Treating chronic wound infections with genetically modified free flaps.
BACKGROUND
The success of antimicrobial therapy has been impaired by the emergence of resistant bacterial strains. Antimicrobial peptides are ubiquitous proteins that are part of the innate immune system and are successful against such antibiotic-resistant microorganisms. The authors have previously demonstrated the feasibility of protein delivery via microvascular free flap gene therapy and here they examine this approach for recalcitrant infections.


METHODS
The authors investigated the production of the human cathelicidin antimicrobial peptide-LL37, delivered by ex vivo transduction of the rodent superficial inferior epigastric free flap with Ad/CMV-LL37. The vascular permeabilizing agent vascular endothelial growth factor (VEGF) was co-administered during ex vivo transduction with adenoviral vectors in an attempt to augment transduction efficiency. A rodent model of chronic wound/foreign body infection seeded with bioluminescent Staphylococcus aureus was used to assess the biological efficacy of delivering therapeutic antimicrobial genes using this technology.


RESULTS
The authors were successful in demonstrating significant LL37 expression, which persisted for 14 days after ex vivo transduction with Ad/CMV-LL37. Transduction efficiency was significantly improved with the co-administration of 5 micrograms of VEGF during transduction without significantly increasing systemic dissemination of adenovirus or systemic toxicity. They were able to demonstrate in the rodent model of chronic wound/foreign body infections a significant reduction in bacterial loads from infected catheters following transduction with Ad/CMV-LL37 and increased bacterial clearance.


CONCLUSIONS
This study demonstrates for the first time that microbicidal gene therapy via microvascular free flaps is able to clear chronic infections such as occurs with osteomyelitis resulting from trauma or an infected foreign body [corrected]
Ghali
Shadi
S
Stanford and San Diego, Calif.; and London, United Kingdom From the Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine, the Department of Plastic and Reconstructive Surgery, Royal Free Hospital, and the Division of Dermatology, University of California, San Diego.
Bhatt
Kirit A
KA
Dempsey
Marlese P
MP
Jones
Deidre M
DM
Singh
Sunil
S
Arabi
Shahram
S
Butler
Peter E
PE
Gallo
Robert L
RL
Gurtner
Geoffrey C
GC