Tools
Tools
Gurung, S, Timmermand, OV, Perocheau, D, Gil-Martinez, AL, Minnion, M, Touramanidou, L, Fang, S, Messina, M, Khalil, Y, Spiewak, J, Barber, AR, Edwards, RS, Pinto, PL, Finn, PF, Cavedon, A, Siddiqui, S, Rice, L, Martini, PGV, Ridout, D, Heywood, W , Hargreaves, I, Heales, S, Mills, PB, Waddington, SN, Gissen, P, Eaton, S, Ryten, M, Feelisch, M, Frassetto, A, Witney, TH and Baruteau, J (2024) mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria. Science Translational Medicine, 16 (729). ISSN 1946-6234
|
Text
mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria.pdf - Accepted Version Available under License Creative Commons Attribution. Download (352kB) | Preview |
Abstract
The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using (S)-4-(3-18F-fluoropropyl)-l-glutamate ([18F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.
| Item Type: | Article |
|---|---|
| Additional Information: | This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on 16(729), DOI: 10.1126/scitranslmed.adh1334. |
| Uncontrolled Keywords: | Animals; Humans; Mice; Liver Diseases; Cysteine; Glutathione; Adult; Metabolomics; Argininosuccinic Aciduria; Adult; Humans; Animals; Mice; Argininosuccinic Aciduria; Cysteine; Glutathione; Metabolomics; Liver Diseases; 06 Biological Sciences; 11 Medical and Health Sciences |
| Subjects: | Q Science > Q Science (General) Q Science > QH Natural history > QH301 Biology R Medicine > R Medicine (General) |
| Divisions: | Pharmacy & Biomolecular Sciences |
| Publisher: | American Association for the Advancement of Science (AAAS) |
| SWORD Depositor: | A Symplectic |
| Date Deposited: | 18 Jun 2024 14:52 |
| Last Modified: | 18 Jun 2024 14:52 |
| DOI or ID number: | 10.1126/scitranslmed.adh1334 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/23604 |
 |
View Item |