (J Vasc Surg) Vol. 39 Issue 5 Pg. 1066-73 (May 2004) ISSN: 0741-5214 [Print] United States
• PMID: 15111863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Polyethylene Terephthalates
• beta-Galactosidase
• Tissue Plasminogen Activator

Topics

• Animals
• Aorta, Abdominal (surgery)
• Blood Vessel Prosthesis Implantation
• Dogs
• Genetic Therapy (methods)
• Genetic Vectors
• Jugular Veins
• Muscle, Smooth, Vascular (cytology)
• Polyethylene Terephthalates
• Retroviridae
• Stents
• Time Factors
• Tissue Plasminogen Activator (genetics)
• Transduction, Genetic
• beta-Galactosidase (genetics)