title: Heparan sulfate proteoglycan binding properties of adeno-associated virus retargeting mutants and consequences for their in vivo tropism.
abstract: Adeno-associated virus type 2 (AAV-2) targeting vectors have been generated by insertion of ligand peptides into the viral capsid at amino acid position 587. This procedure ablates binding of heparan sulfate proteoglycan (HSPG), AAV-2's primary receptor, in some but not all mutants. Using an AAV-2 display library, we investigated molecular mechanisms responsible for this phenotype, demonstrating that peptides containing a net negative charge are prone to confer an HSPG nonbinding phenotype. Interestingly, in vivo studies correlated the inability to bind to HSPG with liver and spleen detargeting in mice after systemic application, suggesting several strategies to improve efficiency of AAV-2 retargeting to alternative tissues.
authors.affiliation: Genzentrum, Ludwig-Maximilians-Universität München, Feodor-Lynen-Str. 25, Munich, Germany.
authors.forename: Luca
authors.initials: L
authors.lastname: Perabo
authors.forename: Daniela
authors.initials: D
authors.lastname: Goldnau
authors.forename: Kathryn
authors.initials: K
authors.lastname: White
authors.forename: Jan
authors.initials: J
authors.lastname: Endell
authors.forename: Jorge
authors.initials: J
authors.lastname: Boucas
authors.forename: Sibille
authors.initials: S
authors.lastname: Humme
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Work
authors.forename: Hanna
authors.initials: H
authors.lastname: Janicki
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.forename: Hildegard
authors.initials: H
authors.lastname: Büning
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism*; D018390:Gene Targeting; D005822:Genetic Vectors / Q000235:genetics; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000821:virology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009928:Organ Specificity / Q000235:genetics; D019151:Peptide Library; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism / Q000821:virology; D014161:Transduction, Genetic
chemical_list: D019812:Heparan Sulfate Proteoglycans; D019151:Peptide Library; D011991:Receptors, Virus