Systemic Alanine Glyoxylate Aminotransferase mRNA Improves Glyoxylate Metabolism in a Mouse Model of Primary Hyperoxaluria Type 1
| Autor: | Anjli Kukreja, Angel L. Pey, Susan Sobolov, Jian-Ping Tang, Xiang Gao, Melissa A. Lasaro, Eduardo Salido, Romesh R. Subramanian, Christian Cobaugh, Cristina Martin-Higueras, Chris Forbes |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Metabolite Genetic Vectors Calcium oxalate Glyoxylate cycle Biochemistry Oxalate Primary hyperoxaluria 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Internal medicine parasitic diseases Drug Discovery Genetics medicine Animals Humans RNA Messenger Molecular Biology Transaminases chemistry.chemical_classification Mice Knockout Kidney Oxalates Chemistry Glyoxylates medicine.disease Disease Models Animal 030104 developmental biology Enzyme Endocrinology medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Glycine Hyperoxaluria Primary Molecular Medicine |
| Zdroj: | Nucleic acid therapeutics. 29(2) |
| ISSN: | 2159-3345 |
| Popis: | Primary Hyperoxaluria Type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism. Loss of alanine glyoxylate aminotransferase (AGT) function to convert intermediate metabolite glyoxylate to glycine causes the accumulation and reduction of glyoxylate to glycolate, which eventually is oxidized to oxalate. Excess oxalate in PH1 patients leads to the formation and deposition of calcium oxalate crystals in the kidney and urinary tract. Oxalate crystal deposition causes a decline in renal function, systemic oxalosis, and eventually end-stage renal disease and premature death. mRNA-based therapies are a new class of drugs that work by replacing the missing enzyme. mRNA encoding AGT has the potential to restore normal glyoxylate to glycine metabolism, thus preventing the buildup of calcium oxalate in various organs. Panels of codon-optimized AGT mRNA constructs were screened in vitro and in wild-type mice for the production of a functional AGT enzyme. Two human constructs, wild-type and engineered AGT (RHEAM), were tested in Agxt-/- mice. Repeat dosing in Agxt-/- mice resulted in a 40% reduction in urinary oxalate, suggesting therapeutic benefit. These studies suggest that mRNA encoding AGT led to increased expression and activity of the AGT enzyme in liver that translated into decrease in urinary oxalate levels. Taken together, our data indicate that AGT mRNA may have the potential to be developed into a therapeutic for PH1. |
| Databáze: | OpenAIRE |
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