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 皮肤疾病影响了几乎三分之一的全球人口。当前的皮肤病药不足 这些疾病中有许多，有些疾病几乎没有或没有可用的治疗方法。迫切需要开发新的 皮肤病学疗法。 RNA干扰（RNAi）基于疗法 - 例如，小干扰RNA（siRNA） - 除了小分子和生物制剂外，代表了第三类的热模态 并持续mRNA沉默以防止产生蛋白质驱动疾病。随着核的最新进展 FDA批准了酸化学，五种siRNA药物用于治疗肝相关疾病。 siRNA药物的主要好处包括：（a）易于基于序列的设计； （b）高特异性； （c）定义明确的 作用机理； （d）长期耐用性（一剂最多3-6个月）。这些sirnas的特性允许 疾病靶标的快速药物发现和持久调节先前被认为是“不可用”。 该提案的目的是扩大治疗性siRNA治疗皮肤疾病的临床实用性。 沉默免疫介质JAK1（人和小鼠）表达的siRNA，并支持功能 已经鉴定出对JAK1在体内的抑制作用。 AIM 1（K99阶段）将系统地评估安全性和 热siRNA在自身免疫性和炎症的小鼠模型中选择性JAK1沉默的功效 皮肤疾病（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有效地递送化学设计的siRNA到表达皮肤细胞类型 靶基因。 AIM 2（K99阶段）将剖析疏水性的皮肤生物分布和效率。 在本地和全身交付后，瞄准了针对JAK1的siRNA。 R00阶段将扩大范围 通过确定新siRNA偶联物和效率的皮肤细胞生物分布和效率， 脚手架和针对IFN-γ免疫介质的siRNA（即IFNGR1，JAK2，STAT1和CXCL9/10/11） 和IL15（即IL15和IL15RA）途径，已经确定了铅化合物。 初步工作已开发出双重目标的siRNA支架，支持两个基因的沉默 体内。 AIM 3（K99阶段）将测试调节小鼠模型中两个炎症靶标的效率 在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 将用于构建可编程的单分子多靶向siRNA支架 调节3个或多个炎症靶标，这是治疗患有复杂病理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，并促进 Pi的科学和专业培训。修改K99阶段的研究将在 尊敬的心理委员会的指导，其专业知识从基本RNA生物学到临床 皮肤科。到R00阶段，PI将准备建立一个专注于开发的独立实验室 新颖的siRNA治疗程序针对复杂的皮肤疾病。