Format

Send to

Choose Destination
Cell Rep. 2017 Dec 19;21(12):3548-3558. doi: 10.1016/j.celrep.2017.11.081.

Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia.

Author information

1
Moderna Therapeutics, Cambridge, MA 02139, USA.
2
Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
3
Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: venditti@mail.nih.gov.
4
Moderna Therapeutics, Cambridge, MA 02139, USA. Electronic address: paolo.martini@modernatx.com.

Abstract

Isolated methylmalonic acidemia/aciduria (MMA) is a devastating metabolic disorder with poor outcomes despite current medical treatments. Like other mitochondrial enzymopathies, enzyme replacement therapy (ERT) is not available, and although promising, AAV gene therapy can be limited by pre-existing immunity and has been associated with genotoxicity in mice. To develop a new class of therapy for MMA, we generated a pseudoU-modified codon-optimized mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, and encapsulated it into biodegradable lipid nanoparticles (LNPs). Intravenous (i.v.) administration of hMUT mRNA in two different mouse models of MMA resulted in a 75%-85% reduction in plasma methylmalonic acid and was associated with increased hMUT protein expression and activity in liver. Repeat dosing of hMUT mRNA reduced circulating metabolites and dramatically improved survival and weight gain. Additionally, repeat i.v. dosing did not increase markers of liver toxicity or inflammation in heterozygote MMA mice.

KEYWORDS:

lipid nanoparticle; liver; mRNA therapy; methylmalonic acid; methylmalonic acidemia/aciduria; methylmalonyl-CoA mutase

PMID:
29262333
DOI:
10.1016/j.celrep.2017.11.081
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center