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

Gurung, Sonam ; Timmermand, Oskar Vilhelmsson LU ; Perocheau, Dany ; Gil-Martinez, Ana Luisa ; Minnion, Magdalena ; Touramanidou, Loukia ; Fang, Sherry ; Messina, Martina ; Khalil, Youssef and Spiewak, Justyna , et al. (2024) In Science Translational Medicine 16(729).
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
Adult, Humans, Animals, Mice, Argininosuccinic Aciduria/genetics, Cysteine, Glutathione, Metabolomics, Liver Diseases
in
Science Translational Medicine
volume
16
issue
729
article number
eadh1334
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85182274773
  • pmid:38198573
ISSN
1946-6242
DOI
10.1126/scitranslmed.adh1334
language
English
LU publication?
no
id
c2a4c286-fc77-4a9a-9f04-72309870442b
date added to LUP
2024-09-26 15:12:33
date last changed
2024-09-27 04:02:14
@article{c2a4c286-fc77-4a9a-9f04-72309870442b,
  abstract     = {{<p>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.</p>}},
  author       = {{Gurung, Sonam and Timmermand, Oskar Vilhelmsson and Perocheau, Dany and Gil-Martinez, Ana Luisa and Minnion, Magdalena and Touramanidou, Loukia and Fang, Sherry and Messina, Martina and Khalil, Youssef and Spiewak, Justyna and Barber, Abigail R and Edwards, Richard S and Pinto, Patricia Lipari and Finn, Patrick F and Cavedon, Alex and Siddiqui, Summar and Rice, Lisa and Martini, Paolo G V and Ridout, Deborah and Heywood, Wendy and Hargreaves, Ian and Heales, Simon and Mills, Philippa B and Waddington, Simon N and Gissen, Paul and Eaton, Simon and Ryten, Mina and Feelisch, Martin and Frassetto, Andrea and Witney, Timothy H and Baruteau, Julien}},
  issn         = {{1946-6242}},
  keywords     = {{Adult; Humans; Animals; Mice; Argininosuccinic Aciduria/genetics; Cysteine; Glutathione; Metabolomics; Liver Diseases}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{729}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Translational Medicine}},
  title        = {{mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria}},
  url          = {{http://dx.doi.org/10.1126/scitranslmed.adh1334}},
  doi          = {{10.1126/scitranslmed.adh1334}},
  volume       = {{16}},
  year         = {{2024}},
}