Efficient transduction of primary vascular cells by the rare adenovirus serotype 49 vector

Dakin, R. S., Parker, A. L., Delles, C. , Nicklin, S. A. and Baker, A. H. (2015) Efficient transduction of primary vascular cells by the rare adenovirus serotype 49 vector. Human Gene Therapy, 26(5), pp. 312-319. (doi:10.1089/hum.2015.019) (PMID:25760682) (PMCID:PMC4442572)

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Abstract

Neointima formation and vascular remodelling 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 (Ad5) has been commonly used for pre-clinical gene therapy, however its suitability is potentially limited by relatively poor tropism for vascular cells and high levels of pre-existing 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 (*lt;1hr) 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 seroprevelance rates to Ad49 were observed in a Scottish cohort of patients from cardiovascular clinics, thus circumventing issues with pre-existing immunity. Our results show Ad49 has tropism for vascular cells in vitro and ex vivo and demonstrate Ad49 may be an improved vector for local vascular gene therapy compared to current alternatives.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Baker, Professor Andrew and Dakin, Dr Rachel and Delles, Professor Christian
Authors: Dakin, R. S., Parker, A. L., Delles, C., Nicklin, S. A., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Human Gene Therapy
Publisher:Mary Ann Liebert, Inc.
ISSN:1043-0342
ISSN (Online):1557-7422
Copyright Holders:Copyright © 2015 Rachel S. Dakin et al.
First Published:First published in Human Gene Therapy 26(5):312-319
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
595071ADENOVIRUS SEROTYPE 49: A NOVEL VECTOR FOR VASCULAR GENE THERAPYAndrew BakerBritish Heart Foundation (BHF)PG/12/19/29455RI CARDIOVASCULAR & MEDICAL SCIENCES