Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nucleic Acid Ther. 2020 Dec;30(6):379-391. doi: 10.1089/nat.2020.0886. Epub 2020 Sep 9.
Hyperammonemia is a dangerous life-threatening metabolic complication characterized by markedly elevated ammonia levels that can lead to irreversible brain damage if not carefully monitored. Current pharmacological treatment strategies available for hyperammonemia patients are suboptimal and associated with major side effects. In this study, we focus on developing and evaluating the delivery of novel DNA-encoded glutamine synthetase (GS) enzymes for the treatment of hyperammonemia. Direct delivered DNA-encoded GS enzyme was evaluated in ammonium acetate-induced hyperammonemia and thioacetamide-induced acute liver injury (ALI) models in C57BL/6 mice. In ammonium acetate-induced hyperammonemia model, we achieved a 30.5% decrease in blood ammonia levels 15 min postadministration of ammonium acetate, with DNA-encoded GS-treated group. Significant increase in survival was observed in ALI model with the treated mice. A comparison of the secreted versus intracellular DNA-encoded GS enzyme demonstrated similar increases in survival in the ALI model, with 40% mortality in the secreted enzymes and 30% mortality in the intracellular enzymes, as compared with 90% mortality in the control group. Direct delivery of DNA-encoded GS demonstrated important ammonia-lowering potential. These results provide the initial steps toward development of delivered DNA as a potential new approach to ammonia-lowering therapeutics.
高氨血症是一种具有生命威胁的代谢并发症，其特征是血氨水平显著升高，如果不进行仔细监测，可能会导致不可逆转的脑损伤。目前针对高氨血症患者的药物治疗策略并不理想，并且存在严重的副作用。在这项研究中，我们专注于开发和评估新型 DNA 编码谷氨酰胺合成酶（GS）酶的递送，以用于治疗高氨血症。我们在 C57BL/6 小鼠的乙酸铵诱导的高氨血症和硫代乙酰胺诱导的急性肝损伤（ALI）模型中评估了直接递送的 DNA 编码 GS 酶。在乙酸铵诱导的高氨血症模型中，我们在给予乙酸铵后 15 分钟，实现了血液中氨水平降低 30.5%，而 DNA 编码 GS 治疗组的血液氨水平降低了 30.5%。在 ALI 模型中，观察到治疗小鼠的生存率显著提高。对分泌型与细胞内 DNA 编码 GS 酶的比较表明，在 ALI 模型中，分泌型酶的生存率增加了 40%，而细胞内酶的生存率增加了 30%，而对照组的死亡率则高达 90%。直接递送 DNA 编码 GS 酶显示出具有重要的降低氨的潜力。这些结果为开发递送 DNA 作为一种降低氨的治疗新方法提供了初步步骤。
