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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结