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Principal Investigator: Kent Lai
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2021
Award: $228,750
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY / ABSTRACT
Hereditary deficiency of galactose-1-phosphate uridylyltransferase (GALT, E.C. 2.7.7.12) activity in humans can
lead to a potentially lethal disease called Classic Galactosemia (OMIM 230400). Despite the life-saving consequences of
newborn screening, early diagnosis, and a galactose-restricted diet, many patients with Classic Galactosemia suffer later in
life from complications including growth, neuropsychological, and speech delays as well as primary ovarian insufficiency
(POI). There are currently no satisfactory treatments available to prevent/alleviate any of these complications. The precise
pathogenic mechanisms of these complications remain unclear, although aberrant galactosylation of glycoproteins/lipids
and inositol phospholipid signaling caused by the chronic exposure to toxic intermediates of the blocked galactose metabolic
pathway in susceptible tissues have been proposed. But regardless of the proposed mechanisms and any of the associated
controversies, no one will debate that the root cause for the disease is the deficiency of GALT enzyme activity in the affected
tissues. Therefore, we collaborated with colleagues at Moderna Inc. to explore if we could augment functional GALT
activity in an animal model of Classic Galactosemia with an innovative GALT mRNA therapy. Specifically, we hypothesize
that targeted augmentation of hepatic GALT activity by GALT mRNA therapy is sufficient to restore whole-body galactose
metabolism and ameliorate the disease-relevant phenotypes in Classic Galactosemia. Preliminary results showed that
intravenous injection of human GALT mRNA in GalT-/- mice resulted in hepatic expression of active, long-lasting GALT
enzyme, which rapidly and effectively reduced gal-1P in liver and some other peripheral tissues and significantly lowered
plasma galactose. Yet, it is too early to tell if biomarker correction can lead to actual phenotypic improvements. Therefore,
we aim to demonstrate in this application that sole augmentation of hepatic GALT activity in a mouse model of
Galactosemia is sufficient to ameliorate the disease-relevant phenotypes (Aim 1) and restore normal whole-body galactose
metabolism (oxidation) (Aim 2). If we are successful, we will be able to advance this experimental mRNA therapy to
clinical trials (high reward), and this could bring an innovative therapy to address the unmet medical needs of the patients -
a high-impact outcome. Moreover, the critical information about the optimal timing of treatment and predictive values of
the biomarkers to be revealed in the proposed work will render significant insights to the disease process and guide the
development of other modalities, including gene therapy. Last but not least, if we can show that restoration of galactose
metabolism in the liver can result in significant improvement of whole-body galactose oxidation, this could lead to diet
relaxation (high impact) and such therapeutic strategy could be applied to other metabolic diseases at which targeted therapy
is preferred (wide impact).
Terms: <0-4 weeks old><Address><Affect><Age><Animal Model><Animal Models and Related Studies><Animals><Aran-Duchenne disease><Ataxia><Ataxy><Biological Markers><Bleeding><Blood Plasma><Body Tissues><Brain><Brain Nervous System><CD154><CD40L><CD40LG><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Chronic><Classic Galactosemia><Classical galactosemia><Clinical><Clinical Trials><Coordination Impairment><Cruveilhier disease><D-Galactose><DNA Therapy><Data><Death><Development><Diathesis><Diet><Disease><Disease susceptibility><Disorder><Dose><Dyssynergia><E coli><E. coli><Early Diagnosis><Early treatment><Effectiveness><Encephalon><Enzyme Gene><Enzymes><Escherichia coli><Experimental Therapies><Exposure to><FDA approved><Galactopyranose><Galactopyranoside><Galactose><Galactose Metabolism><Galactose Metabolism Pathway><Galactose-1-Phosphate Uridyl-Transferase Deficiency Disease><Galactosemias><Gene Transfer Clinical><Generalized Growth><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><Glycoproteins><Goals><Growth><Hemorrhage><Hepatic><Hepatotoxic effect><Hepatotoxicity><Hereditary><Hereditary Metabolic Disorder><Human><Inborn Errors of Metabolism><Industry><Inherited><Innovative Therapy><Inositide Phospholipids><Inositol Phosphoglycerides><Inositol Phospholipids><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigational Therapies><Investigational Treatments><Lead><Life><Life Style><Lifestyle><Lipids><Liver><Liver Toxicity><Medical><Messenger RNA><Metabolic Diseases><Metabolic Disorder><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modality><Modern Man><Murine><Mus><Mutant Strains Mice><Mutation><Neonatal><Neonatal Screening><Neuropsychologies><Neuropsychology><Newborn Infant><Newborn Infant Screening><Newborns><OMIM><Online Mendelian Inheritance In Man><Organ><Outcome><Pathogenicity><Patients><Pb element><Peripheral><Phenotype><Phosphatidyl Inositol><Phosphatidylinositols><Phosphoinositides><Plant Roots><Plasma><Plasma Serum><Predictive Value><Premature ovarian insufficiency><Process><Production><PtdIns><Regimen><Relaxation><Research><Rest><Reticuloendothelial System, Serum, Plasma><Retinal Dystrophy><Savings><Sepsis><Signal Transduction><Signal Transduction Systems><Signaling><Speech Delay><Spinal Muscular Atrophy><TNFSF5><TNFSF5 gene><TRAP Gene><Testing><Therapeutic><Thesaurismosis><Tissue Growth><Tissues><Toxic effect on liver cells><Translating><Treatment Efficacy><Tremor><UDPglucose Hexose-1-Phosphate Uridylyltransferase Deficiency><UTP Hexose-1-Phosphate Uridylyltransferase Deficiency><United States><Work><acute toxicity><age group><ages><base><bio-markers><biologic marker><biological signal transduction><biomarker><blood infection><blood loss><bloodstream infection><compare treatment><developmental><diet restriction><dietary><dietary restriction><diets><disease phenotype><early detection><early therapy><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy evaluation><efficacy examination><enzyme activity><evaluate efficacy><examine efficacy><experimental therapeutic agents><experimental therapeutics><galactose 1 phosphate uridylyl transferase deficiency><galactose-1-phosphate><gene therapy><gene-based therapy><genetic therapy><genome mutation><genomic therapy><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><hepatic toxicity><hepatoxicity><high reward><high risk><improved><inborn metabolism disorder><innovate><innovation><innovative><insight><intervention efficacy><interventional strategy><intravenous injection><juvenile animal><liability to disease><lipid nanoparticle><mRNA><mRNA delivery><metabolism disorder><model of animal><model organism><motor impairment><mouse model><mouse mutant><movement impairment><movement limitation><murine model><mutant><neuropsychologic><newborn child><newborn children><newborn screening><novel><ontogeny><oxidation><postnatal><premature><prematurity><prevent><preventing><primary infertility><primary ovarian insufficiency><restoration><restricted diet><root><screening program><side effect><subfertility><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutic efficacy><therapy efficacy><tissue tropism><tool><treatment comparison><young animal>