Therapeutic success and efficacy of nonviral liposomal cDNA gene transfer to the skin in vivo is dose dependent.
It is well documented that responses to growth factor treatment typically display bell-shaped dose responses that can significantly affect efficacy. Here we tested the hypothesis that nonviral liposomal gene delivery also displays this characteristic. We chose two different growth factors, keratinocyte growth factor (KGF) and insulin-like growth factor-I (IGF-I) CMV-driven transfecting constructs at three different concentrations and assessed efficacy on several physiological parameters that are descriptive of wound healing progress in a burn-wound healing model. Rats were given a 60% TBSA scald burn and randomly divided into one of seven groups to receive weekly subcutaneous injections of liposomes containing the cDNA for KGF (0.2 microg, 2.2 microg, or 22.2 microg), or liposomes containing the cDNA for IGF-I (0.2 microg, 2.2 microg, or 22.2 microg) at various concentrations, but constant liposome:DNA ratios and a LacZ gene (0.2 microg) CMV-driven construct for beta-galactosidase as vehicle and marker gene. Transfection was confirmed by histology for beta-galactosidase. Physiological efficacy was evaluated by measuring the wound healing parameters that define dermal and epidermal regeneration. Transfection products were found in the cytoplasm of rapidly dividing cells of the granulation tissue. Different doses of the nonviral cDNA gene transfer coding for KGF or IGF-I resulted in different outcomes for dermal and epidermal regeneration. There was a dose-dependent response to both growth factor gene transfers that was not dissimilar from that typically displayed by treatment with growth factor proteins. Both concentrations below and above the optimal concentration of DNA:liposomal preparations did not yield the results observed at the optimal concentration.
Jeschke
M G
MG
Klinik und Poliklinik für Chirurgie, University of Regensburg, Germany.
Richter
G
G
Herndon
D N
DN
Geissler
E K
EK
Hartl
M
M
Hofstätter
F
F
Jauch
K W
KW
Perez-Polo
J R
JR
D000818:Animals; D017209:Apoptosis; D002056:Burns / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D003094:Collagen / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008081:Liposomes; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D014945:Wound Healing
D018076:DNA, Complementary; C496455:Fgf7 protein, rat; D008081:Liposomes; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D003094:Collagen