Development of topical rapamycin as a novel treatment for skin disorders

开发外用雷帕霉素作为皮肤病的新型治疗方法

• 批准号: 7481638
• 负责人: ROGER L KASPAR
• 金额: $ 22.63万
• 依托单位: TRANSDERM, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481638
• 关键词: 5' Untranslated Regions; 70-kDa Ribosomal Protein S6 Kinases; Adverse effects; Affect; Animal Model; Biodistribution; Biological Assay; Biopsy; Blood; Clinical Treatment; Clinical Trials; Collaborations; Cyclosporine; Cyclosporins; Development; Disease; Down-Regulation; Drug Formulations; EEF1A2 gene; Employee Strikes; Epidermolysis Bullosa Simplex; Epithelial; Evaluation; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Translation; Hereditary Disease; Human; Indium; Keratin; Label; Laboratories; Link; Lipids; Macrolides; Messenger RNA; Modeling; Mutation; Nail plate; Numbers; Pain; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Phase; Polyribosomes; Preparation; Prodrugs; Psoriasis; Public Health; Purpose; Regulatory Element; Research; Resolution; Sirolimus; Site; Skin; Structure; Symptoms; Technology; Testing; Therapeutic; Topical application; Toxic effect; Translating; Translations; Universities; Western Blotting; Work; base; design; experience; foot sole; keratin 5; keratinocyte; mouse model; novel; particle; skin disorder; theories

DESCRIPTION (provided by applicant): In the decade and a half since the discovery of the underlying mutations in the keratin 5 (K5) and K14 genes in the skin disorder epidermolysis bullosa simplex (EBS), there has been a plethora of additional research identifying the genetic bases of many epithelial fragility disorders with 20 of the 54 human keratin genes now linked to genetic diseases, including the skin and nail disorder pachyonychia congenita (PC). Despite these significant discoveries, little progress has been made in developing therapeutics for these genodermatoses. We have recently discovered that the inducible keratins (K6a, K6b, K16, and K17), mutation in any of which can result in PC, contain regulatory motifs in their 5' untranslated regions that may make them susceptible to downregulation following treatment with the macrolide rapamycin (sirulimus). Indeed, treatment of human HaCaT keratinocytes with rapamycin led to a 90% decrease in K6a expression as determined by western blot analysis. A small rapamycin off-label trial in three PC patients showed marked reduction in PC symptoms when therapeutic rapamycin blood trough levels were achieved, with striking resolution observed for painful neurovascular structures on the soles of the feet. These patients, unfortunately, were affected by the well-known side effects arising from systemic administration of rapamycin and two patients withdrew prematurely from the study for these reasons. The purpose of this proposal is to define the pathway involved in downregulation of keratin gene expression following rapamycin treatment in keratinocytes and to develop rapamycin prodrug conjugates (including skin penetrating rapamycin derivatives) that can be applied topically at high local concentrations, thereby avoiding the undesirable side effects resulting from systemic treatment. The wealth of experience achieved by Dr. Paul Wender and colleagues at Stanford University (and Cellgate) in successfully converting cyclosporine, an agent that does not penetrate skin, into cyclosporine transporter conjugates that readily penetrate multiple layers of human skin using oligoarginine or lipid transporters with linkers that release free drug will be incorporated into the rapamycin-conjugate design. The ability to topically deliver rapamycin derivatives to downregulate expression of the inducible keratins may have much broader application, as rapamycin has been shown to be of benefit to patients suffering from psoriasis. PUBLIC HEALTH RELEVANCE Despite the exciting discoveries of the underlying genes and mutations responsible for a large number of genodermatoses, few if any novel clinical treatments have emerged. The purpose of this proposal is to exploit the recent discovery that rapamycin selectively inhibits expression of keratins involved in the skin disorder pachyonychia congenita. In Phase 1, we validate the rapamycin-sensitive pathway involved in keratin mRNA translation and prepare rapamycin prodrugs with skin-penetrating transporter elements and in Phase 2, we utilize animal models to optimize formulations to topically delivery rapamycin and rapamycin conjugates in preparation for a clinical trial. In theory, the platform technology developed should be applicable to other skin disorders including psoriasis caused by over- or inappropriate expression of rapamycin-sensitive keratins.

描述（由申请人提供）：自从发现角蛋白5（K5）中的潜在突变和皮肤疾病表皮疾病的基因表皮细胞单纯形（EBS）以来，已经进行了许多其他研究，这些研究与许多上皮脆弱的遗传学与54遗传学的人脉络有关，现在已经进行了许多其他研究，现在已经进行了许多其他研究。指甲疾病Pachyonychia congenita（PC）。尽管有这些重大发现，但在开发这些胚乳症的治疗剂方面几乎没有取得进展。我们最近发现，诱导型角蛋白（K6A，K6B，K16和K17），其中任何一种可能导致PC的突变，在其5'未翻译区域中包含调节基序，可能会使它们在用摩cacrolide rapamycin（sirulimus）处理后易于下调。实际上，通过蛋白质印迹分析确定，用雷帕霉素治疗人类HACAT角质形成细胞的K6a表达降低了90％。当治疗性雷帕霉素血液槽水平达到治疗性雷帕霉素的一项小型雷帕霉素外试验显示，PC症状显着降低，并且在脚底上观察到疼痛的神经血管结构的惊人分辨率。不幸的是，这些患者受到雷帕霉素的全身性给药的众所周知副作用的影响，出于这些原因，两名患者过早地退出了研究。该提案的目的是定义雷帕霉素治疗角质形成细胞治疗后角蛋白基因表达的途径，并开发雷帕霉素前药（包括可以在高局部浓度下局部应用的，可以局部应用，从而避免造成不良的副作用。 The wealth of experience achieved by Dr. Paul Wender and colleagues at Stanford University (and Cellgate) in successfully converting cyclosporine, an agent that does not penetrate skin, into cyclosporine transporter conjugates that readily penetrate multiple layers of human skin using oligoarginine or lipid transporters with linkers that release free drug will be incorporated into the rapamycin-conjugate design.局部传递雷帕霉素衍生物下调可诱导角蛋白表达的能力可能具有更广泛的应用，因为雷帕霉素已被证明对患有牛皮癣的患者有益。尽管对大量的金属性疾病的基础基因和突变有令人兴奋的发现，但公共卫生的相关性很少，如果出现了任何新颖的临床治疗，很少有人。该提案的目的是利用最近发现的发现，雷帕霉素有选择地抑制角质疾病pachyonychia congenita的角质的表达。在第1阶段，我们验证了涉及角蛋白mRNA翻译的雷帕霉素敏感途径，并制备带有皮肤穿透转运蛋白元素的雷帕霉素前药，在第2阶段中，我们利用动物模型来优化制剂以局部递送Rapamycin和Rapamycin和Rapamycin Conjugates，以准备临床试验。从理论上讲，开发的平台技术应适用于其他皮肤疾病，包括由雷帕霉素敏感的角蛋白表达过度或不适当表达引起的牛皮癣。