mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria

Sonam Gurung, Oskar Vilhelmsson Timmermand, Dany Perocheau, Ana Luisa Gil-Martinez, Magdalena Minnion, Loukia Touramanidou, Sherry Fang, Martina Messina, Youssef Khalil, Justyna Spiewak, Abigail R Barber, Richard S Edwards, Patricia Lipari Pinto, Patrick F Finn, Alex Cavedon, Summar Siddiqui, Lisa Rice, Paolo G V Martini, Deborah Ridout, Wendy HeywoodIan Hargreaves, Simon Heales, Philippa B Mills, Simon N Waddington, Paul Gissen, Simon Eaton, Mina Ryten, Martin Feelisch, Andrea Frassetto, Timothy H Witney, Julien Baruteau

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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.

Original languageEnglish
Article number1334
JournalScience Translational Medicine
Issue number729
Early online date10 Jan 2024
Publication statusPublished - 2024


  • Adult
  • Humans
  • Animals
  • Mice
  • Argininosuccinic Aciduria/genetics
  • Cysteine
  • Glutathione
  • Metabolomics
  • Liver Diseases


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