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The Development of a Topical Therapy for Facial Angiofibromas in TSC Bench to Bedside Medicine Mary Kay Koenig, MD & Hope Northrup, MD Department of Pediatrics The University of Texas Medical School Houston TSC & the Skin • Hypo-pigmented macules TSC & the Skin • Shagreen patch TSC & the Skin • Ungual Fibromas TSC & the Skin • Facial Angiofibromas Facial Angiofibromas • • • • • Benign Skin Tumors seen in patients with TSC Appear around puberty Worsen over time No effective treatments Disfiguring Facial Angiofibromas • Dermal basal cells contain a single mutant copy of either TSC1 or TSC2 • A second hit occurs resulting in loss of heterozygosity and cell growth at a rate faster than the ability to slough dead cells • Visible facial lesions appear over time • TSC mutant cells also secrete vascular growth factors resulting in red appearance to the lesions Facial Angiofibromas TSC & mTOR Rapamycin • Naturally occurring substance • Discovered in 1965 • Binds mTOR and inhibits it’s action, thus preventing cell division and growth • Also decreases levels of VEGF Rapamycin • Approved by the FDA in 1999 as an immunosuppressant drug to be used post renal transplant • Side effect profile well defined: • Immunosuppression • Oral Ulcers • Skin Breakdown • Poor wound healing • Hyperlipidemia • Thrombocytopenia Rapamycin • Theoretically, the action of rapamycin should suppress abnormal cell growth in TSC replacing the action of the malfunctioning proteins Rapamycin & the Skin • Rapamycin has a molecular weight of 914.2 grams allowing for it’s absorption through the superficial layers of the epidermis • With the appropriate delivery system, a topically applied formulation of rapamycin should be able to penetrate the superficial dermal layers to reach the deep basal layers implicated in the formation of facial angiofibromas Topical Rapamycin Therapy to Alleviate Cutaneous Manifestations of TSC & NF-1 PI: Mary Kay Koenig, MD Co-PIs: Hope Northrup, MD Adelaide A. Hebert, MD Joshua A. Samuels, MD John M. Slopis, MD Study Coordinator: Joan M. Roberson, BSN Contributors: Laura Lester, Laura Marusinec, Audrey Woerner Support: Society for Pediatric Dermatology Pilot Project Award Race Across America for Neurofibromatosis Topical Rapamycin Therapy to Alleviate Cutaneous Manifestations of TSC Trial Objectives I Determine if a topically applied formulation of rapamycin can be used safely II Determine if the topically applied formulation of rapamycin is effective at decreasing: • the appearance of facial angiofibromas in TSC Topical Rapamycin Therapy to Alleviate Cutaneous Manifestations of TSC • Study Design – randomized, double-blind, placebocontrolled 60 subjects 3 arms - 30 TSC - 30 NF-1 - Placebo - Low Dose - High Dose • Study drug applied topically each night to skin surface • Followed for 6 months to assess for improvements in size and/or appearance of fibromatous lesions Results to Date • Enrolled 28 TSC subjects • Two patients voluntarily withdrew because of discomfort with study product application – burning – tingling – eye watering TSC Arm Results • 6 month data in TSC arm shows a reduction in the appearance of facial angiofibromas in 73% of subjects on treatment vs 38% of subjects on placebo Before Treatment After Treatment Side Effects/Adverse Events • Subjects seen monthly to assess for known side effects – Lipid levels – CBC – Skin breakdown - Oral ulcers - Infections • Two Major Adverse Events – Hospitalization for aspiration pneumonia/septic shock – Hospitalization for hypertensive crisis • Rapamycin levels undetectable in all subjects Future Directions • Data publication later this year • Multi-Center Trail pending involving 200 TSC subjects at 10 sites across the country (funding approved) Thank You • Society for Pediatric Dermatology • Race Across America for Neurofibromatosis • Research Team: – – – – – Joan Roberson, RN Hope Northrup, MD Adelaide Hebert, MD Joshua Samuels, MD John Slopis, MD • Collaborators: – Audrey Woerner, MD – Laura Lester, MD – Laura Marusinec, MD UT Tuberous Sclerosis Complex Center of Excellence