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RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models.

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Title: RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models.
Authors: Haase N; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., Foster DJ; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA., Cunningham MW; Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA., Bercher J; Experimental and Clinical Research Center, Berlin, Germany., Nguyen T; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA., Shulga-Morskaya S; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA., Milstein S; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA., Shaikh S; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA., Rollins J; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA., Golic M; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., Herse F; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., Kräker K; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., Bendix I; Department of Pediatrics I Neonatology and Experimental Perinatal Neurosciences and., Serdar M; Department of Pediatrics I Neonatology and Experimental Perinatal Neurosciences and., Napieczynska H; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Heuser A; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany., Gellhaus A; Department of Gynecology and Obstetrics, University Hospital Essen, University Duisburg-Essen, Essen, Germany., Thiele K; Department of Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Wallukat G; Experimental and Clinical Research Center, Berlin, Germany., Müller DN; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., LaMarca B; Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.; Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi, USA., Dechend R; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.; HELIOS-Klinikum, Berlin, Germany.Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt, ) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt, with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow mid-gestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt, ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia.
Source: The Journal of clinical investigation [J Clin Invest] 2020 Jun 01; Vol. 130 (6), pp. 2928-2942.
Publication Type: Journal Article; Research Support, Non-U.S. Gov't
Journal Info: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
Database: MEDLINE Ultimate
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  Data: RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models.
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  Data: <searchLink fieldCode="AU" term="%22Haase+N%22">Haase N</searchLink>; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22Foster+DJ%22">Foster DJ</searchLink>; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Cunningham+MW%22">Cunningham MW</searchLink>; Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.<br /><searchLink fieldCode="AU" term="%22Bercher+J%22">Bercher J</searchLink>; Experimental and Clinical Research Center, Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22Nguyen+T%22">Nguyen T</searchLink>; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Shulga-Morskaya+S%22">Shulga-Morskaya S</searchLink>; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Milstein+S%22">Milstein S</searchLink>; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Shaikh+S%22">Shaikh S</searchLink>; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Rollins+J%22">Rollins J</searchLink>; Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.<br /><searchLink fieldCode="AU" term="%22Golic+M%22">Golic M</searchLink>; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22Herse+F%22">Herse F</searchLink>; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22Kräker+K%22">Kräker K</searchLink>; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22Bendix+I%22">Bendix I</searchLink>; Department of Pediatrics I Neonatology and Experimental Perinatal Neurosciences and.<br /><searchLink fieldCode="AU" term="%22Serdar+M%22">Serdar M</searchLink>; Department of Pediatrics I Neonatology and Experimental Perinatal Neurosciences and.<br /><searchLink fieldCode="AU" term="%22Napieczynska+H%22">Napieczynska H</searchLink>; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22Heuser+A%22">Heuser A</searchLink>; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22Gellhaus+A%22">Gellhaus A</searchLink>; Department of Gynecology and Obstetrics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.<br /><searchLink fieldCode="AU" term="%22Thiele+K%22">Thiele K</searchLink>; Department of Experimental Feto-Maternal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.<br /><searchLink fieldCode="AU" term="%22Wallukat+G%22">Wallukat G</searchLink>; Experimental and Clinical Research Center, Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22Müller+DN%22">Müller DN</searchLink>; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.<br /><searchLink fieldCode="AU" term="%22LaMarca+B%22">LaMarca B</searchLink>; Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.; Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi, USA.<br /><searchLink fieldCode="AU" term="%22Dechend+R%22">Dechend R</searchLink>; Max-Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.; Charité - Universitätsmedizin Berlin, Berlin Germany.; Experimental and Clinical Research Center, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany.; HELIOS-Klinikum, Berlin, Germany.Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt, ) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt, with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow mid-gestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt, ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia.
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  Data: <searchLink fieldCode="JN" term="%227802877%22">The Journal of clinical investigation</searchLink> [J Clin Invest] 2020 Jun 01; Vol. 130 (6), pp. 2928-2942.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22American+Society+for+Clinical+Investigation%22">American Society for Clinical Investigation </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>7802877 <i>Publication Model: </i>Print <i>Cited Medium: </i>Internet <i>ISSN: </i>1558-8238 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2200219738%22">00219738 </searchLink><i>NLM ISO Abbreviation: </i>J Clin Invest <i>Subsets: </i>MEDLINE
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