title: Efficient transduction of primary vascular cells by the rare adenovirus serotype 49 vector.
abstract: Neointima formation and vascular remodeling through vascular smooth muscle cell migration and proliferation can limit the long-term success of coronary interventions, for example, in coronary artery bypass grafting (CABG). Ex vivo gene therapy has the potential to reduce unnecessary cell proliferation and limit neointima formation in vascular pathologies. To date, the species C adenovirus serotype 5 has been commonly used for preclinical gene therapy; however, its suitability is potentially limited by relatively poor tropism for vascular cells and high levels of preexisting immunity in the population. To avoid these limitations, novel species of adenovirus are being tested; here we investigate the potential of adenovirus 49 (Ad49) for use in gene therapy. Transduction of primary human vascular cells by a range of adenovirus serotypes was assessed; Ad49 demonstrated highest transduction of both vascular smooth muscle and endothelial cells. Gene transfer with Ad49 in vascular smooth muscle and endothelial cells was possible following short exposure times (<1 hr) and with low MOI, which is clinically relevant. Ex vivo delivery to surplus CABG tissue showed efficient gene transfer with Ad49, consistent with the in vitro findings. Luminal infusion of Ad49GFP into intact CABG samples ex vivo resulted in efficient vessel transduction. In addition, no seroprevalence rates to Ad49 were observed in a Scottish cohort of patients from cardiovascular clinics, thus circumventing issues with preexisting immunity. Our results show that Ad49 has tropism for vascular cells in vitro and ex vivo and demonstrate that Ad49 may be an improved vector for local vascular gene therapy compared with current alternatives.
authors.affiliation: 1Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Dakin
authors.affiliation: 1Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Parker
authors.affiliation: 1Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom.
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.affiliation: 1Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Nicklin
authors.affiliation: 1Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000256:Adenoviridae / Q000145:classification / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D014161:Transduction, Genetic; D056189:Viral Tropism