Development of topical formulations for delivery of next generation mTOR inhibito

描述(申请人提供)：我们发现可诱导角蛋白6a和6b的突变可导致皮肤和指甲疾病先天性厚甲(PC)，在其5‘-非翻译区包含调控基序，使它们对包括雷帕霉素在内的mTOR抑制剂敏感。通过对来自PC病变或邻近未受影响皮肤的足底活检组织的RNA图谱和免疫组织化学分析，我们发现证据支持PC病变中的mTOR信号被激活，如过度磷酸化的核糖体蛋白S6所指示的那样。在临床前数据的基础上，我们完成了一项对三名PC患者口服Rapamune(R)的小型标签外研究，在该研究中，PC症状得到改善，疼痛的神经血管结构显著减少。然而，由于全身口服雷帕霉素的不良反应，这项研究被提前终止。最近的一项外用雷帕霉素的非标签研究导致PC症状的显著改善，包括减轻疼痛和改善体力活动。为了避免雷帕霉素众所周知的副作用，我们建议发现并研制一种有效的下一代mTOR抑制剂，用于局部给药，不仅对PC患者有利，而且对大量患有其他皮肤病的人也有好处。为了实现第一阶段研究中概述的这一目标，我们计划使用基于角质形成细胞的分析来筛选最有效的角蛋白6a抑制剂(S)，然后在活体小鼠模型和人类皮肤移植中进行局部配方和评估。

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.