Long-term efficacy and safety of mRNA therapy in two murine models of methylmalonic acidemia

• Published in: EBioMedicine Vol. 45; pp. 519 - 528
• Main Authors: An, Ding, Frassetto, Andrea, Jacquinet, Eric, Eybye, Marianne, Milano, Joseph, DeAntonis, Christine, Nguyen, Vi, Laureano, Rodrigo, Milton, Jaclyn, Sabnis, Staci, Lukacs, Christine M., Guey, Lin T.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2019; Elsevier
• Subjects: Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Metabolism, Inborn Errors - pathology; Amino Acid Metabolism, Inborn Errors - therapy; Animals; Child; Disease Models, Animal; Enzyme replacement; Humans; Lipids - genetics; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver targeted therapy; Methylmalonyl-CoA mutase; Methylmalonyl-CoA Mutase - genetics; Methylmalonyl-CoA Mutase - pharmacology; Mice; Organic acidemia; Research paper; RNA, Messenger - genetics; RNA, Messenger - pharmacology; Systemic mRNA therapy; Systemic mRNA therapy; Organic acidemia; Enzyme replacement; Liver targeted therapy; Methylmalonyl-CoA mutase
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2019.07.003

Isolated methylmalonic acidemia/aciduria (MMA) is an ultra-rare, serious, inherited metabolic disorder with significant morbidity and mortality. Exogenously delivered mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, is a potential therapy to produce functional MUT enzyme in liver. Two 12-week repeat-dose studies were conducted to evaluate the efficacy and safety of intravenously-administered hMUT mRNA encapsulated in lipid nanoparticles in two murine models of MMA. In MMA hypomorphic mice, hMUT mRNA treatment resulted in dose-dependent and reproducible biomarker responses after each dose. Enzymatically-active MUT protein was produced in liver in a dose-dependent manner. hMUT mRNA was well-tolerated with no adverse effects, as indicated by the lack of clinical observations, minimal changes in clinical chemistry parameters, and histopathology examination across all tissues. In severe MMA mice, hMUT mRNA led to substantially improved survival and growth and ameliorated biochemical abnormalities, all of which are cardinal clinical manifestations in severely affected patients. These data demonstrate durable functional benefit of hMUT mRNA and support development of this new class of therapy for a devastating, pediatric disorder. This work was funded by Moderna, Inc.