Targeted RNA delivery using ribonucleoprotein

使用核糖核蛋白进行靶向 RNA 递送

基本信息

批准号：
10611640
负责人：
Xiaohu Gao
金额：
$ 60.41万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2023-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611640
关键词：
A/J Mouse Address Antisense Oligonucleotide Therapy Binding Biological Products Biology Biomimetics Cell Line Cells Charge Chemicals Chimera organism Chronic Clinical Clinical Trials Complex Conflict (Psychology)Development Double-Stranded RNA Binding Domain Elements Endosomes Engineering Ensure Epitopes Evaluation Evolution FDA approved Genetic Goals Grant Human Immobilization Immune system In Vitro Inflammation Inflammatory Ligands Link Lipids Liposomes Liver Mediating Medicine Messenger RNA Methods Modification Molecular Mus Nanotechnology Nature Organoids Pathologic Patients Peptides Performance Pharmaceutical Preparations Phase Physical condensation Polymers Production Property Proteins RNA RNA Interference RNA delivery RNA-Binding Proteins Ribonucleoproteins Safety Serology Shapes Site Small Interfering RNA Surface Technology Therapeutic Agents Toxic effect Treatment Efficacy attenuation base biodegradable polymer biomaterial compatibility cancer therapy cell type clinical translation combinatorial cytotoxicity delivery vehicle design efficacy evaluation flexibility immunogenicity improved in vivo innovation interest knock-down monomer nanocarrier nanoparticle phase III trial self assembly small molecule sortase targeted delivery technology platform therapeutic RNA tool translational potential tumor eradication tumor progression virtual

项目摘要

ABSTRACT Silencing RNA (siRNA) is of considerable current interest in medicine because it can elicit potent, target specific knockdown of virtually any mRNA, creating a useful and proven genetic surrogate tool. Three siRNA- based therapies have been FDA-approved, while another seven candidates are in phase 3 trials. A key obstacle limiting the scope of siRNA clinical uses, however, is in vivo targeted delivery, a `chronic' problem that has plagued the development of virtually all antisense therapies. Recent advances in nanotechnology have produced many nanocarriers such as cationic lipids, polymers, inorganic nanoparticles, and peptides. Although the cationic charge is important for siRNA condensation and endosomal escape, it interferes with specific targeting by non-specifically binding to most proteins and cells. To address this fundamental and chronic problem, here we propose to further develop a one-of-its-kind RNA nanocarrier for delivery of siRNA cocktails building on a recent breakthrough we made on human RNA-binding proteins (Corey & Gao Nature BME, PCT filed, US phase granted). Optimized through millions of years of evolution, these proteins are neutral or slightly negatively charged yet still binding to cargo RNA tightly and with a very high payload. The absence of excessive cationic charges is in direct contrast to conventional delivery technologies. Through orientation controlled self-assembly with siRNA-targeting ligand chimeras, the complex simultaneously achieves all the desired properties for efficient siRNA delivery and cancer treatment.

抽象的沉默 RNA (siRNA) 目前在医学领域引起了相当大的兴趣，因为它可以引发有效的靶点几乎任何 mRNA 的特异性敲除，创造了一种有用且经过验证的遗传替代工具。三个 siRNA- 基于的疗法已获得 FDA 批准，另外七种候选药物正在进行 3 期试验。一把钥匙然而，限制 siRNA 临床应用范围的障碍是体内靶向递送，这是一个“长期”问题一直困扰着几乎所有反义疗法的发展。纳米技术的最新进展生产了许多纳米载体，如阳离子脂质、聚合物、无机纳米颗粒和肽。虽然阳离子电荷对于 siRNA 凝聚和内体逃逸很重要，它会干扰特定的通过与大多数蛋白质和细胞非特异性结合来靶向。为了解决这个根本性的、长期的问题为了解决这一问题，我们建议进一步开发一种独一无二的 RNA 纳米载体，用于递送 siRNA 混合物以我们最近在人类 RNA 结合蛋白方面取得的突破为基础（Corey＆Gao Nature BME，PCT 已提交，美国阶段已获批准）。经过数百万年的进化优化，这些蛋白质是中性的或轻微的带负电但仍与货物 RNA 紧密结合且具有非常高的有效负载。缺席过多的阳离子电荷与传统的递送技术形成鲜明对比。通过定向与 siRNA 靶向配体嵌合体进行受控自组装，该复合物同时实现了所有高效 siRNA 递送和癌症治疗所需的特性。