Gene Therapy-mediated Angiogenesis of Transplanted Fat
Xue Dong*1, Sadia Salahuddin2, Miguel de Mulder Rougvie2, Philip Leopold2, Jonathan Rosenberg2, Neil R. Hackett2, Ronald G. Crystal2, Jason A. Spector1
1Surgery, Weill Cornell Medical College, New York, NY; 2Genetic Medicine, Weill Cornell Medical College, New York, NY
Autologous fat transfer is an increasingly common aesthetic procedure. However, the long-term results are often disappointing due to the variable and often significant loss of up to 70% or more of the graft, as well as complications such as fat necrosis/nodule or oil cyst formation. The primary cause of all these negative outcomes is insufficiently rapid and robust vascularization of the fat following transplantation. Thus, we propose genetically modifying harvested fat prior to transplantation with an adenovirus (Ad) gene transfer vector coding for all 3 major isoforms of vascular endothelial growth factor (VEGF) (capable of inducing expression for 1-2 weeks), to improve angiogenesis and promote engraftment of transplanted fat.
Fat was harvested via standard liposuction from the abdomen and concentrated by decantation followed by Telfa rolling. Ad5VEGF-All6A+, a E1-E3- serotype 5 Ad vector coding for all 3 major isoforms of hVEGF 121, 165 and 189, was administrated to the harvested autologous fat at different doses (109 and 1010 pfu) and incubated for 1 hour before in vivo subcutaneous implantation in nude mice with 500ul fat graft each side. Fat graft mixed with Ad-null (1010 pfu) was also implanted as control.
Upon assessment of fat grafts on day 7, there was significantly improved vascular formation grossly on the surface of fat grafts and enlarged branches of nearby subcutaneous blood vessels in the high Ad vector group when compared to the low Ad and Ad-null groups. Histologic findings also demonstrated significantly increased vessel formation between viable adipocytes in Ad vector groups, especially the higher dose group. No evidence of off target effects was seen.
We have demonstrated the administration of Ad5VEGF-All6A+ to human lipoaspirate significantly increased the vascularity after in vivo implantation for 7 days, which we hypothesize is crucial to rescue ischemic transplanted fat. Studies of long-term fat grafting retention and evaluation of overall safety are continuing.
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