Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile.
BACKGROUND
Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.


METHODS
Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).


RESULTS
Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.


CONCLUSIONS
We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.
BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.
Katie M
KM
White
Raul
R
Alba
Alan L
AL
Parker
Audrey F
AF
Wright
Angela C
AC
Bradshaw
Christian
C
Delles
Robert A
RA
McDonald
Andrew H
AH
Baker
D000256:Adenoviridae / Q000235:genetics*; D002213:Capsid; D002478:Cells, Cultured; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D012501:Saphenous Vein; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis / Q000494:pharmacology; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000032:analysis
D019717:Tissue Inhibitor of Metalloproteinase-3; D001616:beta-Galactosidase