Adenovirus Encoding Human Platelet-Derived Growth Factor-B Delivered in Collagen Exhibits Safety, Biodistribution, and Immunogenicity Profiles Favorable for Clinical Use

Abstract

We have developed a therapeutic approach to wound repair involving immobilization of gene transfer vectors within biocompatible matrices (gene-activated matrix, or GAM). The matrix also serves as a scaffold for cellular in-growth and subsequent gene uptake and expression. An adenoviral vector encoding human platelet-derived growth factor-B delivered in collagen (AdPDGF-B/GAM) has demonstrated efficacy in models of wound repair. The safety, biodistribution, and immunogenicity profiles of AdPDGF-B/GAM were examined using a rabbit dermal wound model. Four weekly doses at 1 x 10(10) and 1 x 10(11) viral particles/cm2 of wound surface stimulated dose-related increases in granulation tissue formation and cell proliferation. In situ hybridization and immunostaining demonstrated concordant expression of human PDGF-B mRNA and protein. No treatment-related changes in hematology, serum chemistry, or histopathology were observed. Although AdPDGF-B DNA and PDGF-B mRNA were detected in wounds and axillary lymph nodes of treated animals, no AdPDGF-B was detected in blood or other organs. No immunologic responses against collagen were observed; however, as expected, IgG responses to AdPDGF-B and human PDGF-BB protein were detected. In adenovirus-preimmunized rats, attenuation of the wound healing response was modest (approximately 16%). Collectively, these observations indicate that repeat doses of AdPDGF-B/GAM are well tolerated and lead to robust, localized tissue repair.

Transplantation of BMSCs expressing hPDGF-A/hBD2 promotes wound healing in rats with combined radiation-wound injury

“…Viral and non-viral vectors have been applied to introduce various transgenes, including PDGF, vascular endothelial growth factor, basic fibroblast growth factor and transforming growth factor-b into chronic wounds in animal models 23 to circumvent the limitations of direct application of recombinant proteins, such as rapid degradation. Recombinant adenovirus-delivered transgenes express in a non-persistent, non-integrated manner.…”

RETRACTED: Gene therapy and wound healing

“…In preclinical in vivo models, direct GAM plasmid gene transfer to repair cells in skin, in bone, tendon and ligament, heart and skeletal muscle, and cranial nerve has been reported (88). Clinical trials are underway with a GAM-formulated adenoviral PDGF for diabetic foot ulcers (92).…”

Gene therapy in wound healing: present status and future directions

“…In spite of their limited genome size of 36 kb, they can accommodate up to 34 bp of foreign DNA -10 11 viral particles/ml) and show the ability to transduce both dividing and non-dividing target cells. 20,23 Adenoviruses as carriers were shown to exert a 95% efficiency in infecting skin cells in vitro 24 and safe in regard to infection rates in a skin-transfection model. 25 Integration of viral genome into the host genome does not occur; therefore, the expression of foreign-delivered genes is only temporal.…”