In vivo imaging models for evaluating siRNA delivery to skin

用于评估 siRNA 递送至皮肤的体内成像模型

基本信息

批准号：
7405503
负责人：
ROGER L KASPAR
金额：
$ 14.82万
依托单位：
TRANSDERM, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-20 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7405503
关键词：
Animal Model Animals Biological Assay Biological Models Bos taurus Cattle Cells Clinic Clinical Trials Condition Data Drug Formulations Drug Kinetics Electroporation Epidermis Epithelial Exposure to Freezing Gene Targeting Genes Goals Growth Factor Receptors Hair Hair follicle structure Half-Life Human Image Immunocompromised Host Iontophoresis Keratin Label Luciferases Measures Methodology Methods Modeling Monitor Mus Nucleic Acids Numbers Pancreatic ribonuclease Patients Phase Polymerase Chain Reaction Preparation RNA Interference Reporter Reporter Genes Serum Skin Small Interfering RNA Stratum Basale System Technology Temperature Testing Therapeutic Time Toxicology Transgenic Mice Transgenic Model Transgenic Organisms Translating Translations clinically relevant design disease phenotype epidermis cell fetal in vivo inhibitor/antagonist innovation innovative technologies intradermal injection keratin 5 keratinocyte mouse model mutant novel therapeutics promoter research study skin disorder sonoporation success

项目摘要

DESCRIPTION (provided by applicant): RNA interference offers the potential of a novel therapeutic approach for treating skin disorders. The technology to design, screen and identify potent, selective, and stable small interfering RNAs (siRNAs) is now relatively straightforward. The ability to deliver these potential therapeutics to appropriate skin cells has not kept pace. The long-term goal of this project is to develop a mechanism to efficiently and effectively deliver siRNAs to appropriate skin cells in a way that can be readily translated to use in humans. In Phase I, we investigate a number of mouse skin reporter systems for their suitability to monitor siRNA delivery to keratinocytes. Several of these models use reporter genes that can be non-invasively detected at multiple timepoints using in vivo whole-animal imaging, while others rely on real-time PCR quantitation of endogenous gene targets. A human skin equivalent, with or without mutant keratin genes resulting in disease phenotype, is also analyzed as a model for delivery of functional siRNA to keratinocytes. In addition, the stability, half-lives, and distribution of siRNAs will be determined in both human and mouse skin. The proposed aims in Phase 1 are quite straightforward; however, these reporter systems are crucial for laying the groundwork for demonstrating effective delivery of functional siRNAs. In Phase 2, innovative skin delivery technologies for selected siRNAs are screened and optimized in the most appropriate systems identified in Phase 1, and animal toxicology and pharmacokinetic experiments are performed in preparation for clinical trials.

描述（由申请人提供）：RNA干扰提供了一种新型治疗方法治疗皮肤疾病的潜力。现在，设计，筛选和识别有效，选择性和稳定的小型干扰RNA（SIRNA）的技术现在相对简单。交付能力这些对适当皮肤细胞的潜在疗法尚未保持步伐。该项目的长期目标是开发一种机制，以一种可以轻松翻译成人类使用的方式，可以有效地将siRNA提供给适当的皮肤细胞。在第一阶段，我们研究了许多小鼠皮肤记者系统，以适合监测siRNA向角质形成细胞的递送。这些模型中有几种使用报告基因，可以在多个时间点使用体内检测到无创的基因全动物成像，而其他成像则依靠内源基因靶标的实时PCR定量。还将人类皮肤当量具有或没有突变的角蛋白基因导致疾病表型，也被分析为将功能性siRNA传递到角质形成细胞的模型。另外，将在人和小鼠皮肤中确定siRNA的稳定性，半衰期和分布。提出的目标在第1阶段非常简单。但是，这些记者系统对于为证明有效传递功能性siRNA的基础至关重要。在第二阶段，创新的皮肤在第1阶段确定的最合适的系统中筛选和优化了所选siRNA的输送技术，并进行了动物毒理学和药代动力学实验以准备临床试验。