Treating Chronic Wound Infections with Genetically Modified Free Flaps

Ghali, Shadi; Bhatt, Kirit A.; Dempsey, Marlese; Jones, D. L.; Singh, Sunil P.; Arabi, Shahram; Butler, Peter E. M.; Gallo, Richard L.; Gurtner, Geoffrey C.

doi:10.1097/prs.0b013e31819f25a4

Cited by 26 publications

(24 citation statements)

References 40 publications

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“…The importance to the field of VCA is apparent when one considers that a free flap is a vascularized composite autotransplant which shares many of the physiological properties of a VCA without the allotype mismatch. Using ex vivo perfusion of the vascular bed of the free flap with adenovirus viral vector system, Dr. Gurtner and his group have published a series of studies in which they express first a marker gene (LacZ) and then several physiologically active substances, including the angiogenesis inhibitor endostatin, the human cathelicidin antimicrobial peptide-LL37, and IL-12 [116][117][118]. This group coined the term "biologic brachytherapy" to describe the localized delivery of a biologically active molecule using gene transduction of a graft.…”

Section: Gene Therapy In Vcamentioning

confidence: 99%

Strategies for Gene Transfer to Vascularized Composite Allografts

Lough

Cooney

2015

The Science of Reconstructive Transplantation

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Section: Gene Therapy In Vcamentioning

confidence: 99%

Strategies for Gene Transfer to Vascularized Composite Allografts

Lough

Cooney

2015

The Science of Reconstructive Transplantation

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“…It has, in fact, been described in several experimental publications where viral vectors were used for various therapeutic end points, including the production of cytokines to achieve local immune modulation with antitumor effects. 5–10 Outside of this work, there are no other reports of gene-modified tissues being used in this manner.…”

Section: Introductionmentioning

confidence: 99%

Gene-directed enzyme prodrug therapy for localized chemotherapeutics in allograft and xenograft tumor models

et al. 2014

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Most chemotherapy regimens rely on systemic administration of drugs leading to a wide array of toxicities. Using viral-vector-mediated gene modification of muscle tissues, we have developed a method for gene-directed enzyme prodrug therapy that allows for localized drug administration. An inactive prodrug of geldanamycin was activated locally for inhibition of tumor growth without systemic toxicities. A recombinant adeno-associated virus (rAAV) was used to deliver β-galactosidase (LacZ) to the treatment group and green fluorescent protein to the control group. After 1 week, both groups received adenocarcinoma cells in the same location as the previous rAAV injection. The geldanamycin prodrug was administered 1 h later via intraperitoneal injection. Tumor growth was significantly suppressed in animals whose muscles were gene modified to express β-galactosidase compared with the control. Serum assay to access hepatotoxicity resulted in no significant differences between the animals treated with the inactive or activated form of geldanamycin, indicating minimal damage to non-target organs. Using gene-directed enzyme prodrug therapy, in combination with novel recombinant AAV vectors, we have developed a method for localized activation of chemotherapeutic agents that limits the toxicities seen with traditional systemic administration of these potent drugs.

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“…In addition, most of these studies utilized viral transfection methods that are problematic due to preexisting immunogenicity toward adenoviruses in the population, and regulatory challenges in adopting viral approaches for clinical use. Gene therapy approaches in rats using viral transfer of hCAP-18 into infected burn wounds, 17 or by ex vivo transfer of LL-37 into free skin flaps, 18 have also proven successful. These approaches were able to reduce bacterial burden of Pseudomonus aeruginosa or Staphlococcus aureus in their respective studies, further establishing the efficacy of cathelicidin to combat infection in vivo.…”

Section: Clinical Problemmentioning

confidence: 99%