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Investigational new drug enabling angiotensin oral-delivery studies to attenuate pulmonary hypertension.
Biomaterials ( IF 12.8 ) Pub Date : 2019-12-30 , DOI: 10.1016/j.biomaterials.2019.119750 Henry Daniell 1 , Venkata Mangu 1 , Bakhtiyor Yakubov 2 , Jiyoung Park 1 , Peyman Habibi 1 , Yao Shi 1 , Patricia A Gonnella 1 , Amanda Fisher 2 , Todd Cook 2 , Lily Zeng 2 , Steven M Kawut 3 , Tim Lahm 4
Biomaterials ( IF 12.8 ) Pub Date : 2019-12-30 , DOI: 10.1016/j.biomaterials.2019.119750 Henry Daniell 1 , Venkata Mangu 1 , Bakhtiyor Yakubov 2 , Jiyoung Park 1 , Peyman Habibi 1 , Yao Shi 1 , Patricia A Gonnella 1 , Amanda Fisher 2 , Todd Cook 2 , Lily Zeng 2 , Steven M Kawut 3 , Tim Lahm 4
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Pulmonary arterial hypertension (PAH) is a deadly and uncurable disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. Angiotensin Converting Enzyme 2 (ACE2) and its product, angiotensin-(1-7) [ANG-(1-7)] were expressed in lettuce chloroplasts to facilitate affordable oral drug delivery. Lyophilized lettuce cells were stable up to 28 months at ambient temperature with proper folding, assembly of CTB-ACE2/ANG-(1-7) and functionality. When the antibiotic resistance gene was removed, Ang1-7 expression was stable in subsequent generations in marker-free transplastomic lines. Oral gavage of monocrotaline-induced PAH rats resulted in dose-dependent delivery of ANG-(1-7) and ACE2 in plasma/tissues and PAH development was attenuated with decreases in right ventricular (RV) hypertrophy, RV systolic pressure, total pulmonary resistance and pulmonary artery remodeling. Such attenuation correlated well with alterations in the transcription of Ang-(1-7) receptor MAS and angiotensin II receptor AGTRI as well as IL-1β and TGF-β1. Toxicology studies showed that both male and female rats tolerated ~10-fold ACE2/ANG-(1-7) higher than efficacy dose. Plant cell wall degrading enzymes enhanced plasma levels of orally delivered protein drug bioencapsulated within plant cells. Efficient attenuation of PAH with no toxicity augurs well for clinical advancement of the first oral protein therapy to prevent/treat underlying pathology for this disease.
中文翻译：
研究性新药使血管紧张素口服给药研究能够减轻肺动脉高压。
肺动脉高压（PAH）是一种致命且无法治愈的疾病，其特征是肺血管重塑和肺动脉压力升高。血管紧张素转换酶 2 (ACE2) 及其产物血管紧张素-(1-7) [ANG-(1-7)] 在生菜叶绿体中表达，以促进经济实惠的口服药物递送。冻干生菜细胞在环境温度下可稳定保存长达 28 个月，并且具有正确的折叠、CTB-ACE2/ANG-(1-7) 的组装和功能。当抗生素抗性基因被去除后，Ang1-7在无标记转质体系的后代中表达稳定。野百合碱诱导的 PAH 大鼠经口灌胃导致血浆/组织中 ANG-(1-7) 和 ACE2 的剂量依赖性递送，并且 PAH 的发展随着右心室 (RV) 肥大、RV 收缩压、总肺阻力的降低而减弱和肺动脉重塑。这种减弱与 Ang-(1-7) 受体 MAS 和血管紧张素 II 受体 AGTRI 以及 IL-1β 和 TGF-β1 转录的改变密切相关。毒理学研究表明，雄性和雌性大鼠都能耐受比有效剂量高约 10 倍的 ACE2/ANG-(1-7)。植物细胞壁降解酶提高了生物封装在植物细胞内的口服蛋白质药物的血浆水平。有效减弱 PAH 且无毒性，预示着第一种口服蛋白质疗法预防/治疗该疾病潜在病理的临床进展。
更新日期：2019-12-30
中文翻译：
研究性新药使血管紧张素口服给药研究能够减轻肺动脉高压。
肺动脉高压（PAH）是一种致命且无法治愈的疾病，其特征是肺血管重塑和肺动脉压力升高。血管紧张素转换酶 2 (ACE2) 及其产物血管紧张素-(1-7) [ANG-(1-7)] 在生菜叶绿体中表达，以促进经济实惠的口服药物递送。冻干生菜细胞在环境温度下可稳定保存长达 28 个月，并且具有正确的折叠、CTB-ACE2/ANG-(1-7) 的组装和功能。当抗生素抗性基因被去除后，Ang1-7在无标记转质体系的后代中表达稳定。野百合碱诱导的 PAH 大鼠经口灌胃导致血浆/组织中 ANG-(1-7) 和 ACE2 的剂量依赖性递送，并且 PAH 的发展随着右心室 (RV) 肥大、RV 收缩压、总肺阻力的降低而减弱和肺动脉重塑。这种减弱与 Ang-(1-7) 受体 MAS 和血管紧张素 II 受体 AGTRI 以及 IL-1β 和 TGF-β1 转录的改变密切相关。毒理学研究表明，雄性和雌性大鼠都能耐受比有效剂量高约 10 倍的 ACE2/ANG-(1-7)。植物细胞壁降解酶提高了生物封装在植物细胞内的口服蛋白质药物的血浆水平。有效减弱 PAH 且无毒性，预示着第一种口服蛋白质疗法预防/治疗该疾病潜在病理的临床进展。
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