ASL mRNA-LNP Therapeutic for the Treatment of Argininosuccinic Aciduria Enables Survival Benefit in a Mouse Model.
argininosuccinate lyase deficiency (ASLD)
argininosuccinic aciduria (ASA)
lipid nanoparticle-mRNA (LNP-mRNA)
mRNA optimization
mRNA therapeutic
rare disease
Journal
Biomedicines
ISSN: 2227-9059
Titre abrégé: Biomedicines
Pays: Switzerland
ID NLM: 101691304
Informations de publication
Date de publication:
16 Jun 2023
16 Jun 2023
Historique:
received:
29
03
2023
revised:
05
06
2023
accepted:
11
06
2023
medline:
28
6
2023
pubmed:
28
6
2023
entrez:
28
6
2023
Statut:
epublish
Résumé
Argininosuccinic aciduria (ASA) is a metabolic disorder caused by a deficiency in argininosuccinate lyase (ASL), which cleaves argininosuccinic acid to arginine and fumarate in the urea cycle. ASL deficiency (ASLD) leads to hepatocyte dysfunction, hyperammonemia, encephalopathy, and respiratory alkalosis. Here we describe a novel therapeutic approach for treating ASA, based on nucleoside-modified messenger RNA (modRNA) formulated in lipid nanoparticles (LNP). To optimize ASL-encoding mRNA, we modified its cap, 5' and 3' untranslated regions, coding sequence, and the poly(A) tail. We tested multiple optimizations of the formulated mRNA in human cells and wild-type C57BL/6 mice. The ASL protein showed robust expression in vitro and in vivo and a favorable safety profile, with low cytokine and chemokine secretion even upon administration of increasing doses of ASL mRNA-LNP. In the ASL
Identifiants
pubmed: 37371829
pii: biomedicines11061735
doi: 10.3390/biomedicines11061735
pmc: PMC10296609
pii:
doi:
Types de publication
Journal Article
Langues
eng
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