دورية أكاديمية
mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria
| العنوان: | mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria |
|---|---|
| المؤلفون: | 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, Baruteau, J |
| المصدر: | Science Translational Medicine , 16 (729) , Article eadh1334. (2024) |
| بيانات النشر: | American Association for the Advancement of Science |
| سنة النشر: | 2024 |
| المجموعة: | University College London: UCL Discovery |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | text |
| اللغة: | English |
| العلاقة: | https://discovery.ucl.ac.uk/id/eprint/10178381/1/STM.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10178381Test/ |
| الإتاحة: | https://discovery.ucl.ac.uk/id/eprint/10178381/1/STM.pdfTest https://discovery.ucl.ac.uk/id/eprint/10178381Test/ |
| حقوق: | open |
| رقم الانضمام: | edsbas.5F8D9436 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |