利用微生理系统来解决在寡核苷酸治疗发展过程中遇到的挑战。

ALTEX Pub Date : 2022-01-01 Epub Date: 2021-11-11 DOI:10.14573/altex.2108241
Diane Ramsden, David G Belair, Saket Agarwal, Patrik Andersson, Sara Humphreys, Deidre A Dalmas, Simone H Stahl, Chris Maclauchlin, Joseph A Cichocki
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引用次数: 8

摘要

寡核苷酸疗法(ONTs)包括有选择性地靶向和潜在地改善以前无法治疗和通常罕见疾病的药物类别。几种独特的ont提供了多功能性,可以通过沃森-克里克碱基配对直接调节基因表达,或者通过结构模仿或干扰蛋白质受体相互作用来调节细胞信号。由于缺乏能够概括或预测ONTs体内效应的合适体外模型,它们的发现和优化在很大程度上依赖于动物研究来预测人类的疗效和安全性。由于ont通常缺乏跨物种活性,因此通常需要具有遗传人源化和/或物种特异性替代ont的动物模型。人体微生理系统(MPS)提供了一个减少动物使用的机会,可以评估药物机制,优化细胞和组织靶向配体或递送载体,以及表征候选ONTs的药代动力学(PK),药效学(PD)和安全性。MPS应用与ONT缺乏公开的例子表明,需要集中精力来描述和建立对其效用的信心。本综述的目的是总结当前ONT的现状,并强调在ONT的发现和开发过程中,MPS应用的潜在机遇和挑战。此外,本综述旨在提高ONT药物开发人员和监管机构对MPS在表征药理学、ADME和毒性方面的潜在影响的认识,并教育MPS平台开发人员充分认识MPS在ONT开发中的优势所需的独特设计属性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Leveraging microphysiological systems to address challenges encountered during development of oligonucleotide therapeutics.

Oligonucleotide therapeutics (ONTs) encompass classes of medicines that selectively target and potentially ameliorate previously untreatable and often rare diseases. Several unique classes of ONTs provide versatility, enabling direct modu­lation of gene expression by virtue of Watson-Crick base pairing or modulation of cell signaling through structural mimicry or interference with protein-receptor interactions. Due to a lack of suitable in vitro models capable of recapitulating or predicting in vivo effects of ONTs, their discovery and optimization has relied heavily on animal studies for predicting efficacy and safety in humans. Since ONTs often lack cross-species activity, animal models with genetic humanization and/or species-specific surrogate ONTs are often required. Human microphysiological systems (MPS) offer an oppor­tunity to reduce the use of animals and may enable evaluation of drug mechanisms, optimization of cell and tissue targeting ligands or delivery vehicles, and characterization of pharmacokinetics (PK), pharmacodynamics (PD), and safety of candidate ONTs. The lack of published examples for MPS applications with ONT demonstrates the need for a focused effort to characterize and build confidence in their utility. The goals of this review are to summarize the current landscape of ONTs and highlight potential opportunities and challenges for application of MPS during ONT discovery and development. In addition, this review aims to raise awareness with ONT drug developers and regulatory authorities on the potential impact of MPS with respect to characterizing pharmacology, ADME, and toxicity and to educate MPS platform developers on unique design attributes needed to fully appreciate MPS advantages in ONT development.

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