Chronic wounds are a significant worldwide problem with enormous health-related and economic impacts. These adversities are particularly striking in patients with diabetes mellitus, who have an estimated lifetime incidence rate of 19-34%, with a cost of total patient care of ~$25B. Two key issues hindering repair include limitations in growth factor activity and accessibility, and the prevalence of infection and biofilm formation in the chronic wound environment. Our studies demonstrate a new approach with a high likelihood to overcome these issues through application of collagen mimetic peptides (CMPs) as drivers of growth factor gene therapy and drug delivery during wound healing. Local gene therapies offer compelling potential advantages for improved growth factor delivery due to their modularity and inherent benefits in protein stability, protein bioactivity, sustained release, and cost, as well as the relative ease of delivering multiple genes and the spatial control achievable through use of tissue-specific promoters. CMP gene therapies, in particular, provide exceptionally stable and tunable links between DNA nanocarriers (polyplexes) and collagen, leading to localized and efficient expression of growth factors including PDGF and VEGF, even after prolonged exposure to serum. This talk will highlight the design principles underlying CMP gene scaffold design for application in wound repair, along with results demonstrating the efficacy of CMP-PDGF and CMP-VEGF gene therapies for inducing faster wound closure with minimal scar formation as well as improved collagen production, myofibroblast activity, collagen orientation, and angiogenesis in murine wounds. We also highlight new work showing the benefits of CMPs for controlling the delivery of multiple gene and/or drug therapeutics in the wound environment to enable holistic wound management. These results are indicative of the potential of matrix-modified biomaterial scaffolds in effective treatment of chronic non-healing wounds.

Peptide-mediated growth factor gene therapy using extracellular matrix-inspired biomaterials

ACS Fall 2021

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