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) (PMID:22929662) (PMCID:PMC3514487)
Full text not currently available from Enlighten.
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: | Baker, Professor Andrew and White, Miss Katie and Robinson, Dr Helen and Nicklin, Professor Stuart and Bradshaw, Dr Angela and Parker, Dr Alan and Coughlan, Dr Lynda |
| 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 > School of Cardiovascular & Metabolic Health |
| Journal Name: | Molecular Therapy |
| Publisher: | Nature Publishing Group |
| ISSN: | 1525-0016 |
| ISSN (Online): | 1525-0024 |
| Published Online: | 28 August 2012 |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information