Cutaneous fibrosis (scarring) affects up to 100 million patients per year in developed countries. Scarring - especially hypertrophic scarring - can have significant morphologic and functional sequelae, requiring multiple revision surgeries to restore function and improve appearance. The incidence of hypertrophic scarring varies 40-70% following surgery, and can be up to 90% following burn injury. Current methods for the treatment of hypertrophic scars are minimally effective or have undesirable side effects. Steroids (e.g. Triamcinolone) are FDA-approved for intralesional injection into hypertrophic scars, but have significant side effects including granulomas and skin atrophy that leads to reduced wound strength. Moreover, many hypertrophic scars are refractory to steroids or other non-surgical therapies and require revision surgery. However, revision surgery for hypertrophic scar also has a high rate of recurrence. Through a sustained, 12 year research effort examining models of fetal wound healing, we have identified fibromodulin (FMOD) as a novel molecule required for fetal scarless skin repair. In a technological innovation, we have identified a 40 amino acid peptide sequence, F06-C40, which has similar anti-fibrotic effects as the 376 amino acid full FMOD protein. Excitingly, we have demonstrated using a pig model of human hypertrophic scarring that both FMOD protein and its peptide derivative F06-C40 can significantly reduce scar formation. In this proposal, we will test the hypothesis that F06-C40 is more efficacious than corticosteroids for reduction of hypertrophic scar formation. AIM 1 (Months 1-12): Optimize F06-C40 for scar prevention in pig hypertrophic scar models and compare it with corticosteroids. AIM 1 will optimize the dose of F06-C40 for hypertrophic scar reduction and compare the optimized formulation with corticosteroid injection. Two wound models in Red Duroc pigs, a porcine breed that most closely simulates human hypertrophic scarring, will be used. Primary outcome measures will include improved gross visual appearance without a reduction in wound tensile strength. AIM 2 (Months 13-24): Accomplish initial safety studies for F06-C40 first-in-man studies. AIM 2 will focus on accomplishing key studies required by the FDA at the pre-IND meeting for F06-C40. Studies will consist of preliminary genotoxicity and intravenous toxicology studies in rats. Hypertrophic scars cause significant functional and cosmetic impairment. This SHIFT SBIR proposal focuses on optimizing the treatment regimen for F06-C40, proving its superior efficacy compared with current strategies for scar reduction, and verifying its initial product safety.
Public Health Relevance Statement: Public Health Relevance: Costs of excessive cutaneous scarring and other wound healing complications approach 3 billion dollars per annum and up to 100 million patients acquire scars per year. In addition, hypertrophic scarring is especially prevalent in minority populations, while pathologic scarring affects numerous other organ systems such as liver, lung, and kidney in often fatal disease processes. This project seeks to develop effective, novel peptide- based treatment to reduce hypertrophic scarring.
Project Terms: Adjuvant; Adrenal Cortex Hormones; Adult; Adverse effects; Affect; Algorithms; Alternative Therapies; Amino Acids; analog; Animals; Appearance; Atrophic condition of skin; base; Biological Models; Biomechanics; body system; Breeding; Burn injury; Bypass; Cells; Cicatrix; clinical practice; commercialization; comparative efficacy; Cosmetics; cost; Cutaneous; cytotoxicity; Developed Countries; Development; Disease; Dose; Drug Formulations; efficacy testing; Exhibits; Extracellular Matrix; Family suidae; FDA approved; fetal; fibromodulin; Fibrosis; functional restoration; Generations; genotoxicity; Goals; Granuloma; Health; Histology; Human; Hypertrophic Cicatrix; Image; Impairment; improved; In Vitro; in vivo; Incidence; Injectable; Injection of therapeutic agent; innovation; Intralesional Injections; Intravenous; Keloid; Kidney; Knockout Mice; Label; Laboratories; Laser Scanning Confocal Microscopy; Lasers; Liver; Liver Cirrhosis; Lung; man; meetings; Methods; Minority; Modeling; Mus; novel; Ointments; operation; Operative Surgical Procedures; Outcome Measure; Pathologic; Patients; Peptides; Population; Prevention; primary outcome; Process; Production; protein aminoacid sequence; Proteins; Pulmonary Fibrosis; Rattus; Recurrence; Refractory; repaired; Research; Resolution; Safety; safety study; safety testing; Scleroderma; second harmonic; Silicones; Skin; Small Business Innovation Research Grant; Steroids; success; Techniques; technological innovation; Tensile Strength; Testing; Time; Toxic effect; Toxicology; Trauma; Treatment Protocols; Triamcinolone; Ultrasonography; Visual; wound; Wound Healing
