Matrix-Enabled Gene Delivery for Tissue Repair

Background: Inflammatory cells and fibroblasts orchestrate repair of hard and soft tissues by infiltrating the injured site and secreting growth factors and cytokines, stimulating tissue regeneration, progenitor cells, and laying down scar tissue. Although growth factor proteins have demonstrated efficacy in preclinical models of tissue repair, most have failed to produce significant improvements in the clinical setting. The Problem: The limited clinical success of growth factor proteins has been attributed to poor delivery methods and short half-lives. If the gene encoding a growth factor could be transfected into cells in the tissue defect, prolonged production of growth factor could improve efficacy over protein therapy. Combining gene therapy vectors with biocompatible matrices to hold the vector for transfection and provide a scaffolding for cell migration could improve tissue repair. This approach is called gene-activated matrix (GAM). Basic/Clinical Science Advances: Stimulation of tissue repair with GAMs has been demonstrated in preclinical models of cutaneous wound repair, nerve regeneration, ischemia, and bony defects. A phase 1=2 clinical study for the treatment of chronic diabetic neuropathic wounds utilizing the gene encoding human platelet-derived growth factor-B (Ad5PDGF-B in 2.6% collagen, GAM501) demonstratedsafetyandpotentialbiologicalactivity.Adoubled-blinded,randomized, placebo-controlled phase 2b study to evaluate the safety and efficacy of a single and double application is currently underway. Clinical Care Relevance: New treatment options are needed to provide a better daily quality of life and avoid amputations in patients having diabetic foot ulcers. Advanced productssuchas GAM501withasingleordoubleadministrationcould offer medical practitioners and patients an important new treatment option having a potentially higher therapeutic efficacy, as well as enhancing patient compliance.