We discovered that the inducible keratins 6a and 6b, mutations in which can result in the skin and nail disorder pachyonychia congenita (PC), contain regulatory motifs in their 5'-untranslated regions that make them susceptible to mTOR inhibitors, including rapamycin. Using RNA profiling and immunohistochemistry of foot sole biopsies taken from PC lesions or adjacent unaffected skin, we found evidence to support that mTOR signaling in PC lesions is activated as indicated by hyperphosphorylated ribosomal protein S6. Based on the preclinical data, we completed a small off- label study of orally-administered Rapamune(R) in three PC patients in which improvement of PC symptoms was observed, with dramatic reduction of painful neurovascular structures. However, the study was prematurely terminated due to the adverse events associated with systemic oral rapamycin administration. A recent off-label study with topical rapamycin led to marked improvement of PC symptoms, including reduction of pain and improved physical activity. To avoid the well-known side effects of rapamycin, we propose to identify and formulate a potent next generation mTOR inhibitor to be delivered topically, which will be beneficial not only for PC patients, but also a large number of individuals suffering from other skin disorders. To achieve this goal as outlined in Phase I studies, we plan to use a human keratinocyte-based assay to screen for the most potent keratin 6a inhibitor(s) followed by topical formulation and evaluation in an in vivo mouse model and human skin explants.

Public Health Relevance

Although the underlying genes and mutations responsible for a large number of genodermatoses have been identified, few if any novel clinical treatments have emerged that modulate these molecular targets. The purpose of this proposal is to exploit the discovery that mTOR inhibitors selectively inhibit expression of keratins involved in the skin disorder pachyonychia congenita (PC) and the clinical observation that one of them, rapamycin (the only one tested), reduces PC symptoms when administered orally and topically. In Phase 1, using a disease-relevant biological endpoint, we will screen a collection of next generation mTOR inhibitors using an in vitro human keratinocyte-based assay. The most promising inhibitors will be formulated for topical delivery and evaluated in mouse skin and human skin explants. In Phase 2, we propose a human xenograft model (human skin grafted and tested on immunocompromised mice) to confirm the most promising combination of next generation mTOR inhibitor with its appropriate topical formulation, together with IND-enabling toxicology studies in mice and minipigs in preparation for clinical trials. In theory, the final drug products developed should be applicable to other skin disorders including psoriasis, facial angiofibromas in tuberous sclerosis complex and scarring resulting from laser treatment of birthmarks that have been shown to benefit from rapamycin treatment.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Baker, Carl
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Transderm, Inc.
Santa Cruz
United States
Zip Code
Cao, Yu-An; Hickerson, Robyn P; Seegmiller, Brandon L et al. (2015) Gene expression profiling in pachyonychia congenita skin. J Dermatol Sci 77:156-65