Cross-Species Translation of Biophase Half-Life and Potency of GalNAc-Conjugated siRNAs.

IF 4 2区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Nucleic acid therapeutics Pub Date : 2022-12-01 DOI:10.1089/nat.2022.0010

Alessandro Boianelli, Yasunori Aoki, Maxim Ivanov, Anders Dahlén, Peter Gennemark

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引用次数: 2

Abstract

Small interfering RNAs (siRNAs) with N-acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat liver diseases. Understanding how pharmacokinetics and pharmacodynamics translate is pivotal for in vivo study design and human dose prediction. However, the literature is sparse on translational data for this modality, and pharmacokinetics in the liver is seldom measured. To overcome these difficulties, we collected time-course biomarker data for 11 GalNAc-siRNAs in various species and applied the kinetic-pharmacodynamic modeling approach to estimate the biophase (liver) half-life and the potency. Our analysis indicates that the biophase half-life is 0.6-3 weeks in mouse, 1-8 weeks in monkey, and 1.5-14 weeks in human. For individual siRNAs, the biophase half-life is 1-8 times longer in human than in mouse, and generally 1-3 times longer in human than in monkey. The analysis indicates that the siRNAs are more potent in human than in mouse and monkey.

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galnac偶联sirna的生物期半衰期和效力的跨物种翻译。

小干扰rna (sirna)与n -乙酰半乳糖胺(GalNAc)偶联改善肝脏摄取是一类治疗肝脏疾病的新兴药物。了解药代动力学和药效学如何转化是体内研究设计和人体剂量预测的关键。然而，关于这种方式的翻译数据的文献很少，并且很少测量肝脏中的药代动力学。为了克服这些困难，我们收集了不同物种中11种galnac - sirna的时间过程生物标志物数据，并应用动力学药效学建模方法来估计生物期(肝脏)半衰期和效力。结果表明，小鼠的半衰期为0.6-3周，猴的半衰期为1-8周，人的半衰期为1.5-14周。对于单个sirna，人类的生物期半衰期是小鼠的1-8倍，一般是猴子的1-3倍。分析表明，sirna在人体内比在小鼠和猴子体内更有效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nucleic acid therapeutics BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL

CiteScore

7.60

自引率

7.50%

发文量

审稿时长

>12 weeks

期刊介绍： Nucleic Acid Therapeutics is the leading journal in its field focusing on cutting-edge basic research, therapeutic applications, and drug development using nucleic acids or related compounds to alter gene expression. The Journal examines many new approaches for using nucleic acids as therapeutic agents or in modifying nucleic acids for therapeutic purposes including: oligonucleotides, gene modification, aptamers, RNA nanoparticles, and ribozymes.