RARE DISEASE
Classic galactosemia
Classic galactosemia
Classic galactosemia
Synonyms: GALT deficiency, Galactose-1-phosphate uridyltransferase deficiency, Galactosemia type 1
Synonyms: GALT deficiency, Galactose-1-phosphate uridyltransferase deficiency, Galactosemia type 1
Synonyms: GALT deficiency, Galactose-1-phosphate uridyltransferase deficiency, Galactosemia type 1
Drug discovery
1
drug
With orphan designation
Overview
Classic galactosemia is an autosomal recessive disorder caused by deficient galactose-1-phosphate uridylyltransferase (GALT) activity, impairing galactose metabolism. Neonatal presentation includes feeding difficulties, hepatic dysfunction, and sepsis risk without prompt dietary intervention. Lifelong galactose restriction prevents acute toxicity but fails to halt chronic complications: neurocognitive impairments, primary ovarian insufficiency (79.9% of females), and low bone density (26.5%) [1][2][6].
Burden
Clinical: 85% develop neurocognitive deficits (speech, memory), tremors, and social challenges; progressive functional decline [4][9][13].
Psychosocial: Caregiver dependency (67% adults require daily support), social isolation, and mental health impacts [4][5][13].
Economic: High costs of lifelong medical care, therapies, and dietary management [5][14].
Therapies
Dietary: Lifelong lactose-free formula (infancy) and strict galactose avoidance, though endogenous production persists [1][6][8].
Adjuncts: Calcium, vitamin D/K supplementation; developmental/gonadal monitoring [2][3][12].
Emerging therapies: GALT gene/mRNA therapy, GALK1 inhibitors, and pharmacological chaperones under investigation [1][16].
Categories: rare endocrine diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare hepatic diseases, rare inborn errors of metabolism, rare infertility disorders, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
343 drug discovery papers about Classic galactosemia, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
343 drug discovery papers about Classic galactosemia, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-11-15 | Pretreatment With a Selected Strain of Baker's Yeast, GY007, Prevents the Accumulation of Galactose Metabolites Following Dietary Galactose Exposure in a GALT-Null Rat Model of Classic Galactosemia.
The current standard of care for patients with classic galactosemia (CG) involves lifelong dietary restriction of high galactose foods, including most dairy products. Here, we present the results of a pilot study testing whether pretreatment with GY007, a strain of baker's yeast selected to metabolize galactose despite the presence of other sugars, would be sufficient to prevent the metabolic impact of dietary galactose exposure in a GALT-null rat model of CG. Specifically, we dosed cohorts of adolescent GALT-null rats with either (a) placebo alone, (b) placebo followed by galactose, or (c) GY007 yeast followed by galactose. All rats were treated 3 times daily for 8 consecutive days, for a combined daily dose of almost 27 mg galactose per rat. Wild-type rats dosed with placebo served as controls. All rats also had ad libitum access to water and chow that contained about 0.15% calories from galactose. Rats grew at the expected pace for the duration of the study regardless of treatment group. To test the metabolic efficacy of the GY007 pretreatment, we followed galactose, galactitol, and gal-1P longitudinally in blood, and at euthanasia in brain and liver. In both liver and red blood cells, most metabolites remained near placebo levels despite the galactose exposure, limiting our ability to test the efficacy of GY007 pretreatment in those tissues. However, in both plasma and brain, metabolites showed a significant elevation following galactose exposure, and this rise was prevented by pretreatment with GY007. These results demonstrate the potential of GY007 yeast to prevent the metabolic consequences of transient low-level dietary galactose exposure in GALT deficiency.
2025-07-14 | A Pilot Study of Bone Marrow Transplantation in a GALT-Null Rat Model of Classic Galactosemia.
Classic galactosemia (CG) is a rare inborn error of metabolism with substantial unmet medical need. Early detection, often by population newborn screening, enables immediate and life-long dietary restriction of galactose, which is the current standard of care. This treatment minimizes or prevents the potentially lethal acute symptoms of disease in infants but fails to prevent the long-term developmental complications experienced by most patients later in childhood. Many possible approaches to improved intervention have been proposed, ranging from small molecule inhibitors or effectors to chaperones to DNA or RNA-based gene therapy, among others. Here, we describe the results of a pilot study testing the potential efficacy of GALT+ bone marrow transplantation (BMT) as a candidate intervention in a GALT-null rat model of CG. Specifically, we pre-treated adolescent GALT-null rats with busulfan for myeloablation and then administered major histocompatibility complex (MHC)-matched GFP+ bone marrow cells harvested from either GALT+ or GALT-null donors. Successful engraftment of GALT+ but not GALT-null cells resulted in > 50% wild-type levels of GALT activity in red blood cells (RBC) and normalized RBC galactose-1-phosphate, a biomarker commonly followed in CG patients. However, GALT activity and galactose metabolites in both liver and brain samples remained essentially unchanged, demonstrating that successful GALT+ BMT in adolescent GALT-null rats was not protective of other tissues.
2024-07-04 | Restoring galactose metabolism without restoring GALT rescues both compromised survival in larvae and an adult climbing deficit in a GALT-null D. Melanogaster model of classic galactosemia.
Classic galactosemia (CG) is an autosomal recessive disorder that results from profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), the middle enzyme in the highly conserved Leloir pathway of galactose metabolism. That galactose metabolism is disrupted in patients with CG, and in GALT-null microbial, cell culture, and animal models of CG, has been known for many years. However, whether the long-term developmental complications of CG result from disrupted galactose metabolism alone, or from loss of some independent moonlighting function of GALT, in addition to disrupted galactose metabolism, has been posed but never resolved. Here, we addressed this question using a GALT-null Drosophila melanogaster model of CG engineered to express uridine diphosphate (UDP)-glucose/galactose pyrophosphorylase (UGGP), a plant enzyme that effectively bypasses GALT in the Leloir pathway by converting substrates uridine triphosphate (UTP) plus galactose-1-phosphate (gal-1P) into products UDP-galactose plus pyrophosphate (PPi). While GALT and UGGP share one substrate (gal-1P) and one product (UDP-galactose), they are structurally and evolutionarily unrelated enzymes. It is therefore extremely unlikely that they would also share a moonlighting function. We found that GALT-null flies expressing UGGP showed not only partial rescue of metabolic abnormalities and acute larval sensitivity to dietary galactose, as expected, but also full rescue of an adult motor deficit otherwise seen in this model. By extension, these results may offer insights to the underlying bases of at least some acute and long-term complications experienced by patients with CG.
2010-11-01 | Towards enhanced galactose utilization by Lactococcus lactis.
Accumulation of galactose in dairy products due to partial lactose fermentation by lactic acid bacteria yields poor-quality products and precludes their consumption by individuals suffering from galactosemia. This study aimed at extending our knowledge of galactose metabolism in Lactococcus lactis, with the final goal of tailoring strains for enhanced galactose consumption. We used directed genetically engineered strains to examine galactose utilization in strain NZ9000 via the chromosomal Leloir pathway (gal genes) or the plasmid-encoded tagatose 6-phosphate (Tag6P) pathway (lac genes). Galactokinase (GalK), but not galactose permease (GalP), is essential for growth on galactose. This finding led to the discovery of an alternative route, comprising a galactose phosphotransferase system (PTS) and a phosphatase, for galactose dissimilation in NZ9000. Introduction of the Tag6P pathway in a galPMK mutant restored the ability to metabolize galactose but did not sustain growth on this sugar. The latter strain was used to prove that lacFE, encoding the lactose PTS, is necessary for galactose metabolism, thus implicating this transporter in galactose uptake. Both PTS transporters have a low affinity for galactose, while GalP displays a high affinity for the sugar. Furthermore, the GalP/Leloir route supported the highest galactose consumption rate. To further increase this rate, we overexpressed galPMKT, but this led to a substantial accumulation of α-galactose 1-phosphate and α-glucose 1-phosphate, pointing to a bottleneck at the level of α-phosphoglucomutase. Overexpression of a gene encoding α-phosphoglucomutase alone or in combination with gal genes yielded strains with galactose consumption rates enhanced up to 50% relative to that of NZ9000. Approaches to further improve galactose metabolism are discussed.
2002-04-02 | Tolerization of Gal alpha 1,3Gal-reactive B cells in pre-sensitized alpha 1,3-galactosyltransferase-deficient mice by nonmyeloablative induction of mixed chimerism.
Using a alpha 1,3-galactosyltransferase wild-type (GalT(+/+)) to deficient (GalT(-/-)) mouse bone marrow transplantation model, we have previously demonstrated that a non-myeloablative conditioning regimen is capable of permitting induction of allogeneic and xenogeneic mixed chimerism. Chimerism is associated with the rapid and lasting tolerization of anti-Gal alpha 1,3Gal (Gal) natural antibody (Ab)-producing B cells. However, one limitation of this model is that anti-Gal natural Ab levels are lower in GalT(-/-) mice than in humans and other primates. To overcome this limitation, we have now investigated the possibility of inducing such tolerance in GalT(-/-) mice that produce much higher levels of anti-Gal Abs due to presensitization with Gal-bearing xenogeneic cells. B6 GalT(-/-) mice that were pre-sensitized with rabbit red blood cells received non-myeloablative conditioning with depleting anti-CD4 and CD8 mAbs, 3Gy whole body and 7Gy thymic irradiation, and infusion of BALB/c GalT(+/+) bone marrow cells (BMC). Although engraftment of standard marrow doses was inhibited by the presensitization, long-lasting mixed chimerism could be induced in recipients of a high dose [160 x 10(6)] of allogeneic wild-type BMC. Achievement of persistent chimerism was associated with high levels of anti-Gal IgG(1) pretransplant, suggesting an inhibitory effect of non-complement-fixing IgG(1) Ab on anti-Gal-mediated marrow rejection. Induction of mixed chimerism was associated with a rapid disappearance of serum anti-Gal and tolerization of anti-Gal Ab-producing cells. B cells with anti-Gal receptors became undetectable in mixed chimeras. Mixed chimeras accepted subsequently transplanted donor-type GalT(+/+) hearts (> 140 days), whereas rapid (within 2 days) rejection of GalT(+/+) hearts occurred in conditioned control GalT(-/-) mice. In conclusion, when a high dose of GalT(+/+) BMC was administered to pre-sensitized GalT(-/-) mice, chimerism and tolerance were achieved. The absence of B cells with receptors recognizing Gal in mixed chimeras suggests a role for clonal deletion/receptor editing in the maintenance of B cell tolerance.
proteins
2021-12-21 | Virus-Based Nanoreactors with GALT Activity for Classic Galactosemia Therapy.
Enzymatic nanoreactors were obtained by galactose-1-phosphate uridylyl-transferase (GALT) encapsulation into plant virus capsids by a molecular self-assembly strategy. The aim of this work was to produce virus-like nanoparticles containing GALT for an enzyme-replacement therapy for classic galactosemia. The encapsulation efficiency and the catalytic constants of bio-nanoreactors were determined by using different GALT and virus coat protein ratios. The substrate affinity of nanoreactors was slightly lower than that of the free enzyme; the activity rate was 16 % of the GALT free enzyme. The enzymatic nanoreactors without functionalization were internalized into different cell lines including fibroblast and kidney cells, but especially into hepatocytes. The enzymatic nanoreactors are an innovative enzyme preparation with potential use for the treatment of classic galactosemia.
2021-01-28 | Current and Future Treatments for Classic Galactosemia
Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches.
2019-10-17 | Dynamic origins of substrate promiscuity in bacterial galactokinases
Galactokinase catalyses the ATP-dependent phosphorylation of galactose and structurally related sugars. The enzyme has attracted interest as a potential biocatalyst for the production of sugar 1-phosphates and several attempts have been made to broaden its specificity. In general, bacterial galactokinases have wider substrate ranges than mammalian ones. The enzymes from Escherichia coli and Lactococcus lactis have received particular attention and a number of variants with increased promiscuity have been identified. Here, we present a molecular dynamics study designed to investigate the molecular causes of the wider substrate ranges of these enzymes and their variants with particular reference to protein mobility. Some regions close to the active site of the enzyme have different structures in the bacterial enzymes compared to the human one. Alterations known to increase the substrate range (e.g. Y371H in the E. coli enzyme), tend to alter the conformation of a key α-helical region (residues 216–232 in the E. coli enzyme). The equivalent helix in the human enzyme has previously been predicted to be altered in variants which affect catalytic activity or protein stability. This helix appears to be a key region in galactokinases from a range of species and may represent an interesting target for future attempts to broaden the specificity of galactokinases.
2016-07-27 | Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models.
The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4'-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-galactose from uridine triphosphate and galactose-1-phosphate. All four UDP-sugars are essential donors for glycoprotein biosynthesis with critical roles at the developing neuromuscular synapse. Drosophila galactosemia I (dGALT) and II (dGALK) disease models genetically interact; manifesting deficits in coordinated movement, neuromuscular junction (NMJ) development, synaptic glycosylation, and Wnt trans-synaptic signalling. Similarly, dGALE and dUGP mutants display striking locomotor and NMJ formation defects, including expanded synaptic arbours, glycosylation losses, and differential changes in Wnt trans-synaptic signalling. In combination with dGALT loss, both dGALE and dUGP mutants compromise the synaptomatrix glycan environment that regulates Wnt trans-synaptic signalling that drives 1) presynaptic Futsch/MAP1b microtubule dynamics and 2) postsynaptic Frizzled nuclear import (FNI). Taken together, these findings indicate UDP-sugar balance is a key modifier of neurological outcomes in all three interacting galactosemia disease models, suggest that Futsch homolog MAP1B and the Wnt Frizzled receptor may be disease-relevant targets in epimerase and transferase galactosemias, and identify UGP as promising new potential therapeutic target for galactosemia neuropathology.
2016-01-06 | Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis
Classical galactosaemia (OMIM #230400), a rare disorder of carbohydrate metabolism, is caused by a deficient activity of galactose-1-phosphate uridyltransferase (EC 2.7.7.12). The pathophysiology of the long-term complications, mainly cognitive, neurological and female fertility problems remains poorly understood. The lack of validated biomarkers to determine prognosis, monitor disease progression and responses to new therapies, pose a huge challenge. We report the detailed analysis of an automated robotic hydrophilic interaction ultra-performance liquid chromatography N-glycan analytical method of high glycan peak resolution applied to serum IgG. This has revealed specific N-glycan processing defects observed in 40 adult galactosaemia patients (adults and adolescents), in comparison with 81 matched healthy controls. We have identified a significant increase in core fucosylated neutral glycans (P<0.0001) and a significant decrease in core fucosylated (P<0.001), non-fucosylated (P<0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (P<0.0001), in galactosaemia patients. We also report the abnormal expression of a number of related relevant N-glycan biosynthesis genes in peripheral blood mononuclear cells from 32 adult galactosaemia patients. We have noted significant dysregulation of two key N-glycan biosynthesis genes: ALG9 upregulated (P<0.001) and MGAT1 downregulated (P<0.01) in galactosaemia patients, which may contribute to its ongoing pathophysiology. Our data suggest that the use of IgG N-glycosylation analysis with matched N-glycan biosynthesis gene profiles may provide useful biomarkers for monitoring response to therapy and interventions. They also indicate potential gene modifying steps in this N-glycan biosynthesis pathway, of relevance to galactosaemia and related N-glycan biosynthesis disorders.
gene therapies
2026-09-21 | Prenatal consequences of GALT deficiency in a rat model of classic galactosemia.
Classic galactosemia (CG) is a potentially lethal disease that results from profound deficiency of galactose-1-P uridylyltransferase (GALT). Prior reports document elevated galactose metabolites beginning in utero in CG, raising concern that long-term complications in CG might also trace their origins to the prenatal period. However, studies document that elevated galactose metabolites in the postnatal period do not predict later developmental complications, challenging the connection. Here, we explored the relationship between elevated galactose metabolites in utero and fetal outcome using a GALT-null rat model of CG. To modify galactose metabolites in utero, we arranged rat crosses to produce GALT-null pups developing within either a GALT-null or heterozygous dam, and with or without heterozygous siblings. We reasoned that GALT activity present outside the fetus, but within the maternal-fetal compartment, might limit metabolic abnormalities in a developing GALT-null fetus -- and it did. Specifically, while galactose metabolites in GALT-null fetal pups from all crosses remained elevated over controls, the levels varied. When the dam and some siblings were heterozygous, amniotic fluid galactitol from GALT-null fetal pups at GD21 was comparable to the levels reported from second trimester human CG amniotic fluid. When the dam was GALT-null, but some siblings were heterozygous, the median galactitol level in amniotic fluid was 2.45-fold higher. When the dam and all siblings were GALT-null, the median amniotic fluid galactitol level was 5.67-fold higher. GALT-null fetal pups also showed significant growth delay in utero, but only when the dam and all siblings were GALT-null. That growth of GALT-null fetal pups was fully rescued by gestation within a heterozygous dam despite the persistence of moderately elevated galactose metabolites raises the possibility that babies with CG developing within a carrier mother might also be at least partially protected in utero from the adverse consequences of their GALT-deficiency.
2025-02-15 | Reshaping the Treatment Landscape of a Galactose Metabolism Disorder.
The Leloir pathway was elucidated decades ago, unraveling how galactose is metabolized in the body. Different inborn errors of metabolism in this pathway are known, the most frequent and well-studied being Classic Galactosemia (CG) (OMIM 230400) due to pathogenic variants in the GALT gene. Substrate reduction using dietary restriction of galactose is currently the only available treatment option. Although this burdensome diet resolves the life-threatening clinical picture in neonates, patients still face long-term complications, including cognitive and neurological deficits as well as primary ovarian insufficiency. Emerging therapies aim to address these challenges on multiple fronts: (1) restoration of GALT activity with nucleic acid therapies, pharmacological chaperones, or enzyme replacement; (2) influencing the pathological cascade of events to prevent accumulation of metabolites (Galactokinase 1 (GALK1) inhibitors, aldose reductase inhibitors), address myo-inositol deficiency, or alleviate cellular stress responses; (3) substrate reduction with synthetic biotics or galactose uptake inhibitors to eliminate the need for lifelong diet; and (4) novel approaches to mitigate existing symptoms, such as non-invasive brain stimulation and reproductive innovations. Early, personalized intervention remains critical for optimizing patient outcomes. We review the advances in the development of different treatment modalities for CG and reflect on the factors that need to be considered and addressed to reshape the landscape of treatment.
2024-02-14 | Whole-body galactose oxidation as a robust functional assay to assess the efficacy of gene-based therapies in a mouse model of Galactosemia.
Despite the implementation of lifesaving newborn screening programs and a galactose-restricted diet, many patients with classic galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that the administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which decreased not only galactose-1 phosphate (gal-1P) in the liver but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, noninvasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of galactosemia. Although our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that targets the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety.
2022-07-28 | Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment.
Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented.
2022-05-11 | AAV-mediated expression of galactose-1-phosphate uridyltransferase corrects defects of galactose metabolism in classic galactosemia patient fibroblasts.
Classic galactosemia (CG) is a rare disorder of autosomal recessive inheritance. It is caused predominantly by point mutations as well as deletions in the gene encoding the enzyme galactose-1-phosphate uridyltransferase (GALT). The majority of the more than 350 mutations identified in the GALT gene cause a significant reduction in GALT enzyme activity resulting in the toxic buildup of galactose metabolites that in turn is associated with cellular stress and injury. Consequently, developing a therapeutic strategy that reverses both the oxidative and ER stress in CG cells may be helpful in combating this disease. Recombinant adeno-associated virus (AAV)-mediated gene therapy to restore GALT activity offers the potential to address the unmet medical needs of galactosemia patients. Here, utilizing fibroblasts derived from CG patients we demonstrated that AAV-mediated augmentation of GALT protein and activity resulted in the prevention of ER and oxidative stress. We also demonstrate that these CG patient fibroblasts exhibit reduced CD109 and TGFβRII protein levels and that these effectors of cellular homeostasis could be restored following AAV-mediated expression of GALT. Finally, we show initial in vivo proof-of-concept restoration of galactose metabolism in a GALT knockout mouse model following treatment with AAV-GALT.
small molecules
2025-10-14 | Myo-Inositol Deficiency, Structural Brain Changes, and Cerebral Perfusion Alterations in Classic Galactosemia: Preliminary Insights From a Multiparametric MRI Study.
Classic galactosemia is a rare metabolic disorder resulting from galactose-1-phosphate uridylyltransferase deficiency, which disrupts normal galactose metabolism, leading to toxic accumulation of galactose-1-phosphate and galactitol. Despite early dietary intervention, patients remain at risk for long-term neurological impairments, including cognitive deficits, motor speech disorders, and psychiatric conditions. The mechanisms driving these persistent abnormalities remain unclear. This study investigated brain metabolic and structural alterations in adults with classic galactosemia using advanced multiparametric MRI. Six patients (3 males, 3 females; mean age 34.0 ± 7.3 years) adhering to lifelong galactose-restricted diets and six age- and sex-matched controls underwent 3T and 7T MRI, including T1-weighted imaging, pseudo-continuous arterial spin labeling, and high-resolution MR spectroscopic imaging. Patients exhibited significantly lower myo-inositol (mIns) concentrations in cerebellum (p = 0.007), putamen (p = 0.023), and cerebral white matter (p = 0.001), reflecting a chronic mIns deficiency despite dietary management. Structural analyses revealed reduced volumes of white matter (p < 0.001), bilateral putamen (p < 0.038), and left thalamus (p = 0.044); alongside increased cortical thickness and reduced cortical surface area, indicating abnormal cortical maturation, particularly in regions associated with motor and cognitive processing. Additionally, cerebral blood flow was elevated in emotion-processing regions, including bilateral amygdala (p < 0.022) and thalamus (p < 0.038). These preliminary findings highlight persistent neurological alterations in classic galactosemia despite dietary management and suggest that chronic mIns deficiency may contribute to the pathophysiology. They underscore the need for larger, longitudinal studies to confirm these results, investigate potential correlations with clinical severity and biochemical markers, and explore therapeutic strategies aimed at modulating mIns metabolism.
2025-10-01 | Exit interviews with caregivers of pediatric patients with classic galactosemia to explore meaningfulness of changes in the ACTION-galactosemia kids trial.
Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate uridylyltransferase (GALT) enzyme, converting to an aberrant and toxic metabolite, galactitol. Living with the debilitating symptoms and long-term consequences of Classic Galactosemia creates a heavy burden on patients' and their families' lives. Objectives were to: (1) Evaluate the impact and burden of disease; (2) Qualitatively explore changes in patient symptoms following treatment; and (3) Document the meaningfulness of changes resulting from treatment with govorestat as assessed by the Caregiver Global Impression of Severity (CGIS) and Caregiver Global Impression of Change (CGIC) scales. The AT-007-1002 clinical trial involved a Phase 1/2 dose escalation component (Part A) followed by a Phase 3, randomized, double-blind, placebo-controlled long-term administration component (Part B) that evaluated potential clinical benefit. Exit Interviews were completed prior to unblinding of data. The in-depth, qualitative interviews were semi-structured, using a discussion guide, and conducted by either Zoom or GoToMeeting. Thirty-six caregiver interviews were conducted, capturing the experience of 37 pediatric patients (one caregiver had 2 patients enrolled in the study). Thematic analysis was undertaken to identify themes or patterns within the data. All analyses were conducted on blinded data. Following finalization of the analysis and report findings, post-hoc analysis of the unblinded data was then conducted to explore the meaningfulness of patients experience by treatment arm. This study confirms the substantial burden known to be associated with Classic Galactosemia in a pediatric population. The difficulties experienced were across multiple areas including cognitive function, behavior/social function, motor function, emotional function, communication, vision problems, ovarian insufficiency, sensory difficulties, and sleep problems. The interviews demonstrated that most patients (approximately two thirds) experienced an improvement in symptoms and impacts associated with classic galactosemia over the course of the trial. Nearly all caregivers reported that they perceived a 1-category change on the Caregiver Global Impression of Severity or Caregiver Global Impression of Change items, indicating severity and change respectively, was meaningful to them and the patient. Unblinded analysis of the exit interview data confirmed the patient experience reported by caregivers was different between the treatment arms, providing qualitative support for the treatment benefit of govorestat when compared to placebo. Furthermore, the qualitative data from caregivers provide in-depth insights of their unique lived experience that highlight the substantial impact that this improvement had on the caregiver's and the patient's quality of life. The improvements observed led to a reduction on the burden of Classic Galactosemia and may lead to a greater patient's greater independence. The exit interviews confirmed the burden of Classic Galactosemia disease across multiple domains. Qualitative investigation suggests that observed changes are meaningful to the patient and caregiver, and changes were more commonly reported in those receiving govorestat compared to placebo. Full clinical trial findings will be published separately.
2025-07-01 | Galactosemia Presenting as Neonatal Hemochromatosis: A Case of Acute Liver Failure Managed Successfully with Medical Therapy
Neonatal acute liver failure often has a heterogenous presentation. Extensive workup is essential for prompt diagnosis and efficient treatment. Neonatal hemochromatosis (NH) and Galactosemia are both serious conditions that can manifest with acute liver dysfunction, but they require different treatment approaches. We describe a neonate who presented with acute liver failure, characterized by severe jaundice, deranged liver function and coagulopathy. Diagnostic imaging and other investigations implied a diagnosis of neonatal hemochromatosis due to hepatic and extra hepatic iron deposition along with raised serum alpha fetoprotein and ferritin levels. However, further metabolic testing revealed the diagnosis of classic galactosemia, identified by a deficiency in galactose-1-phosphate uridyltransferase (GALT). Infant showed significant improved with normalization of liver function with antioxidant cocktail and galactose free formula. This case highlights the significance of considering galactosemia in the differential diagnosis of neonatal hemochromatosis-like presentations and the importance for a comprehensive metabolic workup in neonates with liver dysfunction. It also emphasizes that early identification and management can successfully resolve liver dysfunction and prevent the need for liver transplant.
2025-02-06 | Galactose Impairs Motor Performance and Cerebellar Signaling in Young Male Wistar Rats.
Galactosemias are a group of inborn errors of galactose metabolism that causes different motor symptoms such as ataxia, tremor, and fine motor dysfunction. The objective was to investigate the cerebellar damage caused by an acute galactose administration. Thirty-day-old male and female Wistar rats were used. Animals were randomized into the following groups: I) galactose group, receiving a single subcutaneous administration of galactose; II) control group, receiving the vehicle solution under the same conditions. One, 3 or 24 h after administration, the animals were evaluated in the Rotarod test. A lower motor performance was observed in male rats 3 h after a galactose administration. This effect was not seen in females or with galactose exposure for 1 or 24 h. The activities of acetylcholinesterase and choline acetyltransferase were found unaltered in the cerebellum of males 3 h after galactose injection. We also found lower TH levels in cerebellar hemispheres and higher TH levels in cerebellar vermis 3 h after galactose administration in male rats, without differences in MAO-A or MAO-B activities. Galactose administration resulted in lower p-CREB(Ser133) and GAD67 levels in cerebellar hemispheres, without altering these parameters in cerebellar vermis of male rats. Finally, a decrease in TrkB-FL immunocontent (but not of TrkB-T levels) was observed in male cerebellar hemispheres. The absence of neurochemical alterations 1 h or 24 h after galactose administration indicates a transient effect for this hexose. The signs and symptoms of galactosemic patients underscore the need to study galactose effects in males and females and in various brain areas. Our findings enhance the understanding of therapeutic mechanisms of catecholaminergic drugs, which are proposed as a potential therapy for galactosemia.
2025-02-03 | Assessment of Long-Term Safety and Efficacy of Purple Sweet Potato Color (PSPC) and Myo-Inositol (MI) Treatment for Motor Related and Behavioral Phenotypes in a Mouse Model of Classic Galactosemia.
Classic galactosemia (CG) is a rare inherited metabolic disease caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase in galactose metabolism. The condition develops as a potentially fatal illness during the newborn period, but its acute clinical manifestations can be alleviated through a galactose restricted diet. Nonetheless, such dietary intervention is inadequate in preventing significant long-term consequences, including neurological impairments, growth restriction, cognitive delays, and, for most females, primary ovarian insufficiency. At present, no effective therapy exists to stop the progression of these complications, highlighting the urgent need for new treatment approaches to be developed. Supplements have been used in the treatment of other inborn errors of metabolism; however, they are not typically included in the clinical therapeutic regimen for CG. Recently, our research team has demonstrated that two generally recognized as safe supplements (purple weet potato color, PSPC and myo-inositol, MI) have been effective in partially restoring functions in the ovaries of our GalT-KO mouse model. However, the toxicological profile of both PSPC and MI has not been determined. In this study, we investigated the acute (30 days) and chronic (180 days) oral toxicities of PSPC and MI both in WT control and GalT-KO mice. Furthermore, our study aims to evaluate the effectiveness of oral feeding of PSPC and MI in correcting motor-related and behavioral phenotypes in GalT-KO mice. The long-term treatment of MI at a lower dose demonstrated promising improvements in motor deficit and anxiety driven hyperactivity in the mutant mice.
other
2025-11-21 | Experimental Galactose-1-Phosphate Uridylyltransferase (GALT) mRNA Therapy Improves Motor-Related Phenotypes in a Mouse Model of Classic Galactosemia—A Pilot Study
Background: Despite life-saving newborn screening programs and a life-long galactose-restricted diet, many patients with classic galactosemia continue to develop long-term debilitating neurological deficits, speech dyspraxia, and primary ovarian insufficiency (POI). In an earlier study, we showed that administration of an experimental human GALT mRNA predominantly expressed in the liver of the GalT gene-trapped mouse model augmented the expression of hepatic GALT activity, which reduced build-up of galactose and its toxic metabolites not only in the liver but also in the peripheral tissues. Moreover, we showed that the administration of GALT mRNA in the mutant mice restored whole-body galactose oxidation (WBGO), which is a functional biomarker. Methods: In this pilot study, we extended our proof-of-concept efficacy studies to a disease-relevant phenotype: motor impairment. GalT-KO mice aged 3 and 6 weeks old administered biweekly intravenous injections of 100 µL GALT mRNA at a dose of 2 mg/kg for 2 months. Motor performance was assessed using rotarod testing and composite phenotype scoring, 3 and 9 weeks following the dosing regimen. Results: Preliminary results showed that a biweekly dosing at 2 mg/kg for 2 months improved the motor performance of the animals in rotarod and composite phenotype scoring tests in a short-term experiment. Conclusions: Despite being a small-scale study, our findings suggest that when treated early in life, the experimental GALT mRNA is effective in improving the motor-related phenotypes in GalT-KO mice using the specified dosing regimen. These findings highlight the potential of mRNA-based therapies for mitigating neurological symptoms in Classic galactosemia.
2025-04-24 | Experimental galactose-1 phosphate uridylyltransferase (GALT) mRNA therapy improves motor-related phenotypes in a mouse model of Classic Galactosemia
Abstract Despite life-saving newborn screening programs and a life-long galactose-restricted diet, many patients with Classic Galactosemia continue to develop long-term debilitating neurological deficits, speech dyspraxia, and primary ovarian insufficiency (POI). Earlier, we showed that administration of an experimental human GALT mRNA predominantly expressed in the liver of the GalT gene-trapped mouse model augmented the expression of hepatic GALT activity, which reduced build-up of galactose and its toxic metabolites not only in the liver, but also in the peripheral tissues. Moreover, we showed that administration of GALT mRNA in the mutant mice restored whole-body galactose oxidation (WBGO), a functional biomarker. In this study, we extended our proof-of-concept (POC) efficacy studies to a disease-relevant phenotype, motor impairment. We found that a biweekly dosing regimen at 2mg/kg for 2 months could improve the motor performance of the animals in Rotarod and Composite Phenotype Scoring tests.
2022-05-09 | Novel mRNA therapy restores GALT protein and enzyme activity in a zebrafish model of classic galactosemia.
Abstract Messenger RNA (mRNA) has emerged as a novel therapeutic approach for inborn errors of metabolism. Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a severe deficiency of galactose‐1‐phosphate:uridylyltransferase (GALT) activity leading to neonatal illness and chronic impairments affecting the brain and female gonads. In this proof of concept study, we used our zebrafish model for CG to evaluate the potential of human GALT mRNA ( hGALT mRNA) packaged in two different lipid nanoparticles to restore GALT expression and activity at early stages of development. Both one cell‐stage and intravenous single‐dose injections resulted in hGALT protein expression and enzyme activity in the CG zebrafish ( galt knockout) at 5 days post fertilization (dpf). Moreover, the levels of galactose‐1‐phosphate (Gal‐1‐P) and galactonate, metabolites that accumulate because of the deficiency, showed a decreasing trend. LNP‐packaged mRNA was effectively translated and processed in the CG zebrafish without signs of toxicity. This study shows that mRNA therapy restores GALT protein and enzyme activity in the CG zebrafish model, and that the zebrafish is a suitable system to test this approach. Further studies are warranted to assess whether repeated injections safely mitigate the chronic impairments of this disease.
2021-12-23 | A pilot study of neonatal GALT gene replacement using AAV9 dramatically lowers galactose metabolites in blood, liver, and brain and minimizes cataracts in GALT-null rat pups.
Classic galactosemia (CG) is a rare metabolic disorder that results from profound deficiency of galactose-1-P uridylyltransferase (GALT). Despite early detection by newborn screening and rapid and lifelong dietary restriction of galactose, which is the current standard of care, most patients grow to experience a broad constellation of long-term complications. The mechanisms underlying these complications remain unclear and likely differ by tissue. Here we conducted a pilot study testing the safety and efficacy of GALT gene replacement using our recently-described GALT-null rat model for CG. Specifically, we administered AAV9.CMV.HA-hGALT to seven GALT-null rat pups via tail vein injection on day 3 of life; eight GALT-null pups injected with PBS served as the negative control, and four GALT+ heterozygous pups injected with PBS served as the positive control. All pups were returned to their nursing mothers, weighed daily, and euthanized for tissue collection 2 weeks later. Among the AAV9-injected pups in this study, we achieved GALT levels in liver ranging from 64% to 595% wild-type, and in brain ranging from 3% to 42% wild-type. In liver, brain, and blood samples from these animals we also saw a striking drop in galactose, galactitol, and gal-1P. Finally, all treated GALT-null pups showed dramatic improvement in cataracts relative to their mock-treated counterparts. Combined, these results demonstrate that GALT restoration in both liver and brain of GALT-null rats by neonatal tail vein administration using AAV9 is not only attainable but effective.
2020-12-21 | 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 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.
cell therapies
2025-11-15 | Pretreatment With a Selected Strain of Baker's Yeast, GY007, Prevents the Accumulation of Galactose Metabolites Following Dietary Galactose Exposure in a GALT-Null Rat Model of Classic Galactosemia.
The current standard of care for patients with classic galactosemia (CG) involves lifelong dietary restriction of high galactose foods, including most dairy products. Here, we present the results of a pilot study testing whether pretreatment with GY007, a strain of baker's yeast selected to metabolize galactose despite the presence of other sugars, would be sufficient to prevent the metabolic impact of dietary galactose exposure in a GALT-null rat model of CG. Specifically, we dosed cohorts of adolescent GALT-null rats with either (a) placebo alone, (b) placebo followed by galactose, or (c) GY007 yeast followed by galactose. All rats were treated 3 times daily for 8 consecutive days, for a combined daily dose of almost 27 mg galactose per rat. Wild-type rats dosed with placebo served as controls. All rats also had ad libitum access to water and chow that contained about 0.15% calories from galactose. Rats grew at the expected pace for the duration of the study regardless of treatment group. To test the metabolic efficacy of the GY007 pretreatment, we followed galactose, galactitol, and gal-1P longitudinally in blood, and at euthanasia in brain and liver. In both liver and red blood cells, most metabolites remained near placebo levels despite the galactose exposure, limiting our ability to test the efficacy of GY007 pretreatment in those tissues. However, in both plasma and brain, metabolites showed a significant elevation following galactose exposure, and this rise was prevented by pretreatment with GY007. These results demonstrate the potential of GY007 yeast to prevent the metabolic consequences of transient low-level dietary galactose exposure in GALT deficiency.
2025-07-14 | A Pilot Study of Bone Marrow Transplantation in a GALT-Null Rat Model of Classic Galactosemia.
Classic galactosemia (CG) is a rare inborn error of metabolism with substantial unmet medical need. Early detection, often by population newborn screening, enables immediate and life-long dietary restriction of galactose, which is the current standard of care. This treatment minimizes or prevents the potentially lethal acute symptoms of disease in infants but fails to prevent the long-term developmental complications experienced by most patients later in childhood. Many possible approaches to improved intervention have been proposed, ranging from small molecule inhibitors or effectors to chaperones to DNA or RNA-based gene therapy, among others. Here, we describe the results of a pilot study testing the potential efficacy of GALT+ bone marrow transplantation (BMT) as a candidate intervention in a GALT-null rat model of CG. Specifically, we pre-treated adolescent GALT-null rats with busulfan for myeloablation and then administered major histocompatibility complex (MHC)-matched GFP+ bone marrow cells harvested from either GALT+ or GALT-null donors. Successful engraftment of GALT+ but not GALT-null cells resulted in > 50% wild-type levels of GALT activity in red blood cells (RBC) and normalized RBC galactose-1-phosphate, a biomarker commonly followed in CG patients. However, GALT activity and galactose metabolites in both liver and brain samples remained essentially unchanged, demonstrating that successful GALT+ BMT in adolescent GALT-null rats was not protective of other tissues.
2024-07-04 | Restoring galactose metabolism without restoring GALT rescues both compromised survival in larvae and an adult climbing deficit in a GALT-null D. Melanogaster model of classic galactosemia.
Classic galactosemia (CG) is an autosomal recessive disorder that results from profound deficiency of galactose-1-phosphate uridylyltransferase (GALT), the middle enzyme in the highly conserved Leloir pathway of galactose metabolism. That galactose metabolism is disrupted in patients with CG, and in GALT-null microbial, cell culture, and animal models of CG, has been known for many years. However, whether the long-term developmental complications of CG result from disrupted galactose metabolism alone, or from loss of some independent moonlighting function of GALT, in addition to disrupted galactose metabolism, has been posed but never resolved. Here, we addressed this question using a GALT-null Drosophila melanogaster model of CG engineered to express uridine diphosphate (UDP)-glucose/galactose pyrophosphorylase (UGGP), a plant enzyme that effectively bypasses GALT in the Leloir pathway by converting substrates uridine triphosphate (UTP) plus galactose-1-phosphate (gal-1P) into products UDP-galactose plus pyrophosphate (PPi). While GALT and UGGP share one substrate (gal-1P) and one product (UDP-galactose), they are structurally and evolutionarily unrelated enzymes. It is therefore extremely unlikely that they would also share a moonlighting function. We found that GALT-null flies expressing UGGP showed not only partial rescue of metabolic abnormalities and acute larval sensitivity to dietary galactose, as expected, but also full rescue of an adult motor deficit otherwise seen in this model. By extension, these results may offer insights to the underlying bases of at least some acute and long-term complications experienced by patients with CG.
2010-11-01 | Towards enhanced galactose utilization by Lactococcus lactis.
Accumulation of galactose in dairy products due to partial lactose fermentation by lactic acid bacteria yields poor-quality products and precludes their consumption by individuals suffering from galactosemia. This study aimed at extending our knowledge of galactose metabolism in Lactococcus lactis, with the final goal of tailoring strains for enhanced galactose consumption. We used directed genetically engineered strains to examine galactose utilization in strain NZ9000 via the chromosomal Leloir pathway (gal genes) or the plasmid-encoded tagatose 6-phosphate (Tag6P) pathway (lac genes). Galactokinase (GalK), but not galactose permease (GalP), is essential for growth on galactose. This finding led to the discovery of an alternative route, comprising a galactose phosphotransferase system (PTS) and a phosphatase, for galactose dissimilation in NZ9000. Introduction of the Tag6P pathway in a galPMK mutant restored the ability to metabolize galactose but did not sustain growth on this sugar. The latter strain was used to prove that lacFE, encoding the lactose PTS, is necessary for galactose metabolism, thus implicating this transporter in galactose uptake. Both PTS transporters have a low affinity for galactose, while GalP displays a high affinity for the sugar. Furthermore, the GalP/Leloir route supported the highest galactose consumption rate. To further increase this rate, we overexpressed galPMKT, but this led to a substantial accumulation of α-galactose 1-phosphate and α-glucose 1-phosphate, pointing to a bottleneck at the level of α-phosphoglucomutase. Overexpression of a gene encoding α-phosphoglucomutase alone or in combination with gal genes yielded strains with galactose consumption rates enhanced up to 50% relative to that of NZ9000. Approaches to further improve galactose metabolism are discussed.
2002-04-02 | Tolerization of Gal alpha 1,3Gal-reactive B cells in pre-sensitized alpha 1,3-galactosyltransferase-deficient mice by nonmyeloablative induction of mixed chimerism.
Using a alpha 1,3-galactosyltransferase wild-type (GalT(+/+)) to deficient (GalT(-/-)) mouse bone marrow transplantation model, we have previously demonstrated that a non-myeloablative conditioning regimen is capable of permitting induction of allogeneic and xenogeneic mixed chimerism. Chimerism is associated with the rapid and lasting tolerization of anti-Gal alpha 1,3Gal (Gal) natural antibody (Ab)-producing B cells. However, one limitation of this model is that anti-Gal natural Ab levels are lower in GalT(-/-) mice than in humans and other primates. To overcome this limitation, we have now investigated the possibility of inducing such tolerance in GalT(-/-) mice that produce much higher levels of anti-Gal Abs due to presensitization with Gal-bearing xenogeneic cells. B6 GalT(-/-) mice that were pre-sensitized with rabbit red blood cells received non-myeloablative conditioning with depleting anti-CD4 and CD8 mAbs, 3Gy whole body and 7Gy thymic irradiation, and infusion of BALB/c GalT(+/+) bone marrow cells (BMC). Although engraftment of standard marrow doses was inhibited by the presensitization, long-lasting mixed chimerism could be induced in recipients of a high dose [160 x 10(6)] of allogeneic wild-type BMC. Achievement of persistent chimerism was associated with high levels of anti-Gal IgG(1) pretransplant, suggesting an inhibitory effect of non-complement-fixing IgG(1) Ab on anti-Gal-mediated marrow rejection. Induction of mixed chimerism was associated with a rapid disappearance of serum anti-Gal and tolerization of anti-Gal Ab-producing cells. B cells with anti-Gal receptors became undetectable in mixed chimeras. Mixed chimeras accepted subsequently transplanted donor-type GalT(+/+) hearts (> 140 days), whereas rapid (within 2 days) rejection of GalT(+/+) hearts occurred in conditioned control GalT(-/-) mice. In conclusion, when a high dose of GalT(+/+) BMC was administered to pre-sensitized GalT(-/-) mice, chimerism and tolerance were achieved. The absence of B cells with receptors recognizing Gal in mixed chimeras suggests a role for clonal deletion/receptor editing in the maintenance of B cell tolerance.
proteins
2021-12-21 | Virus-Based Nanoreactors with GALT Activity for Classic Galactosemia Therapy.
Enzymatic nanoreactors were obtained by galactose-1-phosphate uridylyl-transferase (GALT) encapsulation into plant virus capsids by a molecular self-assembly strategy. The aim of this work was to produce virus-like nanoparticles containing GALT for an enzyme-replacement therapy for classic galactosemia. The encapsulation efficiency and the catalytic constants of bio-nanoreactors were determined by using different GALT and virus coat protein ratios. The substrate affinity of nanoreactors was slightly lower than that of the free enzyme; the activity rate was 16 % of the GALT free enzyme. The enzymatic nanoreactors without functionalization were internalized into different cell lines including fibroblast and kidney cells, but especially into hepatocytes. The enzymatic nanoreactors are an innovative enzyme preparation with potential use for the treatment of classic galactosemia.
2021-01-28 | Current and Future Treatments for Classic Galactosemia
Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches.
2019-10-17 | Dynamic origins of substrate promiscuity in bacterial galactokinases
Galactokinase catalyses the ATP-dependent phosphorylation of galactose and structurally related sugars. The enzyme has attracted interest as a potential biocatalyst for the production of sugar 1-phosphates and several attempts have been made to broaden its specificity. In general, bacterial galactokinases have wider substrate ranges than mammalian ones. The enzymes from Escherichia coli and Lactococcus lactis have received particular attention and a number of variants with increased promiscuity have been identified. Here, we present a molecular dynamics study designed to investigate the molecular causes of the wider substrate ranges of these enzymes and their variants with particular reference to protein mobility. Some regions close to the active site of the enzyme have different structures in the bacterial enzymes compared to the human one. Alterations known to increase the substrate range (e.g. Y371H in the E. coli enzyme), tend to alter the conformation of a key α-helical region (residues 216–232 in the E. coli enzyme). The equivalent helix in the human enzyme has previously been predicted to be altered in variants which affect catalytic activity or protein stability. This helix appears to be a key region in galactokinases from a range of species and may represent an interesting target for future attempts to broaden the specificity of galactokinases.
2016-07-27 | Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models.
The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4'-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-galactose from uridine triphosphate and galactose-1-phosphate. All four UDP-sugars are essential donors for glycoprotein biosynthesis with critical roles at the developing neuromuscular synapse. Drosophila galactosemia I (dGALT) and II (dGALK) disease models genetically interact; manifesting deficits in coordinated movement, neuromuscular junction (NMJ) development, synaptic glycosylation, and Wnt trans-synaptic signalling. Similarly, dGALE and dUGP mutants display striking locomotor and NMJ formation defects, including expanded synaptic arbours, glycosylation losses, and differential changes in Wnt trans-synaptic signalling. In combination with dGALT loss, both dGALE and dUGP mutants compromise the synaptomatrix glycan environment that regulates Wnt trans-synaptic signalling that drives 1) presynaptic Futsch/MAP1b microtubule dynamics and 2) postsynaptic Frizzled nuclear import (FNI). Taken together, these findings indicate UDP-sugar balance is a key modifier of neurological outcomes in all three interacting galactosemia disease models, suggest that Futsch homolog MAP1B and the Wnt Frizzled receptor may be disease-relevant targets in epimerase and transferase galactosemias, and identify UGP as promising new potential therapeutic target for galactosemia neuropathology.
2016-01-06 | Classical galactosaemia: novel insights in IgG N-glycosylation and N-glycan biosynthesis
Classical galactosaemia (OMIM #230400), a rare disorder of carbohydrate metabolism, is caused by a deficient activity of galactose-1-phosphate uridyltransferase (EC 2.7.7.12). The pathophysiology of the long-term complications, mainly cognitive, neurological and female fertility problems remains poorly understood. The lack of validated biomarkers to determine prognosis, monitor disease progression and responses to new therapies, pose a huge challenge. We report the detailed analysis of an automated robotic hydrophilic interaction ultra-performance liquid chromatography N-glycan analytical method of high glycan peak resolution applied to serum IgG. This has revealed specific N-glycan processing defects observed in 40 adult galactosaemia patients (adults and adolescents), in comparison with 81 matched healthy controls. We have identified a significant increase in core fucosylated neutral glycans (P<0.0001) and a significant decrease in core fucosylated (P<0.001), non-fucosylated (P<0.0001) bisected glycans and, of specific note, decreased N-linked mannose-5 glycans (P<0.0001), in galactosaemia patients. We also report the abnormal expression of a number of related relevant N-glycan biosynthesis genes in peripheral blood mononuclear cells from 32 adult galactosaemia patients. We have noted significant dysregulation of two key N-glycan biosynthesis genes: ALG9 upregulated (P<0.001) and MGAT1 downregulated (P<0.01) in galactosaemia patients, which may contribute to its ongoing pathophysiology. Our data suggest that the use of IgG N-glycosylation analysis with matched N-glycan biosynthesis gene profiles may provide useful biomarkers for monitoring response to therapy and interventions. They also indicate potential gene modifying steps in this N-glycan biosynthesis pathway, of relevance to galactosaemia and related N-glycan biosynthesis disorders.
gene therapies
2026-09-21 | Prenatal consequences of GALT deficiency in a rat model of classic galactosemia.
Classic galactosemia (CG) is a potentially lethal disease that results from profound deficiency of galactose-1-P uridylyltransferase (GALT). Prior reports document elevated galactose metabolites beginning in utero in CG, raising concern that long-term complications in CG might also trace their origins to the prenatal period. However, studies document that elevated galactose metabolites in the postnatal period do not predict later developmental complications, challenging the connection. Here, we explored the relationship between elevated galactose metabolites in utero and fetal outcome using a GALT-null rat model of CG. To modify galactose metabolites in utero, we arranged rat crosses to produce GALT-null pups developing within either a GALT-null or heterozygous dam, and with or without heterozygous siblings. We reasoned that GALT activity present outside the fetus, but within the maternal-fetal compartment, might limit metabolic abnormalities in a developing GALT-null fetus -- and it did. Specifically, while galactose metabolites in GALT-null fetal pups from all crosses remained elevated over controls, the levels varied. When the dam and some siblings were heterozygous, amniotic fluid galactitol from GALT-null fetal pups at GD21 was comparable to the levels reported from second trimester human CG amniotic fluid. When the dam was GALT-null, but some siblings were heterozygous, the median galactitol level in amniotic fluid was 2.45-fold higher. When the dam and all siblings were GALT-null, the median amniotic fluid galactitol level was 5.67-fold higher. GALT-null fetal pups also showed significant growth delay in utero, but only when the dam and all siblings were GALT-null. That growth of GALT-null fetal pups was fully rescued by gestation within a heterozygous dam despite the persistence of moderately elevated galactose metabolites raises the possibility that babies with CG developing within a carrier mother might also be at least partially protected in utero from the adverse consequences of their GALT-deficiency.
2025-02-15 | Reshaping the Treatment Landscape of a Galactose Metabolism Disorder.
The Leloir pathway was elucidated decades ago, unraveling how galactose is metabolized in the body. Different inborn errors of metabolism in this pathway are known, the most frequent and well-studied being Classic Galactosemia (CG) (OMIM 230400) due to pathogenic variants in the GALT gene. Substrate reduction using dietary restriction of galactose is currently the only available treatment option. Although this burdensome diet resolves the life-threatening clinical picture in neonates, patients still face long-term complications, including cognitive and neurological deficits as well as primary ovarian insufficiency. Emerging therapies aim to address these challenges on multiple fronts: (1) restoration of GALT activity with nucleic acid therapies, pharmacological chaperones, or enzyme replacement; (2) influencing the pathological cascade of events to prevent accumulation of metabolites (Galactokinase 1 (GALK1) inhibitors, aldose reductase inhibitors), address myo-inositol deficiency, or alleviate cellular stress responses; (3) substrate reduction with synthetic biotics or galactose uptake inhibitors to eliminate the need for lifelong diet; and (4) novel approaches to mitigate existing symptoms, such as non-invasive brain stimulation and reproductive innovations. Early, personalized intervention remains critical for optimizing patient outcomes. We review the advances in the development of different treatment modalities for CG and reflect on the factors that need to be considered and addressed to reshape the landscape of treatment.
2024-02-14 | Whole-body galactose oxidation as a robust functional assay to assess the efficacy of gene-based therapies in a mouse model of Galactosemia.
Despite the implementation of lifesaving newborn screening programs and a galactose-restricted diet, many patients with classic galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that the administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which decreased not only galactose-1 phosphate (gal-1P) in the liver but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, noninvasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of galactosemia. Although our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that targets the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety.
2022-07-28 | Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment.
Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented.
2022-05-11 | AAV-mediated expression of galactose-1-phosphate uridyltransferase corrects defects of galactose metabolism in classic galactosemia patient fibroblasts.
Classic galactosemia (CG) is a rare disorder of autosomal recessive inheritance. It is caused predominantly by point mutations as well as deletions in the gene encoding the enzyme galactose-1-phosphate uridyltransferase (GALT). The majority of the more than 350 mutations identified in the GALT gene cause a significant reduction in GALT enzyme activity resulting in the toxic buildup of galactose metabolites that in turn is associated with cellular stress and injury. Consequently, developing a therapeutic strategy that reverses both the oxidative and ER stress in CG cells may be helpful in combating this disease. Recombinant adeno-associated virus (AAV)-mediated gene therapy to restore GALT activity offers the potential to address the unmet medical needs of galactosemia patients. Here, utilizing fibroblasts derived from CG patients we demonstrated that AAV-mediated augmentation of GALT protein and activity resulted in the prevention of ER and oxidative stress. We also demonstrate that these CG patient fibroblasts exhibit reduced CD109 and TGFβRII protein levels and that these effectors of cellular homeostasis could be restored following AAV-mediated expression of GALT. Finally, we show initial in vivo proof-of-concept restoration of galactose metabolism in a GALT knockout mouse model following treatment with AAV-GALT.
small molecules
2025-10-14 | Myo-Inositol Deficiency, Structural Brain Changes, and Cerebral Perfusion Alterations in Classic Galactosemia: Preliminary Insights From a Multiparametric MRI Study.
Classic galactosemia is a rare metabolic disorder resulting from galactose-1-phosphate uridylyltransferase deficiency, which disrupts normal galactose metabolism, leading to toxic accumulation of galactose-1-phosphate and galactitol. Despite early dietary intervention, patients remain at risk for long-term neurological impairments, including cognitive deficits, motor speech disorders, and psychiatric conditions. The mechanisms driving these persistent abnormalities remain unclear. This study investigated brain metabolic and structural alterations in adults with classic galactosemia using advanced multiparametric MRI. Six patients (3 males, 3 females; mean age 34.0 ± 7.3 years) adhering to lifelong galactose-restricted diets and six age- and sex-matched controls underwent 3T and 7T MRI, including T1-weighted imaging, pseudo-continuous arterial spin labeling, and high-resolution MR spectroscopic imaging. Patients exhibited significantly lower myo-inositol (mIns) concentrations in cerebellum (p = 0.007), putamen (p = 0.023), and cerebral white matter (p = 0.001), reflecting a chronic mIns deficiency despite dietary management. Structural analyses revealed reduced volumes of white matter (p < 0.001), bilateral putamen (p < 0.038), and left thalamus (p = 0.044); alongside increased cortical thickness and reduced cortical surface area, indicating abnormal cortical maturation, particularly in regions associated with motor and cognitive processing. Additionally, cerebral blood flow was elevated in emotion-processing regions, including bilateral amygdala (p < 0.022) and thalamus (p < 0.038). These preliminary findings highlight persistent neurological alterations in classic galactosemia despite dietary management and suggest that chronic mIns deficiency may contribute to the pathophysiology. They underscore the need for larger, longitudinal studies to confirm these results, investigate potential correlations with clinical severity and biochemical markers, and explore therapeutic strategies aimed at modulating mIns metabolism.
2025-10-01 | Exit interviews with caregivers of pediatric patients with classic galactosemia to explore meaningfulness of changes in the ACTION-galactosemia kids trial.
Classic Galactosemia is a rare, autosomal recessive disease in which galactose is not metabolized properly due to severe deficiency/absence of the galactose-1-phosphate uridylyltransferase (GALT) enzyme, converting to an aberrant and toxic metabolite, galactitol. Living with the debilitating symptoms and long-term consequences of Classic Galactosemia creates a heavy burden on patients' and their families' lives. Objectives were to: (1) Evaluate the impact and burden of disease; (2) Qualitatively explore changes in patient symptoms following treatment; and (3) Document the meaningfulness of changes resulting from treatment with govorestat as assessed by the Caregiver Global Impression of Severity (CGIS) and Caregiver Global Impression of Change (CGIC) scales. The AT-007-1002 clinical trial involved a Phase 1/2 dose escalation component (Part A) followed by a Phase 3, randomized, double-blind, placebo-controlled long-term administration component (Part B) that evaluated potential clinical benefit. Exit Interviews were completed prior to unblinding of data. The in-depth, qualitative interviews were semi-structured, using a discussion guide, and conducted by either Zoom or GoToMeeting. Thirty-six caregiver interviews were conducted, capturing the experience of 37 pediatric patients (one caregiver had 2 patients enrolled in the study). Thematic analysis was undertaken to identify themes or patterns within the data. All analyses were conducted on blinded data. Following finalization of the analysis and report findings, post-hoc analysis of the unblinded data was then conducted to explore the meaningfulness of patients experience by treatment arm. This study confirms the substantial burden known to be associated with Classic Galactosemia in a pediatric population. The difficulties experienced were across multiple areas including cognitive function, behavior/social function, motor function, emotional function, communication, vision problems, ovarian insufficiency, sensory difficulties, and sleep problems. The interviews demonstrated that most patients (approximately two thirds) experienced an improvement in symptoms and impacts associated with classic galactosemia over the course of the trial. Nearly all caregivers reported that they perceived a 1-category change on the Caregiver Global Impression of Severity or Caregiver Global Impression of Change items, indicating severity and change respectively, was meaningful to them and the patient. Unblinded analysis of the exit interview data confirmed the patient experience reported by caregivers was different between the treatment arms, providing qualitative support for the treatment benefit of govorestat when compared to placebo. Furthermore, the qualitative data from caregivers provide in-depth insights of their unique lived experience that highlight the substantial impact that this improvement had on the caregiver's and the patient's quality of life. The improvements observed led to a reduction on the burden of Classic Galactosemia and may lead to a greater patient's greater independence. The exit interviews confirmed the burden of Classic Galactosemia disease across multiple domains. Qualitative investigation suggests that observed changes are meaningful to the patient and caregiver, and changes were more commonly reported in those receiving govorestat compared to placebo. Full clinical trial findings will be published separately.
2025-07-01 | Galactosemia Presenting as Neonatal Hemochromatosis: A Case of Acute Liver Failure Managed Successfully with Medical Therapy
Neonatal acute liver failure often has a heterogenous presentation. Extensive workup is essential for prompt diagnosis and efficient treatment. Neonatal hemochromatosis (NH) and Galactosemia are both serious conditions that can manifest with acute liver dysfunction, but they require different treatment approaches. We describe a neonate who presented with acute liver failure, characterized by severe jaundice, deranged liver function and coagulopathy. Diagnostic imaging and other investigations implied a diagnosis of neonatal hemochromatosis due to hepatic and extra hepatic iron deposition along with raised serum alpha fetoprotein and ferritin levels. However, further metabolic testing revealed the diagnosis of classic galactosemia, identified by a deficiency in galactose-1-phosphate uridyltransferase (GALT). Infant showed significant improved with normalization of liver function with antioxidant cocktail and galactose free formula. This case highlights the significance of considering galactosemia in the differential diagnosis of neonatal hemochromatosis-like presentations and the importance for a comprehensive metabolic workup in neonates with liver dysfunction. It also emphasizes that early identification and management can successfully resolve liver dysfunction and prevent the need for liver transplant.
2025-02-06 | Galactose Impairs Motor Performance and Cerebellar Signaling in Young Male Wistar Rats.
Galactosemias are a group of inborn errors of galactose metabolism that causes different motor symptoms such as ataxia, tremor, and fine motor dysfunction. The objective was to investigate the cerebellar damage caused by an acute galactose administration. Thirty-day-old male and female Wistar rats were used. Animals were randomized into the following groups: I) galactose group, receiving a single subcutaneous administration of galactose; II) control group, receiving the vehicle solution under the same conditions. One, 3 or 24 h after administration, the animals were evaluated in the Rotarod test. A lower motor performance was observed in male rats 3 h after a galactose administration. This effect was not seen in females or with galactose exposure for 1 or 24 h. The activities of acetylcholinesterase and choline acetyltransferase were found unaltered in the cerebellum of males 3 h after galactose injection. We also found lower TH levels in cerebellar hemispheres and higher TH levels in cerebellar vermis 3 h after galactose administration in male rats, without differences in MAO-A or MAO-B activities. Galactose administration resulted in lower p-CREB(Ser133) and GAD67 levels in cerebellar hemispheres, without altering these parameters in cerebellar vermis of male rats. Finally, a decrease in TrkB-FL immunocontent (but not of TrkB-T levels) was observed in male cerebellar hemispheres. The absence of neurochemical alterations 1 h or 24 h after galactose administration indicates a transient effect for this hexose. The signs and symptoms of galactosemic patients underscore the need to study galactose effects in males and females and in various brain areas. Our findings enhance the understanding of therapeutic mechanisms of catecholaminergic drugs, which are proposed as a potential therapy for galactosemia.
2025-02-03 | Assessment of Long-Term Safety and Efficacy of Purple Sweet Potato Color (PSPC) and Myo-Inositol (MI) Treatment for Motor Related and Behavioral Phenotypes in a Mouse Model of Classic Galactosemia.
Classic galactosemia (CG) is a rare inherited metabolic disease caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase in galactose metabolism. The condition develops as a potentially fatal illness during the newborn period, but its acute clinical manifestations can be alleviated through a galactose restricted diet. Nonetheless, such dietary intervention is inadequate in preventing significant long-term consequences, including neurological impairments, growth restriction, cognitive delays, and, for most females, primary ovarian insufficiency. At present, no effective therapy exists to stop the progression of these complications, highlighting the urgent need for new treatment approaches to be developed. Supplements have been used in the treatment of other inborn errors of metabolism; however, they are not typically included in the clinical therapeutic regimen for CG. Recently, our research team has demonstrated that two generally recognized as safe supplements (purple weet potato color, PSPC and myo-inositol, MI) have been effective in partially restoring functions in the ovaries of our GalT-KO mouse model. However, the toxicological profile of both PSPC and MI has not been determined. In this study, we investigated the acute (30 days) and chronic (180 days) oral toxicities of PSPC and MI both in WT control and GalT-KO mice. Furthermore, our study aims to evaluate the effectiveness of oral feeding of PSPC and MI in correcting motor-related and behavioral phenotypes in GalT-KO mice. The long-term treatment of MI at a lower dose demonstrated promising improvements in motor deficit and anxiety driven hyperactivity in the mutant mice.
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2025-11-21 | Experimental Galactose-1-Phosphate Uridylyltransferase (GALT) mRNA Therapy Improves Motor-Related Phenotypes in a Mouse Model of Classic Galactosemia—A Pilot Study
Background: Despite life-saving newborn screening programs and a life-long galactose-restricted diet, many patients with classic galactosemia continue to develop long-term debilitating neurological deficits, speech dyspraxia, and primary ovarian insufficiency (POI). In an earlier study, we showed that administration of an experimental human GALT mRNA predominantly expressed in the liver of the GalT gene-trapped mouse model augmented the expression of hepatic GALT activity, which reduced build-up of galactose and its toxic metabolites not only in the liver but also in the peripheral tissues. Moreover, we showed that the administration of GALT mRNA in the mutant mice restored whole-body galactose oxidation (WBGO), which is a functional biomarker. Methods: In this pilot study, we extended our proof-of-concept efficacy studies to a disease-relevant phenotype: motor impairment. GalT-KO mice aged 3 and 6 weeks old administered biweekly intravenous injections of 100 µL GALT mRNA at a dose of 2 mg/kg for 2 months. Motor performance was assessed using rotarod testing and composite phenotype scoring, 3 and 9 weeks following the dosing regimen. Results: Preliminary results showed that a biweekly dosing at 2 mg/kg for 2 months improved the motor performance of the animals in rotarod and composite phenotype scoring tests in a short-term experiment. Conclusions: Despite being a small-scale study, our findings suggest that when treated early in life, the experimental GALT mRNA is effective in improving the motor-related phenotypes in GalT-KO mice using the specified dosing regimen. These findings highlight the potential of mRNA-based therapies for mitigating neurological symptoms in Classic galactosemia.
2025-04-24 | Experimental galactose-1 phosphate uridylyltransferase (GALT) mRNA therapy improves motor-related phenotypes in a mouse model of Classic Galactosemia
Abstract Despite life-saving newborn screening programs and a life-long galactose-restricted diet, many patients with Classic Galactosemia continue to develop long-term debilitating neurological deficits, speech dyspraxia, and primary ovarian insufficiency (POI). Earlier, we showed that administration of an experimental human GALT mRNA predominantly expressed in the liver of the GalT gene-trapped mouse model augmented the expression of hepatic GALT activity, which reduced build-up of galactose and its toxic metabolites not only in the liver, but also in the peripheral tissues. Moreover, we showed that administration of GALT mRNA in the mutant mice restored whole-body galactose oxidation (WBGO), a functional biomarker. In this study, we extended our proof-of-concept (POC) efficacy studies to a disease-relevant phenotype, motor impairment. We found that a biweekly dosing regimen at 2mg/kg for 2 months could improve the motor performance of the animals in Rotarod and Composite Phenotype Scoring tests.
2022-05-09 | Novel mRNA therapy restores GALT protein and enzyme activity in a zebrafish model of classic galactosemia.
Abstract Messenger RNA (mRNA) has emerged as a novel therapeutic approach for inborn errors of metabolism. Classic galactosemia (CG) is an inborn error of galactose metabolism caused by a severe deficiency of galactose‐1‐phosphate:uridylyltransferase (GALT) activity leading to neonatal illness and chronic impairments affecting the brain and female gonads. In this proof of concept study, we used our zebrafish model for CG to evaluate the potential of human GALT mRNA ( hGALT mRNA) packaged in two different lipid nanoparticles to restore GALT expression and activity at early stages of development. Both one cell‐stage and intravenous single‐dose injections resulted in hGALT protein expression and enzyme activity in the CG zebrafish ( galt knockout) at 5 days post fertilization (dpf). Moreover, the levels of galactose‐1‐phosphate (Gal‐1‐P) and galactonate, metabolites that accumulate because of the deficiency, showed a decreasing trend. LNP‐packaged mRNA was effectively translated and processed in the CG zebrafish without signs of toxicity. This study shows that mRNA therapy restores GALT protein and enzyme activity in the CG zebrafish model, and that the zebrafish is a suitable system to test this approach. Further studies are warranted to assess whether repeated injections safely mitigate the chronic impairments of this disease.
2021-12-23 | A pilot study of neonatal GALT gene replacement using AAV9 dramatically lowers galactose metabolites in blood, liver, and brain and minimizes cataracts in GALT-null rat pups.
Classic galactosemia (CG) is a rare metabolic disorder that results from profound deficiency of galactose-1-P uridylyltransferase (GALT). Despite early detection by newborn screening and rapid and lifelong dietary restriction of galactose, which is the current standard of care, most patients grow to experience a broad constellation of long-term complications. The mechanisms underlying these complications remain unclear and likely differ by tissue. Here we conducted a pilot study testing the safety and efficacy of GALT gene replacement using our recently-described GALT-null rat model for CG. Specifically, we administered AAV9.CMV.HA-hGALT to seven GALT-null rat pups via tail vein injection on day 3 of life; eight GALT-null pups injected with PBS served as the negative control, and four GALT+ heterozygous pups injected with PBS served as the positive control. All pups were returned to their nursing mothers, weighed daily, and euthanized for tissue collection 2 weeks later. Among the AAV9-injected pups in this study, we achieved GALT levels in liver ranging from 64% to 595% wild-type, and in brain ranging from 3% to 42% wild-type. In liver, brain, and blood samples from these animals we also saw a striking drop in galactose, galactitol, and gal-1P. Finally, all treated GALT-null pups showed dramatic improvement in cataracts relative to their mock-treated counterparts. Combined, these results demonstrate that GALT restoration in both liver and brain of GALT-null rats by neonatal tail vein administration using AAV9 is not only attainable but effective.
2020-12-21 | 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 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.
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Drug Discovery Landscape
1 orphan drug designation for Classic galactosemia.
1 orphan drug designation for Classic galactosemia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Govorestat | small molecules | EMA | Advanz Pharma Limited |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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