Linked Life Data

12727115

Source:http://linkedlifedata.com/resource/pubmed/id/12727115

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2003-5-2
pubmed:abstractText
Recombinant adeno-associated virus (AAV) has become an attractive vector system for a number of gene therapy paradigms. However, the utility of AAV vectors is often limited by the absence of heparan sulfate proteoglycan (HSPG), the virus's primary attachment receptor, on the desired target cell population. In order to achieve HSPG-independent gene delivery, several groups have shown that the endogenous tropism of AAV can be expand by genetically altering the viral capsid. However, the parameters of this developing technology have yet to be defined and it has not yet been determined if these modified vectors actually infect cells via these engineered interactions. Previously we constructed a series of insertion mutants spanning the AAV capsid protein gene and identified specific sites that can tolerate the insertion of small exogenous peptides. Here we describe a number of sites within the AAV capsid gene that can be used for the insertion of integrin-targeting peptide epitopes. Incorporation of an Arg-Gly-Asp (RGD)-containing peptide at these sites enables AAV to infect integrin-expressing cells independent of HSPG. Mutant AAV vectors displaying these peptide ligands can be produced to wild-type titer and have been shown to specifically interact with the targeted integrin receptors and mediate infection via this interaction. We report significant increases in gene transfer to Raji, K562, and SKOV-3 cell lines that express integrin, but little HSPG, suggesting that rAAV vectors displaying RGD peptides may be of great utility for treatment of neoplasms characterized by the deficiency of HSPG expression. We have also demonstrated that due to their expanded tropism, these novel vectors are capable of efficient transduction of AAV2-resistant tumors in vivo suggesting that they may offer significant therapeutic advantages.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1525-0016
pubmed:author
pubmed:issnType
Print
pubmed:volume
7
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
515-25
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12727115-Animals, pubmed-meshheading:12727115-Biological Transport, pubmed-meshheading:12727115-Capsid Proteins, pubmed-meshheading:12727115-Cell Culture Techniques, pubmed-meshheading:12727115-Dependovirus, pubmed-meshheading:12727115-Epitopes, pubmed-meshheading:12727115-Female, pubmed-meshheading:12727115-Genetic Vectors, pubmed-meshheading:12727115-HeLa Cells, pubmed-meshheading:12727115-Heparin, pubmed-meshheading:12727115-Humans, pubmed-meshheading:12727115-Integrins, pubmed-meshheading:12727115-K562 Cells, pubmed-meshheading:12727115-Mice, pubmed-meshheading:12727115-Mice, SCID, pubmed-meshheading:12727115-Oligopeptides, pubmed-meshheading:12727115-Ovarian Neoplasms, pubmed-meshheading:12727115-Proteoglycans, pubmed-meshheading:12727115-Tumor Cells, Cultured, pubmed-meshheading:12727115-Virion
pubmed:year
2003
pubmed:articleTitle
RGD inclusion in VP3 provides adeno-associated virus type 2 (AAV2)-based vectors with a heparan sulfate-independent cell entry mechanism.
pubmed:affiliation
Division of Molecular Medicine, Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA.
pubmed:publicationType
Journal Article, Comment, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't