Novel mRNA-Based Therapy Reduces Toxic Galactose Metabolites and Overcomes Galactose Sensitivity in a Mouse Model of Classic Galactosemia

Mol Ther. 2020 Jan 8;28(1):304-312. doi: 10.1016/j.ymthe.2019.09.018. Epub 2019 Sep 19.


Classic galactosemia (CG) is a potentially lethal inborn error of galactose metabolism that results from deleterious mutations in the human galactose-1 phosphate uridylyltransferase (GALT) gene. Previously, we constructed a GalT-/- (GalT-deficient) mouse model that exhibits galactose sensitivity in the newborn mutant pups, reduced fertility in adult females, impaired motor functions, and growth restriction in both sexes. In this study, we tested whether restoration of hepatic GALT activity alone could decrease galactose-1 phosphate (gal-1P) and plasma galactose in the mouse model. The administration of different doses of mouse GalT (mGalT) mRNA resulted in a dose-dependent increase in mGalT protein expression and enzyme activity in the liver of GalT-deficient mice. Single intravenous (i.v.) dose of human GALT (hGALT) mRNA decreased gal-1P in mutant mouse liver and red blood cells (RBCs) within 24 h with low levels maintained for over a week. Repeated i.v. injections increased hepatic GalT expression, nearly normalized gal-1P levels in liver, and decreased gal-1P levels in RBCs and peripheral tissues throughout all doses. Moreover, repeated dosing reduced plasma galactose by 60% or more throughout all four doses. Additionally, a single intraperitoneal dose of hGALT mRNA overcame the galactose sensitivity and promoted the growth in a GalT-/- newborn pup.

Keywords: GALT; IEM; POI; ataxia; classic galactosemia; galactose toxicity; galactose-1 phosphate; galactose-1 phosphate uridylyltransferase; inborn errors of metabolism; mRNA therapy; primary ovarian insufficiency; speech dyspraxia.

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Disease Models, Animal*
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Female
  • Fibroblasts / metabolism
  • Galactose / blood*
  • Galactosemias / pathology
  • Galactosemias / therapy*
  • Galactosephosphates / metabolism
  • Humans
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • RNA, Messenger / administration & dosage*
  • Signal Transduction / drug effects
  • Transfection
  • Treatment Outcome
  • UTP-Hexose-1-Phosphate Uridylyltransferase / administration & dosage*
  • UTP-Hexose-1-Phosphate Uridylyltransferase / genetics


  • Galactosephosphates
  • RNA, Messenger
  • galactose-1-phosphate
  • UTP-Hexose-1-Phosphate Uridylyltransferase
  • GALT protein, human
  • Galactose