Ad5:Ad48 hexon hypervariable region substitutions lead to toxicity and increased inflammatory responses following intravenous delivery

Coughlan, L. et al. (2012) Ad5:Ad48 hexon hypervariable region substitutions lead to toxicity and increased inflammatory responses following intravenous delivery. Molecular Therapy, 20(12), pp. 2268-2281. (doi:10.1038/mt.2012.162)

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Publisher's URL: http://dx.doi.org/10.1038/mt.2012.162

Abstract

The development of adenoviral vectors for intravascular (i.v.) delivery will require improvements to their in vivo safety and efficacy. The hypervariable regions (HVRs) of the Ad5 hexon are a target for neutralizing antibodies, but also interact with factor X (FX), facilitating hepatocyte transduction. Ad48, a species D adenovirus, does not bind FX and has low seroprevalence. Therefore, it has been suggested that Ad5HVR48(1-7), a hexon-chimeric vector featuring the seven HVRs from Ad48, should display advantageous properties for gene therapy, by evading pre-existing Ad5 immunity and blocking FX interactions. We investigated the in vivobiodistribution of Ad5, Ad5HVR48(1-7), and Ad48 following i.v. delivery. Ad5HVR48(1-7) displayed reduced hepatocyte transduction and accumulation in Kupffer cells (KCs), but triggered a robust proinflammatory response, even at relatively low doses of vector. We detected elevated serum transaminases (48 hours) and increased numbers of periportal CD11b<sup>+</sup>/Gr-1<sup>+</sup> cells in the livers of Ad5HVR48(1-7)-treated animals following i.v., but not intramuscular (i.m.), delivery. In contrast, Ad48 did not elevate transaminases or result in the accumulation of CD11b<sup>+</sup>/Gr-1<sup>+</sup>cells. Collectively, these findings suggest that substantial hexon modifications can lead to unexpected properties which cannot be predicted from parental viruses. Therefore, refined mutations may be preferential for the successful development of targeted vector systems which require i.v. administration.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Bradshaw, Dr Angela and Baker, Professor Andrew and White, Miss Katie and Parker, Dr Alan and Coughlan, Dr Lynda and Robinson, Dr Helen
Authors: Coughlan, L., Bradshaw, A. C., Parker, A. L., Robinson, H., White, K., Custers, J., Goudsmit, J., Van Roijen, N., Barouch, D. H., Nicklin, S. A., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Molecular Therapy
Publisher:Nature Publishing Group
ISSN:1525-0016
ISSN (Online):1525-0024
Published Online:28 August 2012
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
486621Interrogation of the adenovirus hexon: A new paradigm for virus biology and application to therapeutic gene deliveryAndrew BakerBiotechnology and Biological Sciences Research Council (BBSRC)BB/G016844/1RI CARDIOVASCULAR & MEDICAL SCIENCES
478611Interrogation and manipulation of micro RNA during differentiation of human ES cells to cardiomyocyte and vascular lineagesAndrew BakerBritish Heart Foundation (BHF)PG/08/107/26160RI CARDIOVASCULAR & MEDICAL SCIENCES