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
{"title":"使用转基因人PNPLA3I148M敲入小鼠进行siRNA疗法的翻译安全性评估。","authors":"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","doi":"10.1177/21593337251375804","DOIUrl":null,"url":null,"abstract":"<p><p>The <i>PNPLA3</i> 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 <i>PNPLA3</i>, a transgenic human <i>PNPLA3<sup>I148M</sup></i> knock-in mouse (hu<i>PNPLA3<sup>I148M</sup></i>) 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 hu<i>PNPLA3<sup>I148M</sup></i> mice. Overall, these data demonstrate the hu<i>PNPLA3<sup>I148M</sup></i> 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.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":" ","pages":""},"PeriodicalIF":4.7000,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Use of a Transgenic Human PNPLA3<sup>I148M</sup> Knock-in Mouse for Translational Safety Evaluations of siRNA Therapeutics.\",\"authors\":\"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\",\"doi\":\"10.1177/21593337251375804\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The <i>PNPLA3</i> 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 <i>PNPLA3</i>, a transgenic human <i>PNPLA3<sup>I148M</sup></i> knock-in mouse (hu<i>PNPLA3<sup>I148M</sup></i>) 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 hu<i>PNPLA3<sup>I148M</sup></i> mice. Overall, these data demonstrate the hu<i>PNPLA3<sup>I148M</sup></i> 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.</p>\",\"PeriodicalId\":19412,\"journal\":{\"name\":\"Nucleic acid therapeutics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-09-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nucleic acid therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/21593337251375804\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nucleic acid therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/21593337251375804","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Use of a Transgenic Human PNPLA3I148M Knock-in Mouse for Translational Safety Evaluations of siRNA Therapeutics.
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.
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.