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OligoY - a new class of oligonucleotide-based therapeutic means

OligoY——一类新的基于寡核苷酸的治疗手段

基本信息

批准号：
MR/V026674/1
负责人：
金额：
$ 109.54万
依托单位：
Sixfold Bioscience Ltd
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV026674%2F1
关键词：
OligoY new class oligonucleotide based

项目摘要

A number of RNA drugs have been developed to combat polygenic diseases such as cancer. The early enthusiasm for the promise of RNAi therapeutics was quickly weakened by the failure or limited efficacy in early clinical trials.1 Decades of studies on modification of nucleic acids which can affect pairing and chemical stability, conformation and interactions with a proteins and enzymes involved in uptake, transport or processing of targets have been the main focus of the oligonucleotide therapeutic field. While many RNA-based drugs are in development, there are still significant barriers to efficient RNA-based treatment strategies including delivery of the drug to a particular site or tissue, off-target effects and longevity of the treatment.RNAi, antisense and splice-switching oligonucleotides are the main class of therapeutic still under screening. RNAi drugs, although being showing promising result in clinical trial and having some representative drugs already FDA approved, are intrinsically presenting some limitations due to their modality of action. The RNAi and miRNA pathway share common proteins, like Ago2, which are involved in miRNA maturation. Hence, siRNA drugs compete with endogenous miRNAs for Ago2 binding, limiting the efficiency of all siRNA drugs. To compensate this, the concentration of the RNA drug must be carefully optimized avoiding an excess that could saturate the RISC machinery and inhibiting the normal miRNA pathway.The proposed project investigates the design of a new drug RNA drug, 'OligoY', which blocks the most essential mechanism in cell proliferation, DNA replication. DNA replication is the cell process of producing two identical copies of DNA from one DNA template. It is the most essential process in cell division but its initiation is still poorly understood. DNA replication in eukaryotes employs several extracellular signals to coordinate the specialized compartment of the multicellular organisms. OligoYs act indirectly on replication through the binding with a family of non-coding RNA, Y RNAs, specifically blocking the interaction of Y RNA with ORC (Origin Replication complex) during the replication initiation step. OligoYs are complexes formed by two strands of chemically modified RNAs, complementary to the Y RNA target, and a third element (peptide, aptamer, antibody, POD) conferring cell-selectivity. To test their application as drug, they will be initially evaluated in several cancer cell lines. OligoYs are potentially the first example of an oligonucleotide-based drug that acts on the DNA replication mechanism, bypassing all the drawbacks associated to variations of the disease during treatment and between patients.

已经开发了许多RNA药物来对抗多基因疾病，如癌症。早期对RNAi疗法的热情很快被早期临床试验的失败或有限的疗效所削弱。1关于核酸修饰的数十年研究，这些修饰可以影响配对和化学稳定性，构象以及与参与靶标的摄取、转运或加工的蛋白质和酶的相互作用，一直是寡核苷酸治疗领域的主要焦点。虽然许多基于RNA的药物正在开发中，但是基于RNA的有效治疗策略仍然存在显著障碍，包括将药物递送到特定部位或组织、脱靶效应和治疗的寿命。RNAi、反义和剪接转换寡核苷酸是仍在筛选中的主要类别的治疗剂。RNAi药物虽然在临床试验中显示出良好的效果，并且有一些代表性的药物已经被FDA批准，但由于其作用方式，其本质上存在一些限制。RNAi和miRNA途径共享共同的蛋白质，如Ago2，其参与miRNA成熟。因此，siRNA药物与内源性miRNA竞争Ago2结合，限制了所有siRNA药物的效率。为了弥补这一点，RNA药物的浓度必须仔细优化，避免过量，可能饱和RISC机器和抑制正常的miRNA途径。拟议的项目研究了一种新的药物RNA药物，'OligoY'的设计，它阻断细胞增殖中最重要的机制，DNA复制。DNA复制是从一个DNA模板产生两个相同的DNA拷贝的细胞过程。它是细胞分裂中最重要的过程，但其起始仍然知之甚少。真核生物中的DNA复制利用几种细胞外信号来协调多细胞生物体的特化区室。OligoY通过与非编码RNA（Y RNA）家族的结合间接作用于复制，特异性阻断Y RNA与复制起始步骤期间的ORC（起始复制复合物）的相互作用。OligoY是由与Y RNA靶标互补的两条化学修饰RNA链和赋予细胞选择性的第三元件（肽、适体、抗体、POD）形成的复合物。为了测试它们作为药物的应用，它们将在几种癌细胞系中进行初步评估。OligoY可能是第一个作用于DNA复制机制的基于阿托伐他汀的药物的例子，绕过了治疗期间和患者之间与疾病变化相关的所有缺点。