Use of a Transgenic Human PNPLA3I148M Knock-in Mouse for Translational Safety Evaluations of siRNA Therapeutics.

IF 4.7 2区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ben Brooks, Artem Shkumatov, Jackson Kalanzi, Kim Henderson Park, Julie M Lade, Diana Wong, Hui Dou, Jason Long, Ingrid C Rulifson, Justin K Murray, Lauren Mihalcik, Tod A Harper
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引用次数: 0

Abstract

The PNPLA3 single nucleotide polymorphism, rs738409, is the strongest known genetic risk factor for metabolic dysfunction-associated steatotic liver disease; thus, targeting the minor allele with a GalNAc-conjugated siRNA is an attractive strategy to treat patients carrying the genetic variant. To enable translational safety assessment of a GalNAc-conjugated siRNA that specifically targets the rs738409 sequence of PNPLA3, a transgenic human PNPLA3I148M knock-in mouse (huPNPLA3I148M) was utilized. This model showed no significant genotype-related phenotypic differences to wild-type mice in a phenotype characterization study when maintained on standard rodent chow. Additionally, a repeat-dose toxicology study using a GalNAc-conjugated siRNA specific for rs738409 resulted in comparable findings between genotypes (i.e., liver enzyme and histopathology changes), indicating the findings were due to the siRNA therapeutic and not a result of target knockdown in huPNPLA3I148M mice. Overall, these data demonstrate the huPNPLA3I148M mouse is suitable for repeat-dose toxicology studies, suggesting this approach could be applied to other siRNA programs lacking a pharmacologically relevant nonclinical species to support translational safety assessments during drug development.

使用转基因人PNPLA3I148M敲入小鼠进行siRNA疗法的翻译安全性评估。
PNPLA3单核苷酸多态性rs738409是已知的代谢功能障碍相关脂肪变性肝病的最强遗传危险因素;因此,用galnac结合的siRNA靶向次要等位基因是治疗携带遗传变异的患者的一种有吸引力的策略。为了对特异性靶向PNPLA3 rs738409序列的galnac偶联siRNA进行翻译安全性评估,我们使用了转基因人PNPLA3I148M敲入小鼠(huPNPLA3I148M)。在表型表征研究中,当维持在标准啮齿动物食物中时,该模型与野生型小鼠没有显着的基因型相关表型差异。此外,一项使用galnac偶联rs738409特异性siRNA的重复剂量毒理学研究得出了基因型之间的相似结果(即肝酶和组织病理学变化),表明这些发现是由于siRNA治疗而不是huPNPLA3I148M小鼠靶标敲低的结果。总的来说,这些数据表明huPNPLA3I148M小鼠适合重复剂量毒理学研究,这表明该方法可以应用于其他缺乏药理学相关非临床物种的siRNA项目,以支持药物开发过程中的转化安全性评估。
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
Nucleic acid therapeutics BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
7.60
自引率
7.50%
发文量
47
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.
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