Adenovirus encoding human platelet-derived growth factor-B delivered in collagen exhibits safety, biodistribution, and immunogenicity profiles favorable for clinical use.
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.
Gu
Dan-ling
DL
Selective Genetics, Inc., San Diego, CA 92121, USA.
Nguyen
Thanh
T
Gonzalez
Ana Maria
AM
Printz
Marie A
MA
Pierce
Glenn F
GF
Sosnowski
Barbara A
BA
Phillips
M Laurie
ML
Chandler
Lois A
LA
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000917:Antibody Formation; D003094:Collagen / Q000737:chemistry*; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006097:Granulation Tissue / Q000166:cytology / Q000254:growth & development; D008198:Lymph Nodes / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011142:Polyvinyl Alcohol / Q000737:chemistry; D020574:Proto-Oncogene Proteins c-sis / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D012867:Skin / Q000473:pathology; D014945:Wound Healing
D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D011142:Polyvinyl Alcohol; D003094:Collagen