title: Derivation of a myeloid cell-binding adenovirus for gene therapy of inflammation.
abstract: The gene therapy field is currently limited by the lack of vehicles that permit efficient gene delivery to specific cell or tissue subsets. Native viral vector tropisms offer a powerful platform for transgene delivery but remain nonspecific, requiring elevated viral doses to achieve efficacy. In order to improve upon these strategies, our group has focused on genetically engineering targeting domains into viral capsid proteins, particularly those based on adenovirus serotype 5 (Ad5). Our primary strategy is based on deletion of the fiber knob domain, to eliminate broad tissue specificity through the human coxsackie-and-adenovirus receptor (hCAR), with seamless incorporation of ligands to re-direct Ad tropism to cell types that express the cognate receptors. Previously, our group and others have demonstrated successful implementation of this strategy in order to specifically target Ad to a number of surface molecules expressed on immortalized cell lines. Here, we utilized phage biopanning to identify a myeloid cell-binding peptide (MBP), with the sequence WTLDRGY, and demonstrated that MBP can be successfully incorporated into a knob-deleted Ad5. The resulting virus, Ad.MBP, results in specific binding to primary myeloid cell types, as well as significantly higher transduction of these target populations ex vivo, compared to unmodified Ad5. These data are the first step in demonstrating Ad targeting to cell types associated with inflammatory disease.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Alberti
authors.forename: Justin C
authors.initials: JC
authors.lastname: Roth
authors.forename: Mourad
authors.initials: M
authors.lastname: Ismail
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuruta
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
authors.forename: Larisa
authors.initials: L
authors.lastname: Pereboeva
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics* / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D022423:Myeloid Cells / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D019151:Peptide Library; D011485:Protein Binding
chemical_list: D010446:Peptide Fragments; D019151:Peptide Library