mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
|---|---|
| Enthalten in: |
Science translational medicine - 16(2024), 729 vom: 10. Jan., Seite eadh1334 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Gurung, Sonam [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Completed 12.01.2024 Date Revised 13.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1126/scitranslmed.adh1334 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366891677 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366891677 | ||
| 003 | DE-627 | ||
| 005 | 20240313234037.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240114s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1126/scitranslmed.adh1334 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1326.xml |
| 035 | |a (DE-627)NLM366891677 | ||
| 035 | |a (NLM)38198573 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Gurung, Sonam |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.01.2024 | ||
| 500 | |a Date Revised 13.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Cysteine |2 NLM | |
| 650 | 7 | |a K848JZ4886 |2 NLM | |
| 650 | 7 | |a Glutathione |2 NLM | |
| 650 | 7 | |a GAN16C9B8O |2 NLM | |
| 700 | 1 | |a Timmermand, Oskar Vilhelmsson |e verfasserin |4 aut | |
| 700 | 1 | |a Perocheau, Dany |e verfasserin |4 aut | |
| 700 | 1 | |a Gil-Martinez, Ana Luisa |e verfasserin |4 aut | |
| 700 | 1 | |a Minnion, Magdalena |e verfasserin |4 aut | |
| 700 | 1 | |a Touramanidou, Loukia |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Sherry |e verfasserin |4 aut | |
| 700 | 1 | |a Messina, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Khalil, Youssef |e verfasserin |4 aut | |
| 700 | 1 | |a Spiewak, Justyna |e verfasserin |4 aut | |
| 700 | 1 | |a Barber, Abigail R |e verfasserin |4 aut | |
| 700 | 1 | |a Edwards, Richard S |e verfasserin |4 aut | |
| 700 | 1 | |a Pinto, Patricia Lipari |e verfasserin |4 aut | |
| 700 | 1 | |a Finn, Patrick F |e verfasserin |4 aut | |
| 700 | 1 | |a Cavedon, Alex |e verfasserin |4 aut | |
| 700 | 1 | |a Siddiqui, Summar |e verfasserin |4 aut | |
| 700 | 1 | |a Rice, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Martini, Paolo G V |e verfasserin |4 aut | |
| 700 | 1 | |a Ridout, Deborah |e verfasserin |4 aut | |
| 700 | 1 | |a Heywood, Wendy |e verfasserin |4 aut | |
| 700 | 1 | |a Hargreaves, Ian |e verfasserin |4 aut | |
| 700 | 1 | |a Heales, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Mills, Philippa B |e verfasserin |4 aut | |
| 700 | 1 | |a Waddington, Simon N |e verfasserin |4 aut | |
| 700 | 1 | |a Gissen, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Eaton, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Ryten, Mina |e verfasserin |4 aut | |
| 700 | 1 | |a Feelisch, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Frassetto, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Witney, Timothy H |e verfasserin |4 aut | |
| 700 | 1 | |a Baruteau, Julien |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Science translational medicine |d 2009 |g 16(2024), 729 vom: 10. Jan., Seite eadh1334 |w (DE-627)NLM195151879 |x 1946-6242 |7 nnns |
| 773 | 1 | 8 | |g volume:16 |g year:2024 |g number:729 |g day:10 |g month:01 |g pages:eadh1334 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1126/scitranslmed.adh1334 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 16 |j 2024 |e 729 |b 10 |c 01 |h eadh1334 | ||