Chemical engineering of therapeutic RNAs for extrahepatic delivery

用于肝外递送的治疗性 RNA 的化学工程

基本信息

批准号：
9913311
负责人：
ANASTASIA KHVOROVA
金额：
$ 43.55万
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：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913311
关键词：
Acetylgalactosamine Architecture Behavior Biodistribution Biology Chemical Engineering Chemicals Chemistry Clinical Disease Disease model Engineering Exhibits Extrahepatic Fatty acid glycerol esters Gene Expression Heart Hepatocyte Hereditary Disease Human Injections Kidney Lead Ligands Liver Lung Medical Medicine Modification Muscle Oligonucleotides Organic Chemistry Pattern Pharmaceutical Preparations Pharmacology Positioning Attribute Problem Solving Property RNA RNA Sequences RNA Stability RNA delivery Research Small Interfering RNA Specificity System Therapeutic Tissues Toxic effect Variant Vertebral column Work base cell type clinical application clinical development combinatorial chemistry design drug candidate immunogenicity improved in vivo interest novel pharmacokinetics and pharmacodynamics phosphonate scaffold targeted delivery therapeutic RNA

项目摘要

Project Summary Small interfering RNAs (siRNAs) are informational drugs that can be designed to treat genetically defined disorders and thereby reshape our approach to human medicine. The clinical utility of siRNAs depends on functional delivery to a tissue and cell type of interest, which is in turn defined by oligonucleotide chemistry. When a chemical architecture—i.e., oligonucleotide modification pattern—that provides functional and non- toxic delivery to a tissue is optimized, candidate drugs can be quickly developed to treat other diseases with the same tissue involvement. Currently, the clinical utility of siRNA is limited to liver, where conjugation of trivalent N-acetylgalactosamine (GalNAc) moiety enables efficient delivery to hepatocytes and therapeutic activity for a year after a single injection. To expand the utility of siRNAs to tissues beyond liver, we must (i) optimize chemical modification patterns that fully stabilize siRNAs and are non-toxic and compatible with the silencing machinery; (ii) understand the mechanisms that define siRNA pharmacokinetic and pharmacodynamic behavior; and (iii) identify and engineer novel ligands that enable targeted tissue delivery and sustained in vivo efficacy. We have the demonstrated expertise in organic chemistry, combinatorial chemistry, oligonucleotide chemistry, RISC biology, and siRNA pharmacology needed to solve these problems. To date, we have identified fully chemically stabilized siRNA scaffolds that exhibit minimal toxicity and immunogenicity; engineered novel conjugates that support functional delivery to liver, kidneys, heart, fat, muscle, and lung; defined chemical approaches to dynamically modulate siRNA clearance; and synthesized novel backbone modifications (phosphonate variants) that improve siRNA stability and, when placed in defined positions, enhance RISC efficacy and specificity. Building on these recent advances, we propose four principal research directions that seek to (i) chemically engineer siRNA scaffolds that enable complete stability and sustained efficacy of any RNA sequence in vivo; (ii) establish phosphonate variants as a new backbone for the modulation of therapeutic RNA properties; (iii) engineer and discover novel ligands that deliver siRNAs to tissues other than liver; and (iv) work with a network of expert collaborators to investigate the therapeutic potential of novel chemical configurations in models of diseases with unmet medical needs. The completion of these studies will establish siRNA chemical architectures that enable functional extrahepatic delivery of siRNAs and lead to the discovery of several compounds with the potential to transform therapeutic approaches for range of diseases.

项目概要小干扰 RNA (siRNA) 是一种信息药物，可用于治疗基因定义的疾病从而重塑我们的人类医学方法 siRNA 的临床效用取决于功能性递送至感兴趣的组织和细胞类型，这又由寡核苷酸化学定义。当化学结构（即寡核苷酸修饰模式）提供功能性和非优化向组织的毒性输送，可以快速开发候选药物来治疗其他疾病目前，siRNA 的临床应用仅限于肝脏，其中缀合。三价 N-乙酰半乳糖胺 (GalNAc) 部分能够有效递送至肝细胞并进行治疗单次注射后活性可达一年。为了将 siRNA 的效用扩展到肝脏以外的组织，我们必须 (i) 优化化学修饰模式，完全 siRNA，无毒且与沉默机制兼容；(ii) 了解定义 siRNA 药代动力学和药效学行为的机制；以及 (iii) 识别和设计能够实现靶向组织递送和持续体内功效的新型配体。有机化学、组合化学、寡核苷酸化学、RISC 方面的专业知识迄今为止，我们已经通过化学方法完全确定了解决这些问题所需的生物学和 siRNA 药理学。稳定的 siRNA 支架具有最小的毒性和免疫原性；支持肝脏、肾脏、心脏、脂肪、肌肉和肺的功能性传递；动态调节 siRNA 清除；并合成新的骨架修饰（磷酸盐变体）可以提高 siRNA 的稳定性，并且当放置在确定的位置时，可以增强 RISC 的功效和特异性。基于这些最新进展，我们提出了四个主要研究方向，旨在（i）化学设计 siRNA 支架，使任何 RNA 序列在体内具有完全稳定性和持续功效； (ii) 建立磷酸盐变体作为调节 RNA 治疗特性的新支柱；设计并发现将 siRNA 递送至肝脏以外的组织的新型配体；以及 (iv) 与网络合作；专家合作者研究新型化学构型在模型中的治疗潜力医疗需求未得到满足的疾病。这些研究的完成将建立 siRNA 化学结构，使功能性肝外 siRNA 的递送并导致发现了几种具有改变治疗方法潜力的化合物针对一系列疾病的方法。