Journal article
DNA-Encoded Glutamine Synthetase Enzyme as Ammonia-Lowering Therapeutic for Hyperammonemia
Nucleic acid therapeutics, v 30(6), pp 379-391
01 Dec 2020
PMID: 32907467
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 thein vivodelivery of novel DNA-encoded glutamine synthetase (GS) enzymes for the treatment of hyperammonemia. Directin vivodelivered 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. Directin vivodelivery 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.
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Details
- Title
- DNA-Encoded Glutamine Synthetase Enzyme as Ammonia-Lowering Therapeutic for Hyperammonemia
- Creators
- Makan Khoshnejad - The Wistar InstituteYaya Dia - The Wistar InstituteAmi Patel - The Wistar InstituteZiyang Xu - University of PennsylvaniaXizhou Zhu - The Wistar InstituteKun Yun - The Wistar InstituteKrzysztof Wojtak - University of PennsylvaniaRehman Qureshi - The Wistar InstituteLaurent Humeau - Inovio Pharmaceuticals (United States)Kar Muthumani - The Wistar InstituteDavid B. Weiner - The Wistar Institute
- Publication Details
- Nucleic acid therapeutics, v 30(6), pp 379-391
- Publisher
- Mary Ann Liebert, Inc
- Number of pages
- 13
- Grant note
- Inovio Pharmaceuticals
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Web of Science ID
- WOS:000569261700001
- Scopus ID
- 2-s2.0-85097577397
- Other Identifier
- 991019350189004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Medicine, Research & Experimental