Development of topical formulations for delivery of next generation mTOR inhibito

描述（由申请人提供）：我们发现可诱导角蛋白6a和6 b（其中突变可导致皮肤和指甲疾病先天性甲肥厚（PC）在其5 '-非翻译区中含有调控基序，使其对mTOR抑制剂（包括雷帕霉素）敏感。使用从PC病变或邻近未受影响的皮肤获取的足底活检的RNA分析和免疫组织化学，我们发现支持PC病变中的mTOR信号传导被激活的证据，如过度磷酸化的核糖体蛋白S6所示。基于临床前数据，我们在三名PC患者中完成了一项口服Rapamune（R）的小型标签外研究，其中观察到PC症状改善，疼痛的神经血管结构显著减少。然而，由于与全身口服雷帕霉素给药相关的不良事件，该研究提前终止。最近的一项外用雷帕霉素的标签外研究导致PC症状的显着改善，包括疼痛减轻和体力活动改善。为了避免雷帕霉素的众所周知的副作用，我们建议鉴定和配制一种有效的下一代mTOR抑制剂以局部递送，这不仅对PC患者有益，而且对大量患有其他皮肤病的个体也有益。为了实现I期研究中概述的这一目标，我们计划使用基于人角质形成细胞的测定来筛选最有效的角蛋白6a抑制剂，然后在体内小鼠模型和人皮肤外植体中进行局部制剂和评价。

DESCRIPTION (provided by applicant): 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.