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mRNA therapy restores ureagenesis and corrects glutathione metabolism dysfunction in argininosuccinic aciduria

S Gurung(1) O V Timmermand(2) D Perocheau(1) A L Gil-Martinez(1) M Minnion(3) L Touramanidou(1) S Fang(8) M Messina(8) Y Khalil(1) J Spiewak(1) A R Barber(2) R S Edwards(2) P L Pinto(4) P F Finn(5) A Cavedon(5) S Siddiqui(5) L Rice(5) P GV Martini(5) W Heywood(1) I Hargreaves(6) S Heales(1,8) P B Mills(1) S N Waddington(7) P Gissen(1,8) S Eaton(1) M Ryten(1) M Feelisch(3) A Frassetto(5) T H Witney(2) J Baruteau(1,8,9)

1:UCL Institute of Child Health; 2:School of Biomedical Engineering and Imaging Sciences, King's College London; 3:Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton; 4:Santa Maria’s Hospital, Lisbon North University Hospital Center; 5:Moderna, Inc., 200 Technology Square, Cambridge, US; 6:Pharmacy and Biomolecular Sciences, Liverpool John Moore University; 7:EGA UCL Institute of Women's Health; 8:Great Ormond Street Hospital for Children NHS Foundation Trust, London; 9:National Institute of Health Research Great Ormond Street Biomedical Research Centre, London

Argininosuccinic lyase (ASL) is a urea cycle enzyme enabling the clearance of neurotoxic ammonia. Inherited ASL deficiency results in argininosuccinic aciduria (ASA), where patients present with hyperammonaemia, chronic liver disease and neurocognitive impairment. Lack of curative therapy and limited efficacy achieved with current standard of care asserts need for novel therapy. mRNA encapsulated in lipid nanoparticles (LNPs) has shown promise in liver inherited metabolic diseases.

We investigate the efficacy of hASL mRNA containing LNPs (ASL-LNP) in ASL-deficient Aslᴺᵉᵒ/ᴺᵉᵒ mouse model and the involvement of glutathione dysfunction in the ASA liver pathophysiology.

Pharmacokinetics at dose of 1mg/kg following single intravenous (IV) injection of ASL-LNP in Aslᴺᵉᵒ/ᴺᵉᵒ mice showed lasting efficacy for up to 7 days. Weekly IV administration from birth normalised survival, growth, fur pattern, ammonaemia, and several biomarkers including in vivo ureagenesis with stable isotopes. Transcriptomics analysis demonstrated the correction of liver metabolic dysfunction with a reduction from 2,600 to 7 significantly differentially expressed genes between untreated versus ASL-LNP treated mutants compared to WT littermates. Weekly IV administration of ASL-LNPs in juvenile Aslᴺᵉᵒ/ᴺᵉᵒ mice significantly increased survival, growth and liver ASL activity and normalised the disease biomarkers and ureagenesis.

Reduced glutathione biosynthesis is hallmark of the chronic liver disease in ASA. In vivo glutathione metabolism assessed with positron emission tomography (PET) imaging using (S)-4-(3-¹⁸F-fluoropropyl)-L-glutamate ([¹⁸F]FSPG) radiotracer showed a significant improvement in ASL-LNP treated versus untreated Aslᴺᵉᵒ/ᴺᵉᵒ compared to WT littermates.

This proof of concept of mRNA-LNP therapy in ASA paves the way for clinical translation.

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