Cutaneous fibrosis (scarring) affects up to 100 million patients per year as a result of 55 million elective operations and 25 million operations after trauma. Besides concerns of cosmesis, scarring can have significant functional sequel. Overall, scar prevention strategies for skin are minimally effective. Currently available techniques focus on reducing the appearance of already formed scars (e.g., silicone sheeting, topical ointments, and lasers). Other scar reduction strategies that target the scar formation process such as steroids and radiation can have undesirable side effects. With these substantial limitations, there remains a pressing need for the development of alternative therapies for the prevention of cutaneous scarring. Through a sustained, 11-year research effort examining models of fetal wound healing; we have identified fibromodulin (FMOD) as a novel molecule required for fetal scarless skin repair. FMOD protein decreases scarring and improves extracellular matrix (ECM) organization in adult wounds. These finding have been confirmed across multiple mammalian species. In a technological innovation, we have identified a 40 amino acid peptide sequence, F06-C40, with similar anti-fibrotic effects to the full FMOD protein. This allows us to bypass costly cell-based techniques for protein production in favor of a synthetic FMOD peptide that can be produced rapidly, inexpensively, and with high purity. Most recently, using a pig model we demonstrated in pilot studies that both FMOD protein and its peptide derivative, F06-C40, significantly reduce scar formation. In this proposal we will test the hypothesis that F06-C40 will have improved efficacy without a change in safety in comparison to placebo for the reduction of cutaneous scar formation. AIM 1 (Months 1-12): Optimize F06-C40 for cutaneous scar prevention. AIM 1 will optimize the dose and duration of F06-C40 for cutaneous scar reduction. A porcine primary intention wound closure model will be used. Porcine skin is the closest animal equivalent to human skin, and is the FDA-preferred model system for testing of wound healing products. Primary outcome measures will include improved gross visual appearance without reduction in wound tensile strength. AIM 2 (Months 13-24): Perform F06-C40 systemic and local toxicology studies. AIM 2 will initiate F06- C40 safety studies required by the FDA for an Investigational New Drug (IND) submission. An escalating dose intravenous study will be performed in rats, and an escalating dose intradermal study will be conducted in pigs. Cutaneous scars cause significant functional and cosmetic impairment. To this day, there exist no FDA approved drugs for prevention of scar recurrence. This Phase I SBIR proposal focuses on optimizing the treatment regimen for F06-C40 and proving its safety and efficacy.
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, pathologic scarring (fibrosis) affects numerous other organ systems in fatal disease processes including the liver, lung, and kidney.
NIH Spending Category: Prevention
Project Terms: Adult; Adverse effects; Affect; Algorithms; Alternative Therapies; Amino Acids; analog; Animals; Appearance; Area; Atrophic condition of skin; base; Biological Models; Biomechanics; body system; Burn injury; Bypass; Cells; Cicatrix; cleft lip and palate; Clinical; commercialization; Cornea; Cosmetics; cost; Cutaneous; Data; Dental Hygiene; design; Development; Disease; Dose; Drug Formulations; Extracellular Matrix; Face; Family suidae; FDA approved; fetal; fibromodulin; Fibrosis; Goals; Granuloma; Growth; Histology; Human; Impairment; improved; innovation; Intention; Intravenous; Investigational Drugs; Keloid; Keratopathy; Kidney; Knockout Mice; Laboratories; Lasers; Liver; Liver Cirrhosis; Lung; Microstomia; Modeling; Mus; novel; Ointments; operation; Operative Surgical Procedures; Oral; Outcome Measure; palate repair; Pathologic; Patients; Peptides; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Prevention; Prevention strategy; primary outcome; Process; Production; protein aminoacid sequence; Proteins; public health relevance; Pulmonary Fibrosis; Radiation; Rattus; Recurrence; Refractory; repaired; Research; Safety; safety study; Scleroderma; Side; Silicones; Skin; Small Business Innovation Research Grant; standard of care; Steroids; success; Techniques; technological innovation; Tensile Strength; Testing; Time; Toxicology; Trauma; Treatment Protocols; Visual; wound; Wound Healing
