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.
Thesaurus Terms: 5' Untranslated Regions;Adverse Effects;Adverse Event;Affect;Angiofibroma;Attention;Base;Biological;Biological Assay;Biopsy;Brightfield Microscopy;Cicatrix;Clinical;Clinical Treatment;Clinical Trials;Collection;Coupled;Data;Dermis;Development;Disease;Drug Formulations;Drug Kinetics;Effectiveness;Enzyme-Linked Immunosorbent Assay;Epidermis;Evaluation;Exhibits;Face;Fda Approved;Fluorescence Microscopy;Foot Sole;Functional Disorder;Gene Expression;Gene Mutation;Goals;Hereditary Disease;High Pressure Liquid Chromatography;Human;Human Activities;Human Frap1 Protein;Hypersensitivity Skin Testing;Image;Immunocompromised Host;Immunohistochemistry;Improved;In Vitro;In Vivo;Individual;Inhibitor/Antagonist;Keloid;Keratin;Keratinocyte;Keratoderma;Label;Lasers;Lead;Lesion;Measures;Mechanical Stress;Miniature Swine;Modeling;Molecular Target;Mouse Model;Mtor Inhibitor;Mtor Signaling Pathway;Mus;Mutant;Mutation;Nail Plate;Next Generation;Novel;Novel Strategies;Oral;Outcome;Overexpression;Pain;Pathology;Pathway Interactions;Patients;Penetration;Pharmaceutical Preparations;Phase;Phase 1 Study;Phosphorylation;Physical Activity;Port-Wine Stain;Pre-Clinical;Preparation;Prevent;Psoriasis;Public Health Relevance;Ribosomal Protein S6;Rna;Safety;Screening;Signal Transduction;Sirolimus;Skin;Skin Disorder;Skin Graft;Staging;Stratum Corneum;Structure;Symptoms;Testing;Theories;Therapeutic;Timeline;Toxicology;Tuberous Sclerosis Protein Complex;Up-Regulation (Physiology);Vascular Blood Supply;Walking;Xenograft Model;
