Developing a programmable siRNA-based therapeutic platform for gene silencing in the skin

开发基于 siRNA 的可编程治疗平台，用于皮肤基因沉默

• 批准号: 10723917
• 负责人: Qi Tang
• 金额: $ 11.32万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723917
• 关键词: Acceleration; Acids; Affect; Alopecia Areata; Atopic Dermatitis; Autoimmune; Autoimmunity; Automobile Driving; Base Sequence; Biodistribution; Biological Products; Biological Response Modifiers; Biology; CXCL10 gene; CXCL11 gene; CXCL9 gene; Cells; Characteristics; Chemical Engineering; Chemicals; Chemistry; Clinic; Clinical; Complex; Cutaneous Lupus Erythematosus; Dermatologic; Dermatology; Development; Disease; Dose; Drug Design; Drug Targeting; Engineering; FDA approved; Fostering; Gene Expression; Gene Silencing; Generations; Genes; Goals; Human; Hydrophobicity; IFNGR1 gene; Immune System Diseases; Immune Targeting; Immunologic Memory; Immunology; Inflammatory; Interferon Type II; Interleukin-15; JAK1 gene; JAK2 gene; JAK3 gene; Janus kinase; Lead; Liver; Mentors; Messenger RNA; Metabolic; Modality; Molecular; Mus; Nanostructures; Nucleic Acids; Outcome; Pathology; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; Production; Property; Proteins; Public Health; RNA; RNA Interference; RNA delivery; Research; Rodent; STAT1 gene; Safety; Signal Pathway; Skin; Small Interfering RNA; Specificity; Structure; TYK2; Therapeutic; Therapeutic Effect; Training; Treatment outcome; Vitiligo; Work; biomaterial compatibility; cell type; clinically relevant; combinatorial; design; drug discovery; efficacy testing; efficacy validation; improved; in vivo; insight; interest; kinase inhibitor; mouse model; novel; novel drug class; prevent; programs; scaffold; side effect; skin disorder; skin fibrosis; small molecule; targeted treatment; technology platform; therapeutic RNA; therapeutic evaluation; treatment strategy

PROJECT SUMMARY Skin diseases affect nearly one-third of the global population. Current dermatological drugs are inadequate for many of these diseases, and some have few or no treatments available. There is an urgent need to develop new dermatological therapies. RNA interference (RNAi)-based therapeutics—e.g., small interfering RNA (siRNA)— represent a third class of therapeutic modalities, in addition to small molecules and biologics, that enable specific and sustained mRNA silencing to prevent production of proteins driving disease. With recent advances in nucleic acid chemistries, five siRNA drugs have been approved by the FDA for treatment of liver-associated diseases. Key benefits of siRNA drugs include: (a) ease of sequence-based design; (b) high specificity; (c) a well-defined mechanism of action; and (d) long durability (up to 3-6 months from one dose). These properties of siRNAs allow rapid drug discovery and durable modulation of disease targets previously considered “undruggable”. The goal of this proposal is to expand the clinical utility of therapeutic siRNAs for the treatment of skin diseases. An siRNA that silences expression of the immune mediator, JAK1 (human and mouse), and supports functional inhibition of JAK1 in vivo, has been identified. Aim 1 (K99 phase) will systematically evaluate the safety and efficacy of selective JAK1 silencing by therapeutic siRNA in mouse models of autoimmune and inflammatory skin diseases (i.e., vitiligo, cutaneous lupus erythematosus, and skin fibrosis). Gene silencing in skin requires efficient delivery of chemically-engineered siRNA to skin cell types expressing the target gene. Aim 2 (K99 phase) will dissect the skin biodistribution and efficacy profiles of hydrophobically conjugated siRNAs targeting JAK1 following local and systemic delivery. The R00 phase will expand the scope of the siRNA delivery platform by determining skin cell biodistribution and efficacy of new siRNA conjugates and scaffolds, and siRNAs targeting immune mediators in the IFN-γ (i.e., IFNGR1, JAK2, STAT1, and CXCL9/10/11) and IL15 (i.e., IL15 and IL15RA) pathways, for which lead compounds have already been identified. Preliminary work has developed a dual-targeting siRNA scaffold supporting simultaneous silencing of two genes in vivo. Aim 3 (K99 phase) will test the efficacy of modulating two inflammatory targets in the mouse models mentioned in Aim 1. In the R00 phase, biocompatible click chemistry and nanostructure engineering strategies will be used to construct programmable unimolecular multi-targeting siRNA scaffolds to potentiate combinatorial modulation of 3 or more inflammatory targets, a crucial goal for treating skin diseases with complex pathology. This project will establish an siRNA-based platform for modulating gene expression in the skin, and foster the PI’s continued scientific and professional training. Research in the mentored K99 phase will be carried out under the guidance of an esteemed mentor committee, whose expertise range from basic RNA biology to clinical dermatology. By the R00 phase, the PI will be ready to establish an independent lab focused on developing novel siRNA therapeutic programs for complex skin diseases.

项目概要 皮肤病影响着全球近三分之一的人口。目前的皮肤科药物不足以 其中许多疾病，有些疾病的治疗方法很少或根本没有治疗方法。迫切需要开发新的 皮肤科治疗。基于 RNA 干扰 (RNAi) 的疗法——例如小干扰 RNA (siRNA)—— 代表除小分子和生物制剂之外的第三类治疗方式，能够实现特定的治疗 持续沉默 mRNA 以防止产生导致疾病的蛋白质。随着核酸技术的最新进展 酸化学方面，FDA 已批准五种 siRNA 药物用于治疗肝脏相关疾病。 siRNA 药物的主要优点包括： (a) 易于基于序列的设计； (b) 高特异性； (c) 明确的 作用机制； (d) 持久性长（一剂可达 3-6 个月）。 siRNA 的这些特性使得 快速药物发现和对以前被认为“不可成药”的疾病靶点的持久调节。 该提案的目标是扩大治疗性 siRNA 在皮肤病治疗中的临床应用。 一种 siRNA，可沉默免疫介质 JAK1（人和小鼠）的表达，并支持功能性 体内 JAK1 的抑制作用已被鉴定。目标1（K99阶段）将系统地评估安全性和 治疗性 siRNA 选择性沉默 JAK1 在自身免疫和炎症小鼠模型中的功效 皮肤病（即白癜风、皮肤红斑狼疮和皮肤纤维化）。 皮肤中的基因沉默需要将化学工程设计的 siRNA 有效递送至表达 siRNA 的皮肤细胞类型 目标基因。目标 2（K99 阶段）将剖析疏水性皮肤生物分布和功效概况 局部和全身递送后靶向 JAK1 的缀合 siRNA。 R00阶段将扩大范围 通过确定新 siRNA 缀合物的皮肤细胞生物分布和功效，开发 siRNA 递送平台 支架和靶向 IFN-γ 中免疫介质的 siRNA（即 IFNGR1、JAK2、STAT1 和 CXCL9/10/11） 和 IL15（即 IL15 和 IL15RA）途径，其先导化合物已被确定。 初步工作已开发出支持同时沉默两个基因的双靶向siRNA支架 体内。目标 3（K99 阶段）将测试在小鼠模型中调节两个炎症靶点的功效 Aim 1中提到，在R00阶段，生物相容性点击化学和纳米结构工程策略 将用于构建可编程单分子多靶向 siRNA 支架以增强组合 调节 3 个或更多炎症靶点，这是治疗具有复杂病理学的皮肤病的关键目标。 该项目将建立一个基于 siRNA 的平台来调节皮肤中的基因表达，并培育 PI的持续科学和专业培训。 K99指导阶段的研究将在 受人尊敬的导师委员会的指导，其专业知识涵盖从基础 RNA 生物学到临床 皮肤科。到 R00 阶段，PI 将准备建立一个独立的实验室，专注于开发 针对复杂皮肤疾病的新型 siRNA 治疗方案。