Molecular adaptors for vascular-targeted adenoviral gene delivery

TY - JOUR

T1 - Molecular adaptors for vascular-targeted adenoviral gene delivery

AU - Trepel, M

AU - Grifman, M

AU - Weitzman, Matthew D

AU - Pasqualini, Renata

PY - 2000/9/20

Y1 - 2000/9/20

N2 - Gene therapy would be considerably more effective if vectors could be targeted to specific organs or tissues after systemic administration. We previously developed an in vivo selection system to isolate organ- and tumor-homing peptides from phage display peptide libraries. The peptides isolated by this approach bind to receptors expressed in vascular endothelia. We describe here the development of molecular adaptors to target adenoviral gene therapy vectors to selective vascular "addresses." The adaptor design consists of an organhoming peptide conjugated to an adenovirus-binding moiety. We isolated and characterized several monoclonal antibodies that bind to adenovirus type 5 (Ad5). Two of the antibodies neutralized Ad5 infection. We linked the Fab fragments of one of these antibodies to a synthetic lung-homing peptide (CGFECVRQCPERC or GFE-1 peptide) and tested the ability of the resulting bispecific conjugate to retarget Ad5. Cells that express the receptor for the GFE-1 peptide and are resistant to Ad5 infection were sensitized to recombinant Ad5 vectors in the presence of the Fab-GFE adaptor. Our findings indicate that selective gene therapy delivery may be developed on the basis of our vascular targeting technology.

AB - Gene therapy would be considerably more effective if vectors could be targeted to specific organs or tissues after systemic administration. We previously developed an in vivo selection system to isolate organ- and tumor-homing peptides from phage display peptide libraries. The peptides isolated by this approach bind to receptors expressed in vascular endothelia. We describe here the development of molecular adaptors to target adenoviral gene therapy vectors to selective vascular "addresses." The adaptor design consists of an organhoming peptide conjugated to an adenovirus-binding moiety. We isolated and characterized several monoclonal antibodies that bind to adenovirus type 5 (Ad5). Two of the antibodies neutralized Ad5 infection. We linked the Fab fragments of one of these antibodies to a synthetic lung-homing peptide (CGFECVRQCPERC or GFE-1 peptide) and tested the ability of the resulting bispecific conjugate to retarget Ad5. Cells that express the receptor for the GFE-1 peptide and are resistant to Ad5 infection were sensitized to recombinant Ad5 vectors in the presence of the Fab-GFE adaptor. Our findings indicate that selective gene therapy delivery may be developed on the basis of our vascular targeting technology.

KW - Adenoviridae

KW - Animals

KW - Antibodies, Monoclonal

KW - Blotting, Western

KW - Cell Line

KW - Cell Membrane

KW - Dose-Response Relationship, Drug

KW - Endothelium, Vascular

KW - Enzyme-Linked Immunosorbent Assay

KW - Female

KW - Gene Transfer Techniques

KW - Genetic Vectors

KW - HeLa Cells

KW - Humans

KW - Immunoglobulin Fab Fragments

KW - Mice

KW - Mice, Inbred BALB C

KW - Microscopy, Fluorescence

KW - Peptide Library

KW - Precipitin Tests

KW - Tumor Cells, Cultured

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

KW - Research Support, U.S. Gov't, P.H.S.

U2 - 10.1089/10430340050143408

DO - 10.1089/10430340050143408

M3 - SCORING: Journal article

C2 - 11020797

VL - 11

SP - 1971

EP - 1981

JO - HUM GENE THER

JF - HUM GENE THER

SN - 1043-0342

IS - 14

ER -