FGF2-Targeted adenovirus encoding platelet-derived growth factor-B enhances de novo tissue formation.
Gene therapy has yet to achieve reproducible clinical efficacy, due to inadequate gene delivery, inadequate gene expression, or dose-limiting toxicity. We have developed a gene therapy technology for tissue repair and regeneration that employs a structural matrix for DNA delivery. The matrix holds the DNA vector at the treatment site and provides a scaffolding for in-growth and accumulation of repair cells and efficient DNA transfection. We now report, for the first time, matrix-mediated delivery of targeted DNA vectors for soft tissue repair. A collagen matrix was used to deliver an adenoviral vector encoding platelet-derived growth factor-B (AdPDGF-B), resulting in efficient transgene expression in vitro and in vivo. Increases in the overall levels of expression and in the relative amounts of secreted PDGF-BB were achieved when AdPDGF-B was conjugated to fibroblast growth factor (FGF2) such that the virus was targeted for cellular uptake via FGF receptors. Matrix-mediated delivery of AdPDGF-B enhanced wound healing responses in vivo, and FGF2 targeting generated effects comparable to nontargeted vectors at significantly lower doses. Therefore, matrix-mediated delivery in combination with FGF2 targeting overcomes some of the safety and efficacy limitations of current gene therapy strategies and is an attractive therapeutic approach for tissue repair and regeneration.
Chandler
L A
LA
Selective Genetics, Incorporated, San Diego, California 92121, USA. loisc@selectivegenetics.com
Doukas
J
J
Gonzalez
A M
AM
Hoganson
D K
DK
Gu
D L
DL
Ma
C
C
Nesbit
M
M
Crombleholme
T M
TM
Herlyn
M
M
Sosnowski
B A
BA
Pierce
G F
GF
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D011142:Polyvinyl Alcohol / Q000737:chemistry; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012038:Regeneration; D014162:Transfection; D019076:Transgenes; D014945:Wound Healing
D020574:Proto-Oncogene Proteins c-sis; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D011142:Polyvinyl Alcohol; D003094:Collagen; C496353:FGFR2 protein, human; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2