Adenovirus 5 fibers mutated at the putative HSPG-binding site show restricted retargeting with targeting peptides in the HI loop

Kritz, A. B., Nicol, C. G., Dishart, K. L., Nelson, R., Holbeck, S., Von Seggern, D. J., Work, L. M., Mcvey, J. H., Nicklin, S. A. and Baker, A. H. (2007) Adenovirus 5 fibers mutated at the putative HSPG-binding site show restricted retargeting with targeting peptides in the HI loop. Molecular Therapy, 15, pp. 741-749. (doi:10.1038/sj.mt.6300094)

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Publisher's URL: http://dx.doi.org/10.1038/sj.mt.6300094

Abstract

Adenoviral vectors are commonly used for liver-directed gene therapy following systemic administration owing to their strong propensity for hepatocyte transduction. However, many disease applications would benefit from the delivery of adenoviruses to alternate tissues via this route. Research has thus focused on stripping the virus of native hepatic tropism in conjunction with modifying virus capsid proteins to incorporate novel tropism. Recently, the KO1S* adenovirus serotype 5 fiber mutant, devoid of both coxsackie and adenovirus receptor binding in the fiber knob domain and mutated at the putative heparan sulphate proteoglycan binding site in the fiber shaft, was shown to possess strikingly poor hepatic tropism in mice, rats, and non-human primates. Thus, it is an ideal candidate for retargeting strategies. We therefore assessed the ability of peptide-modified KO1S* fibers to retarget adenovirus. Peptide insertions were well tolerated and virions produced to high titers. However, expected retargeting at the level of transduction was not observed, despite cell-binding studies showing enhanced vector targeting at the cell surface. Cy3 labeling studies showed retarded trafficking of S*-containing fibers. Taken together, our data demonstrates that KO1S* mutant fibers are ineffective for cell retargeting strategies.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Baker, Professor Andrew and Work, Dr Lorraine
Authors: Kritz, A. B., Nicol, C. G., Dishart, K. L., Nelson, R., Holbeck, S., Von Seggern, D. J., Work, L. M., Mcvey, J. H., Nicklin, S. A., and Baker, A. H.
College/School:College of Medical Veterinary and Life Sciences
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:23 January 2007
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
388211Targeted gene therapy for cardiovascular diseaseAndrew BakerMedical Research Council (MRC)G0400052Institute of Cardiovascular and Medical Sciences