Development of Reformulated Hypertension Pharmaceuticals for Treatment of Diabetic Foot Ulcers

Chronic wounds are deficient in the normal mechanisms that regulate healingand dysregulation of these signaling pathways leads to skin breakdown and poor wound healingMost new wound treatments have not targeted this underlying biochemistrybut have instead focused on treating infection and debridementThe renin angiotensin systemRASis active in connective tissue and skin and has a known role in wound healingEffects of RAS dysregulationincluding thinning epidermiscollagen degenerationdermal layer fractureand subcutaneous fat atrophyare consistent with changes seen in aging skinpredisposing older adults to developing chronic woundsThis vulnerability is compounded by co morbiditiessuch as diabeteswhich also cause RAS dysfunctionWe seek to develop small molecule drug leads that address the biology of chronic woundsOur preliminary data established that a common oral hypertension medication restored healing in animal models with diabetic ulcers when reformulated for topical administration in the wound sitean effort that was funded by an Rgrant from the National Institute on AgingRAGIn Specific Aimwe will screen a larger set of RASeffecting drugs to identify a single lead candidate for focused preclinical developmentWe will establish a pipeline for wound healing drug lead development by screening compounds in tissue culture for effects on RAS driven extracellular matrix remodeling and cell migrationIn Specific Aimtwo lead compounds will be selected based on tissue culture results and will be carried forward into an animal study in an ageddiabetic porcine modelThe effects of topical drug treatment on wounds will be evaluated visually throughout the study and by histologyPCRand skin strength measurements at study conclusionSuccessful completion of these aims will achieve two objectiveswe will identify the lead compound for topical treatment of diabetic ulcers to carry into investigational new drugINDenabling studies in Phaseandwe will establish a verified process by which we can screen compounds and down select lead candidates for drug development to address chronic wound healingThis effort will transition directly into Phasein which we will formulate the lead for IND enabling studiesassess toxicity and pharmacokineticsdevelop chemistry and manufacturing controls procedures to support clinical trialsand develop a regulatory strategy for IND approval and clinical trials Chronic wounds are deficient in the normal mechanisms that regulate healingand dysregulation of these signaling pathways leads to skin breakdown and poor wound healingBuilding upon compelling preliminary data demonstrating that a common oral hypertension medication healed diabetic wounds when reformulated for topical administrationwe will develop a lead drug candidate for topical treatment of diabetic foot ulcersa dangerous condition that predisposes patients to lower extremity amputations and deathThere have been no new FDA approved drugs to treat diabetic foot ulcers in the last ten yearsso innovations that lead to new clinical options for patients and physicians are imperative