Wound Care Development

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Summary 1. MicroRNA-based therapeutics Pathogenic transcriptional profiles of non-healing venous ulcers led to the recognition of 1411 differentially regulated genes, 49% of which were suppressed in ulcers. Specific microRNAs (miRNAs) have been indentified that are induced in venous ulcers, contributing to attenuation of signaling pathways that promote wound healing. Furthermore, antagonists have been constructed that specifically inhibit miRNA-mediated down regulation of their target genes to promote healing. Such antagonists represent a new class of therapeutics for chronic and acute wounds, epithelial disorders and a variety of inflammatory conditions. Additionally, they can be formulated to be topically or subcutaneously administered either alone or in conjunction with other therapies. A patent application has been filed for compositions and methods for antagonizing miRNAs over expressed in chronic, non-healing wounds. 2. Small molecule antagonists of GSK3β phosphorylation to promote wound healing Keratinocytes at the leading edge of chronic, non-healing wounds are characterized by activation of glucocorticoid receptors in the skin resulting in GSK3β phosphorylation (on Ser 9) and its subsequent degradation. This in turn leads to accumulation and nuclear translocation of β-catenin where it directs the expression of genes such as c-myc that contributes to chronic wound development. Kinases that directly phosphorylate GSK3β on Ser 9 include protein kinase C (PKC) and its various isoforms. Antagonists that inhibit GSK3β phosphorylation result in the blocking of above processesassociated with chronic wound formation. Antagonists of GSK3β phosphorylation can include inhibitory RNA sequences, PKC inhibitors such as calphostin C or small molecules or peptides that act upstream in the glucocorticoid pathway either by inhibiting its expression or inhibiting its enzymatic activity. A patent application has been filed covering compositions and methods for promotion of epithelialization and wound closure by such antagonists. 3. Modulation of glucocorticoid levels of the epidermis to treat skin disease Glucocorticoids are known inhibitors of wound healing and affect all the essential steps of normal wound healing, including the early inflammatory phase, matrix deposition and angiogenesis. Dr. Brem has established that the epidermis is a steroidogenic tissue that produces and secretes cortisol; with glucocorticoid synthesis and the glucocorticoid receptor pathway erroneously activated in chronic wound tissue. Specifically, chronic wound tissue overexpresses the enzyme CYP11B, responsible for glucocorticoid synthesis and the glucocorticoid receptor is constitutively active. This invention allows for the use of de novo glucocorticoid synthesis antagonists or agonists that would modulate inflammatory responses in the skin order to treat various skin conditions of the skin such as inflammation, acute wounds, chronic non-healing wounds, keloid, fibrotic or hypertrophic scars and epithelial-derived cancer. A patent application has been filed related to methods and compositions that control de novo glucocorticoid synthesis in the skin. 4. Localized delivery of active VEGF to treat diabetic foot ulcers Throughout the wound healing process, angiogenesis maintains a critical role in the healing process. Decreased angiogenesis delays wound closure and in chronic wounds, such as diabetic ulcers, angiogenesis is impaired as long as the wound is present, secondary to multiple etiologies. Dr. Brem has demonstrated in mouse models that application of adenoviral-VEGF leads to angiogenesis and promotes wound healing even when the wound is large. Topical VEGF can be administered as a nucleic acid, in a viral vector, in the form of genetically engineered cells secreting VEGF or as naked DNA. Active VEGF can also be administered to chronic wounds in a sustained release formula. A patent has been issued for a method for treating diabetic foot ulcers based on the above-described technology. 5. Biomarkers of chronic wound tissue Adequate wound debridement is essential for successful outcomes in the management of chronic wounds and is critically important in creating a wound environment receptive to advanced wound therapies. A major challenge to clinicians is the identification of tissue suitable for debridement. Using gene expression profiles and microarray analysis, Dr. Brem has developed a biomarker profile of chronic wound tissue that can be compared to normal tissues. This biomarker profile can be used to determine whether a wound requires further debridement and whether a debridement procedure has been successful. A patent application has been filed covering these biomarkers and methods of using them for criteria in surgical debridement. 6. Prevention of adhesions and scar formation using angiogenesis inhibitors Excessive scar formation is a multi-billion dollar clinical problem, resulting from healed wounds, disease lesions or surgery. Post-surgical intra-abdominal and pelvic adhesions are a cause of significant morbidity and mortality and account for more than 400,000 hospital admissions in the US annually. Therefore, there is an urgent need for treatments that effectively prevent excessive scarring. Inhibitors of angiogenesis such as fumigillin, thalidomide, collagenase inhibitors, penicilliamine or IL-12 can be administered to decrease excessive scarring. A patent has been issued covering such methods and compositions. 7. Enhancing skin quality with VEGF- and GM-CSF-based cosmeceuticals The world market for skin care cosmetics has passed $60 billion and still growing. Cosmeceuticals, being non-prescription cosmetics that include active ingredients with medicinal properties, account for over $7 billion in annual sales. The ability of VEGF to promote angiogenesis, epithelial growth and enhance collagen production and its alignment makes it a popular ingredient in anti-aging products. Similarly, GM-CSF can reverse characteristic skin impairments in animal models of diabetes. Patent applications have been filed covering compositions and methods of use of VEGF and GM-CSF cosmeceuticals for the skin care market.