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.

项目摘要 皮肤病影响着全球近三分之一的人口。目前的皮肤病药物不足以 其中许多疾病，有些几乎没有或根本没有治疗方法。迫切需要开发新的 皮肤病治疗。基于RNA干扰（RNAi）的治疗-例如，小干扰RNA（siRNA）- 代表了第三类治疗方式，除了小分子和生物制剂， 和持续的mRNA沉默以防止产生驱动疾病的蛋白质。随着核酸研究的最新进展， 除了酸化学之外，FDA已经批准了五种siRNA药物用于治疗肝脏相关疾病。 siRNA药物的主要益处包括：（a）易于基于序列的设计;（B）高特异性;（c）明确的靶向分子;（d）特异性靶向分子。 作用机制;和（d）持久性（从一次剂量起长达3-6个月）。siRNA的这些特性使得 快速药物发现和持久调节以前被认为是“不可用药”的疾病靶点。 该提案的目标是扩大治疗性siRNA用于治疗皮肤疾病的临床效用。 沉默免疫介质JAK 1（人和小鼠）表达并支持功能性免疫调节的siRNA JAK 1的体内抑制。目标1（K99阶段）将系统评价安全性， 在自身免疫和炎症小鼠模型中通过治疗性siRNA选择性沉默JAK 1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siRNA有效递送至表达 目标基因。目的2（K99阶段）将剖析疏水性的皮肤生物分布和功效概况。 在局部和全身递送后靶向JAK 1的缀合siRNA。R 00阶段将扩大范围 通过测定新siRNA缀合物的皮肤细胞生物分布和功效， 支架和靶向IFN-γ中的免疫介质的siRNA（即，IFNGR 1、JAK 2、STAT 1和CXCL 9/10/11） 和IL 15（即，IL 15和IL 15 RA）途径，其先导化合物已经被鉴定。 初步工作已经开发出一种支持同时沉默两个基因的双靶向siRNA支架 in vivo.目的3（K99期）将测试在小鼠模型中调节两种炎症靶标的功效 目标1中提到的。在R 00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个或更多个炎症靶点，这是治疗具有复杂病理学的皮肤疾病的关键目标。 该项目将建立一个基于siRNA的平台，用于调节皮肤中的基因表达， PI的持续科学和专业培训。K99阶段的研究将在 一个受人尊敬的指导委员会的指导，其专业知识范围从基本的RNA生物学到临床 皮肤科。到R 00阶段，PI将准备建立一个独立的实验室，专注于开发 用于复杂皮肤病的新型siRNA治疗方案。