Adenoviral-mediated overexpression of platelet-derived growth factor-B corrects ischemic impaired wound healing.
Chronic wounds represent a major clinical problem with significant morbidity and healthcare expenditures, but no effective therapies. Topical platelet-derived growth factor-BB trials have required large and repeated doses to achieve only a modest effect. We examined the ability of an adenovirus containing the platelet-derived growth factor-B transgene to improve the rate of wound healing through induction of platelet-derived growth factor-B overexpression in cells participating in the wound healing response. We treated excisional wounds in the ischemic rabbit ear, which have a 60% delay in healing, with vehicle, 106, or 108 plaque-forming units of an adenovirus containing the platelet-derived growth factor-B per wound (n = 19). At 7 d this resulted in a decrease in the epithelial gap from 3.4 +/- 1 mm (mean +/- SD) in vehicle-treated wounds to 1.9 +/- 1.8 mm (mean +/- SD, p < 0.05) when treated with 106 plaque-forming units of an adenovirus containing the platelet-derived growth factor-B, and 0.7 +/- 1.1 mm (mean +/- SD, p < 0.001) when treated with 108 plaque-forming units of an adenovirus containing the platelet-derived growth factor-B. Ischemic excisional wounds treated with 108 plaque-forming units of an adenovirus containing the platelet-derived growth factor-B even healed more rapidly than non-ischemic excisional wounds treated with vehicle (p < 0.05). In contrast, 5 microg of platelet-derived growth factor-BB protein (n = 2) resulted in only modest granulation tissue at the margin, but no significant differences in epithelial gap (3 +/- 0.6 mm, mean +/- SD). Plaque-forming units (106 or 108) of an adenovirus containing the beta-galactosidase transgene (n = 4) impaired wound re-epithelialization with an epithelial gap of 5.11 +/- 0.69 mm, mean +/- SD, p < 0.004, and 3.8 +/- 0.57 mm, mean +/- SD, p < 0.07, respectively. Adenoviral-mediated gene transfer of platelet-derived growth factor-B overcame the ischemic defect in wound healing and offers promise in the treatment of chronic nonhealing wounds. The vulnerary effects of platelet-derived growth factor-B overexpression were sufficient to overcome the adverse effects of the adenovirus or transgene on wound healing.
Liechty
K W
KW
The Children's Institute for Surgical Science at The Children's Hopsital of Philadelphia, The University of Pennsylvania School of Medicine 19104, USA.
Nesbit
M
M
Herlyn
M
M
Radu
A
A
Adzick
N S
NS
Crombleholme
T M
TM
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000077214:Becaplermin; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007511:Ischemia / Q000503:physiopathology*; D010982:Platelet-Derived Growth Factor / Q000032:analysis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020574:Proto-Oncogene Proteins c-sis; D011817:Rabbits; D019076:Transgenes; D014945:Wound Healing; D014947:Wounds and Injuries / Q000378:metabolism*
D004279:DNA, Viral; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin