Application to vascular adventitia of a nonviral vector for TIMP-1 gene therapy to prevent intimal hyperplasia.
Somatic gene transfer continues to have potential for the study and therapy of cardiovascular disease. We have developed a modular, self-assembling, nonviral system consisting of Lipofectin, integrin-targeting peptides, and plasmid DNA (LID) and we have applied this to a model of vascular injury, rat carotid angioplasty. Marker gene studies identified transfection of adventitial cells after vector delivery to that layer. Human tissue inhibitor of metalloproteinase-1 (hTIMP-1) was tested as a therapeutic gene product after direct application to the exposed adventitial layer. Vascular LID.hTIMP-1 transfection was confirmed by polymerase chain reaction and gene expression by immunohistochemistry at 7 days. Neointimal areas were 0.160 +/- 0.078 and 0.225 +/- 0.052 mm(2) for LID.hTIMP-1-transfected (n = 14) and LID.pCI-transfected (n = 12) vessels, respectively, at 14 days, and 0.116 +/- 0.068 mm(2) (n = 14) and 0.194 +/- 0.095 mm(2) (n = 14), respectively, at 28 days, representing a 29 and 40% reduction in neointimal hyperplasia at 14 and 28 days, respectively, after balloon dilatation. Neointima-to-media ratios were similarly reduced. In addition, expansile remodeling after balloon injury was inhibited at 14 days, the area within the external elastic lamina being 0.50 +/- 0.02 and 0.61 +/- 0.02 mm(2) in LID.hTIMP-1- and LID.pCI-transfected arteries, respectively (p < 0.0005). We have demonstrated an effective system of therapeutic gene transfer, particularly targeting the arterial adventitia, where transfer of genes involved in matrix remodeling and cell migration may be useful.
Meng
Qing-Hai
QH
Molecular Immunology Unit, Institute of Child Health, London WC1N 1EH, UK.
Jamal
Waheed
W
Hart
Stephen L
SL
McEwan
Jean R
JR
D000818:Animals; D020212:Carotid Artery Injuries / Q000473:pathology / Q000628:therapy*; D003238:Connective Tissue / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics; D006965:Hyperplasia / Q000517:prevention & control; D016023:Integrins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010957:Plasmids / Q000737:chemistry; D051381:Rats; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*; D014162:Transfection; D017539:Tunica Intima / Q000473:pathology*
D016023:Integrins; D010455:Peptides; D010714:Phosphatidylethanolamines; D019715:Tissue Inhibitor of Metalloproteinase-1; C020888:1,2-dielaidoylphosphatidylethanolamine