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

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...

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Bibliographic Details
Published in:Molecular therapy 2020-01, Vol.28 (1), p.304-312
Main Authors: Balakrishnan, Bijina, An, Ding, Nguyen, Vi, DeAntonis, Christine, Martini, Paolo G.V., Lai, Kent
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
ataxia
Cells, Cultured
classic galactosemia
Disease Models, Animal
Dosage
Enzymatic activity
Enzymes
Erythrocytes
Erythrocytes - drug effects
Erythrocytes - metabolism
Female
Fibroblasts
Fibroblasts - metabolism
Galactose
Galactose - blood
galactose toxicity
galactose-1 phosphate
galactose-1 phosphate uridylyltransferase
Galactosemia
Galactosemias - pathology
Galactosemias - therapy
Galactosephosphates - metabolism
GALT
Gut-associated lymphoid tissues
Hepatocytes
Humans
IEM
inborn errors of metabolism
Injections, Intraperitoneal
Injections, Intravenous
Intravenous administration
Liver
Liver - drug effects
Liver - metabolism
Male
Medical screening
Metabolism
Metabolites
Mice
Mice, Knockout
Mortality
mRNA
mRNA therapy
Mutants
Original
Patients
POI
primary ovarian insufficiency
Protein expression
Proteins
RNA, Messenger - administration & dosage
Signal Transduction - drug effects
speech dyspraxia
Studies
Transfection
Treatment Outcome
UTP-Hexose-1-Phosphate Uridylyltransferase - administration & dosage
UTP-Hexose-1-Phosphate Uridylyltransferase - genetics
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Summary: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. Intravenous injection of human GALT mRNA in GalT−/− mice resulted in hepatic expression of active, long-lasting GALT enzyme, which rapidly and effectively eliminated gal-1P in liver and other peripheral tissues and significantly reduced plasma galactose. The augmentation of GALT activity also overcame the galactose sensitivity in the GalT−/− newborn pups.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2019.09.018