RARE DISEASE
Galactosemia
Galactosemia
Galactosemia
Drug discovery
2
drugs
With orphan designations
Overview
Galactosemia is an autosomal recessive disorder of galactose metabolism caused by deficient activity of enzymes (GALT, GALK1, or GALE) in the Leloir pathway [1][6]. Classic galactosemia (GALT deficiency) presents with acute neonatal toxicity (jaundice, failure to thrive, sepsis) without dietary restriction and chronic complications including intellectual disability, speech deficits, premature ovarian insufficiency, and movement disorders despite lifelong lactose/galactose avoidance [1][4][5]. While newborn screening enables early diagnosis, endogenous galactose production perpetuates disease progression [8][16].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare renal diseases
Research Papers
470 drug discovery papers about Galactosemia, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
470 drug discovery papers about Galactosemia, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-01 | Reproductive potential in classical galactosemia: A case series based perspective.
Classical galactosemia (CG), caused by galactose-1-phosphate uridylyltransferase (GALT) enzyme deficiency, is associated with premature ovarian insufficiency (POI) and subfertility. The last years, a counseling paradigm shift has been advocated with emphasis on subfertility instead of infertility because spontaneous pregnancy can occur. We describe two women (aged 26 and 30 years) with genetically confirmed CG and POI, who conceived spontaneously. Both adhered to lifelong galactose-restricted diet and had regular endocrine monitoring. Their pregnancies were uncomplicated and each delivered a healthy infant at term. These cases are in line with the counseling paradigm shift, with natural conception being possible in CG. Reproductive counselling of girls and women with CG should entail fertility preservation and spontaneous pregnancy. In case of desired pregnancy, a period of two years to attempt conceiving should be advised. AMH is not a reliable prognostic parameter for predicting the reproductive potential in CG.
2026-03-09 | Galactose tolerance in adults with classical galactosaemia. Considering the gaps.
Classical galactosaemia (CG, OMIM 230400) is a rare inborn error of metabolism caused by deficiency of galactose-1-phosphate uridylyltransferase. The available modality of treatment, a galactose-restricted diet, is effective in preventing life-threatening neonatal symptoms. However long-term complications including neurological, speech and fertility issues in females remain prevalent. This retrospective review reports the experience of mild-moderate relaxation of dietary galactose intake over time in a cohort of 31 Irish CG adult patients with established RBC Gal-1-P, and novel IgG N-glycan analysis. Three groups were categorised based on the retrospective analysis of estimated dietary galactose intake: Group 1 (<200 mg/day), Group 2 (200-500 mg/day) and Group 3 (501-1000 mg/day). Dietary galactose intake was compared to matching RBC Gal-1-P levels and serum IgG N-glycan profiles (measured by HILIC-UPLC). RBC Gal-1-P levels increased with increased galactose intake with statistically significant differences only between the lowest and highest galactose intake group (p < 0.05). Minor changes were seen in a number of IgG N-glycans in the highest galactose intake group with increases in core fucosylated monoantennary and biantennary monogalactosylated monosialylated glycans, pentamannosylated glycans, oligomannosylated glycans and monoantennary glycans with a decrease in grouped biantennary glycans. The most significant change noted was an increase in pentamannosylated glycans with increased dietary galactose intake. Moderate relaxation of dietary galactose intake (up to 500 mg/day) may be well tolerated in the majority of CG adults. These data suggest that serum N-glycan profiling may provide an improved individualised 'personalised medicine' approach for treatment interventions for CG, considering individualised variation in glycosylation, including 'glycosylation outliers'.
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.
2025-07-31 | Galactose-1-phosphate modulates mitochondrial function and Toll-like receptor 2 expression in neonatal skin fibroblast cultures
Introduction: Mitochondrial dysfunction and Toll-like receptors (TLRs) are commonly associated with oxidative stress and apoptotic cell death in metabolic disorders; however, their roles in Classical Galactosemia remain largely unexplored. This study examined the activities of key mitochondrial enzymes, as well as the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and Toll-like receptor-2, under hypergalactosemic or hyperglycemic conditions in fibroblast cultures. Methods: Confluent fibroblast cultures were established from the post-circumcision skin of 2–3-day-old healthy neonates. Next, these fibroblast cultures were treated with D-Galactose (D-Gal, 0–20 mM), galactose-1-phosphate (Gal-1-P, 0–5 mM), or “high glucose” (HG, 25 mM). Peripheral blood mononuclear cells (PBMCs) were isolated from galactosemia patients and control subjects. Activities of medium-chain acyl-CoA dehydrogenase (MCAD), cytochrome c oxidase (CcO), and carnitine palmitoyltransferase-1 (CPT-1) were analyzed in cell homogenates and in PBMCs of both patients and controls. ATP production and malondialdehyde (MDA) levels in fibroblasts were measured using commercial kits. In addition, PGC-1α and TLR-2 were examined in fibroblast cultures by western blot analysis. Results: D-Gal and Gal-1-P significantly (p < 0.05) reduced the enzyme activities of CPT-1, MCAD, and CcO, with Gal-1-P causing a more pronounced (p < 0.01) effect on CPT-1 compared to the control group. HG had no significant impact on these mitochondrial enzymes. Moreover, mitochondrial enzyme activities were markedly lower in PBMCs from galactosemia patients than from control subjects. Galactose-treated fibroblasts showed elevated TLR-2 levels but unchanged PGC-1α expression compared to control cells. Only Gal-1-P significantly diminished PGC-1α levels, whereas HG, D-Gal, and Gal-1-P significantly upregulated the expression of TLR-2. Conclusion: These findings suggest that galactosemia pathogenesis involves Gal-1-P–mediated mitochondrial dysfunction and elevated TLR-2 gene expression.
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.
2025-08-08 | Simultaneous, dual-target, bilateral deep brain stimulation for treatment of galactosemia-induced dystonia and tremor in a pediatric patient.
Movement disorders, including dystonia and tremor, are debilitating in the pediatric population. Neurometabolic syndromes such as classic galactosemia represent a subset of etiologies of pediatric movement disorders for which limited data is available to guide treatment. Deep brain stimulation, though rarely performed, is an option for pediatric patients with refractory symptoms. Here, we report a case of a 14-year-old boy with progressive, refractory generalized dystonia and cerebellar tremor resulting from classic galactosemia. He underwent implantation of bilateral thalamic ventral intermediate nucleus and globus pallidus internus for deep brain stimulation. The patient experienced durable improvement in both tremor and dystonia over a 6-year follow-up period. Dual-target, bilateral deep brain stimulation can be an effective therapy for alleviation of mixed movement disorders resulting from classic galactosemia in carefully selected patients. To our knowledge, this is the first case in which dual-target deep brain stimulation has been implemented in the setting of galactosemia-induced tremor and may be a promising treatment paradigm in this patient population.
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.
2023-11-17 | Programming Probiotics: Diet-responsive gene expression and colonization control in engineeredS. boulardii
Abstract Saccharomyces boulardii ( Sb ) is an emerging probiotic chassis for delivering biomolecules to the mammalian gut, offering unique advantages as the only eukaryotic probiotic. However, precise control over gene expression and gut residence time in Sb have remained challenging. To address this, we developed five ligand-responsive gene expression systems and repaired galactose metabolism in Sb , enabling inducible gene expression in this strain. Engineering these systems allowed us to construct AND logic gates, control the surface display of proteins, and turn on protein production in the mouse gut in response to a dietary sugar. Additionally, repairing galactose metabolism expanded Sb ’s habitat within the intestines and resulted in galactose-responsive control over gut residence time. This work opens new avenues for precise dosing of therapeutics by Sb via control over its in vivo gene expression levels and localization within the gastrointestinal tract.
2023-05-10 | Injection of Platelet Rich Plasma Intra-Ovarian to Treat Inactive Ovaries in Rabbits
In this investigation, we examined the efficiency of PRP as a therapy for inactive ovary (IO) in rabbits.IO in rabbits was induced by administration of D-galactose (200mg/kg) (dissolved in saline, 0.2mL/rabbits/day) for ten consecutive days.Rabbits divide into three groups.After preparing two concentrations of PRP solution, the PRP was injected intraovarian through surgical intervention.Then two weeks later, FSH and estrogen were measured, histopathological examination for ovaries were made according to the routine procedure, and finally, the mating trial was made to evaluate the fertility status.Ten days after D-galactose administration IO had significantly higher levels of FSH (2.30±1.32)and (2.80±0.80)and lower levels of E2 (5.55±0.78)and (5.36±0.91), in comparison to the control group (P<0.05)(1.99±0.80 and 7.16±1.195)respectively.The results after injection of PRP in two different concentrations indicated that the highest value significant (P<0.05) was in E2 levels (7.87±0.9)and (8.08±2.21),and the lowest significant (P<0.05) was in FSH levels (1.60±0.57)and (1.49±0.38)comparison with others induction D-galactose.Histopathological examination showed an increase in follicles in PRP groups compared to galactose group.It was concluded that PRP had a protective effect against galactose toxicity and improved follicular growth.
proteins
2026-05-17 | Decompensated cirrhosis in an adult revealing probable congenital galactosemia: A case report
Congenital galactosemia is an autosomal recessive inborn error of metabolism, most commonly caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT). It typically presents during the neonatal period with acute liver failure, cataracts, and neurological impairment. Diagnosis in adulthood is exceptional. We report the case of a 30-year-old woman admitted for upper gastrointestinal bleeding revealing cirrhosis with portal hypertension. Medical history included bilateral cataract surgery performed twice, psychomotor delay, bilateral hearing impairment, and a history of unexplored neonatal jaundice. A comprehensive etiological workup for chronic liver disease was negative. Plasma galactose level was elevated at 1.2 mg/dL (normal < 0.7 mg/dL). In the absence of enzymatic and genetic confirmation due to socioeconomic constraints, the diagnosis of probable congenital galactosemia was retained based on a consistent set of clinical and biological findings. This case highlights the rare possibility of late presentation in adulthood and emphasizes the importance of considering a metabolic etiology in unexplained cirrhosis associated with suggestive systemic manifestations.
2026-03-20 | Hepatic and Extra-hepatic Outcomes of Classical Galactosemia in Infants: A Longitudinal Observational Study.
Classical galactosemia (CG), if untreated, can be life threatening in early infancy; however, with early galactose restriction, survival has improved markedly. Despite early diagnosis and dietary exclusion, complications may ensue. This study aimed to identify risk factors for adverse outcomes in CG. We conducted an analysis of our prospectively maintained database. Diagnosis was based on galactose-1-phosphate uridyltransferase (GALT) enzyme levels <10u/gm hemoglobin or mutation of the GALT gene. Clinical and laboratory data were retrieved from hospital electronic records and analyzed to identify potential predictors of mortality or neuro-ophthalmic morbidity (poor neurocognition, learning disability, and new-onset or persistent cataract). Fifty-nine CG patients presented with infantile cholestasis. Their median age of symptom onset and diagnosis was 16 (interquartile range [IQR]: 3-90) and 50 (IQR: 4-120) days, respectively. Among the 48 survivors, 41 had follow-up for ≥18 months and were analyzed for long-term outcomes. Complete liver recovery was documented in all 41 patients, with a median time to recovery of 5 months (IQR: 3-8) following diagnosis. On a lactose-free diet (LFD), 8 (19.5%) developed new-onset cataracts, and 21 (51.2%) patients had neurocognitive issues. The univariate analysis of non-survivors (n = 11) versus survivors (n = 48) identified risk factors: older age at diagnosis, high baseline Child-Turcotte-Pugh (CTP) and Pediatric End-Stage Liver Disease (PELD) scores, low serum sodium and albumin levels, and higher international normalized ratio values. In addition, refractory ascites, persistent coagulopathy at 4 weeks on LFD, and culture-positive sepsis were significantly associated risk factors in the non-survival group. No significant predictors were found for neurocognitive issues and cataract in follow-up. PELD and CTP scores at admission predict survival. Long-term neuro-ophthalmic morbidity is not associated with liver disease severity at onset in CG.
2025-07-08 | The Clinical Picture of Galactosemia Can Manifest Itself with Varying Intensity
Galactosemia is a rare hereditary metabolic disorder that influences a person's ability to properly metabolize galactose.Galactosemia has an autosomal recessive inheritance design that comes about in a lack of the chemical dependable for the appropriate breakdown of galactose.The clinical picture can show itself with shifting concentrated.In a normal frame, side effects show up 2-3 days after drain ingestion with heaving, expanded jaundice, diarrhea, flatulence, abdominal distension due to liver enlargement, dehydration, symptoms of hypoglycemia, and a exceptionally poor general condition.
2025-06-14 | Clinical and genetic features of Classic Galactosemia in the south of Brazil.
Classic Galactosemia (CG) is a rare metabolic disorder that leads to acute neonatal hepatic dysfunction, with striking improvement after diet treatment. However, long-term complications, such as intellectual deficits, often persist. To describe the demographic, clinical, and genetic features of CG in a cohort of patients from South Brazil. Data were retrieved through medical charts review of CG patients followed in Rio Grande do Sul, Brazil. Thirty-one patients were included (families = 29; ethnicity: white = 20, indigenous Kaingang = 9, black = 2; female = 14). Five patients were diagnosed through private NBS and began treatment at a median age of 17 days (15-30), while others presented symptoms at 5 days (1-19) starting treatment at 27 days (5-4680). Eight patients presented Cerebral Palsy, Microcephaly, and/or Epilepsy, and two had died. Notable clinical findings were the "double cap sign" in Brain MRI (n = 1), pseudohyperglycemia (n = 3), and elevated chitotriosidase activity (n = 3). GALT sequencing was performed in 25/31 patients, and the most frequent causal variant found was c.563 A > G (p.Gln188Arg). Two novel variants were detected: c.164G > T (p.Gly55Val), associated with clinical variant galactosemia; and a novel haplotype c.[90dup; 529 A > G] (p.[His31Alafs*9;Met177Val]) detected in Kaingang patients. The minimal prevalence of CG in this Indigenous population was estimated in at least 1:900 live births. This data improves the characterization of CG in symptomatic diagnosed patients and identifies a high incidence of CG in the Kaingang people due to a founder effect.
2024-07-25 | Measurement of temperature, pH and substrate levels on the activity of the Galactose-1-Phosphate Uridyltransferase enzyme
Galactose-1-phosphate uridyltransferase (GALT) is an important enzyme involved in galactose metabolism. Understanding the factors influencing GALT activity is critical to elucidate its physiological role and potential therapeutic implications in galactosemia. In developing new drugs, chicken intestine/liver powder can be used as an enzyme source, GALT, to treat galactosemia. Therefore, it is necessary to research the characterization of the GALT enzyme in chicken intestine and liver powder. In this study, we investigated the influence of temperature, pH, and substrate level on GALT enzyme activity using an experimental approach in vitro. The optimum pH extraction results show that the optimum pH for the extraction of the chicken intestine and liver GALT is pH 7, with activity values of 0.47 units/mL and 0.3953 units/mL, respectively. The optimum temperature for the extraction of chicken intestine and liver GALT is 37℃ with substrate hydrolysis capabilities of 0.48 U/mL and 0.57 U/mL, respectively. Meanwhile, the optimum substrate content is 400x. These insights provide a valuable foundation for further research aimed at comprehensively understanding GALT function, developing targeted interventions for disorders of galactose metabolism, and possible application in the development of new drugs for galactosemia
oligonucleotides
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.
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.
2022-05-09 | 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.
other
2021-11-15 | d-Galactose induced early aging in human erythrocytes: Role of band 3 protein.
Aging, a time-dependent multifaceted process, affects both cell structure and function and involves oxidative stress as well as glycation. The present investigation focuses on the role of the band 3 protein (B3p), an anion exchanger essential to red cells homeostasis, in a d-galactose ( d-Gal)-induced aging model. Anion exchange capability, measured by the rate constant of SO₄²- uptake through B3p, levels of lipid peroxidation, oxidation of membrane sulfhydryl groups, B3p expression, methemoglobin, glycated hemoglobin (Hb), and the reduced glutathione/oxidized glutathione ratio were determined after exposure of human erythrocytes to 25, 35, 50, and 100 mmol/L d-Gal for 24 h. Our results show that: (i) in vitro application of d-Gal is useful to model early aging in human erythrocytes; (ii) assessment of B3p ion transport function is a sensitive tool to monitor aging development; (iii) d-Gal leads to Hb glycation and produces substantial changes on the endogenous antioxidant system; (iv) the impact of aging on B3p function proceeds through steps, first involving Hb glycation and then oxidative events at the membrane level. These findings offer a useful tool to understand the mechanisms of aging in human erythrocytes and propose B3p as a possible target for new therapeutic strategies to counteract age-related disturbances.
1988-03-01 | Galactose inhibition of ovulation in mice
Clinical evidence suggests an association between galactosemia and premature ovarian failure. In the present study, adult female mice were fed a diet consisting of 50% galactose for either 2, 4, or 6 weeks. At all times there was a decrease in the normal ovulatory response, as evidenced by a reduction in the number of corpora lutea when compared with controls. Additionally, the exposure of galactose-treated mice to a superovulatory regimen of pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) failed to induce an increased ovulatory response. Morphologic alterations, such as the increase in interstitial tissue and the appearance of lipofuscin, coupled with the failure to respond to exogenous gonadotropins, suggest that the reduced ovulatory response may be occurring at the level of the ovary. This effect, however, is reversible with cessation of galactose treatment.
small molecules
2026-07-01 | Reproductive potential in classical galactosemia: A case series based perspective.
Classical galactosemia (CG), caused by galactose-1-phosphate uridylyltransferase (GALT) enzyme deficiency, is associated with premature ovarian insufficiency (POI) and subfertility. The last years, a counseling paradigm shift has been advocated with emphasis on subfertility instead of infertility because spontaneous pregnancy can occur. We describe two women (aged 26 and 30 years) with genetically confirmed CG and POI, who conceived spontaneously. Both adhered to lifelong galactose-restricted diet and had regular endocrine monitoring. Their pregnancies were uncomplicated and each delivered a healthy infant at term. These cases are in line with the counseling paradigm shift, with natural conception being possible in CG. Reproductive counselling of girls and women with CG should entail fertility preservation and spontaneous pregnancy. In case of desired pregnancy, a period of two years to attempt conceiving should be advised. AMH is not a reliable prognostic parameter for predicting the reproductive potential in CG.
2026-03-09 | Galactose tolerance in adults with classical galactosaemia. Considering the gaps.
Classical galactosaemia (CG, OMIM 230400) is a rare inborn error of metabolism caused by deficiency of galactose-1-phosphate uridylyltransferase. The available modality of treatment, a galactose-restricted diet, is effective in preventing life-threatening neonatal symptoms. However long-term complications including neurological, speech and fertility issues in females remain prevalent. This retrospective review reports the experience of mild-moderate relaxation of dietary galactose intake over time in a cohort of 31 Irish CG adult patients with established RBC Gal-1-P, and novel IgG N-glycan analysis. Three groups were categorised based on the retrospective analysis of estimated dietary galactose intake: Group 1 (<200 mg/day), Group 2 (200-500 mg/day) and Group 3 (501-1000 mg/day). Dietary galactose intake was compared to matching RBC Gal-1-P levels and serum IgG N-glycan profiles (measured by HILIC-UPLC). RBC Gal-1-P levels increased with increased galactose intake with statistically significant differences only between the lowest and highest galactose intake group (p < 0.05). Minor changes were seen in a number of IgG N-glycans in the highest galactose intake group with increases in core fucosylated monoantennary and biantennary monogalactosylated monosialylated glycans, pentamannosylated glycans, oligomannosylated glycans and monoantennary glycans with a decrease in grouped biantennary glycans. The most significant change noted was an increase in pentamannosylated glycans with increased dietary galactose intake. Moderate relaxation of dietary galactose intake (up to 500 mg/day) may be well tolerated in the majority of CG adults. These data suggest that serum N-glycan profiling may provide an improved individualised 'personalised medicine' approach for treatment interventions for CG, considering individualised variation in glycosylation, including 'glycosylation outliers'.
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.
2025-07-31 | Galactose-1-phosphate modulates mitochondrial function and Toll-like receptor 2 expression in neonatal skin fibroblast cultures
Introduction: Mitochondrial dysfunction and Toll-like receptors (TLRs) are commonly associated with oxidative stress and apoptotic cell death in metabolic disorders; however, their roles in Classical Galactosemia remain largely unexplored. This study examined the activities of key mitochondrial enzymes, as well as the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and Toll-like receptor-2, under hypergalactosemic or hyperglycemic conditions in fibroblast cultures. Methods: Confluent fibroblast cultures were established from the post-circumcision skin of 2–3-day-old healthy neonates. Next, these fibroblast cultures were treated with D-Galactose (D-Gal, 0–20 mM), galactose-1-phosphate (Gal-1-P, 0–5 mM), or “high glucose” (HG, 25 mM). Peripheral blood mononuclear cells (PBMCs) were isolated from galactosemia patients and control subjects. Activities of medium-chain acyl-CoA dehydrogenase (MCAD), cytochrome c oxidase (CcO), and carnitine palmitoyltransferase-1 (CPT-1) were analyzed in cell homogenates and in PBMCs of both patients and controls. ATP production and malondialdehyde (MDA) levels in fibroblasts were measured using commercial kits. In addition, PGC-1α and TLR-2 were examined in fibroblast cultures by western blot analysis. Results: D-Gal and Gal-1-P significantly (p < 0.05) reduced the enzyme activities of CPT-1, MCAD, and CcO, with Gal-1-P causing a more pronounced (p < 0.01) effect on CPT-1 compared to the control group. HG had no significant impact on these mitochondrial enzymes. Moreover, mitochondrial enzyme activities were markedly lower in PBMCs from galactosemia patients than from control subjects. Galactose-treated fibroblasts showed elevated TLR-2 levels but unchanged PGC-1α expression compared to control cells. Only Gal-1-P significantly diminished PGC-1α levels, whereas HG, D-Gal, and Gal-1-P significantly upregulated the expression of TLR-2. Conclusion: These findings suggest that galactosemia pathogenesis involves Gal-1-P–mediated mitochondrial dysfunction and elevated TLR-2 gene expression.
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.
2025-08-08 | Simultaneous, dual-target, bilateral deep brain stimulation for treatment of galactosemia-induced dystonia and tremor in a pediatric patient.
Movement disorders, including dystonia and tremor, are debilitating in the pediatric population. Neurometabolic syndromes such as classic galactosemia represent a subset of etiologies of pediatric movement disorders for which limited data is available to guide treatment. Deep brain stimulation, though rarely performed, is an option for pediatric patients with refractory symptoms. Here, we report a case of a 14-year-old boy with progressive, refractory generalized dystonia and cerebellar tremor resulting from classic galactosemia. He underwent implantation of bilateral thalamic ventral intermediate nucleus and globus pallidus internus for deep brain stimulation. The patient experienced durable improvement in both tremor and dystonia over a 6-year follow-up period. Dual-target, bilateral deep brain stimulation can be an effective therapy for alleviation of mixed movement disorders resulting from classic galactosemia in carefully selected patients. To our knowledge, this is the first case in which dual-target deep brain stimulation has been implemented in the setting of galactosemia-induced tremor and may be a promising treatment paradigm in this patient population.
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.
2023-11-17 | Programming Probiotics: Diet-responsive gene expression and colonization control in engineeredS. boulardii
Abstract Saccharomyces boulardii ( Sb ) is an emerging probiotic chassis for delivering biomolecules to the mammalian gut, offering unique advantages as the only eukaryotic probiotic. However, precise control over gene expression and gut residence time in Sb have remained challenging. To address this, we developed five ligand-responsive gene expression systems and repaired galactose metabolism in Sb , enabling inducible gene expression in this strain. Engineering these systems allowed us to construct AND logic gates, control the surface display of proteins, and turn on protein production in the mouse gut in response to a dietary sugar. Additionally, repairing galactose metabolism expanded Sb ’s habitat within the intestines and resulted in galactose-responsive control over gut residence time. This work opens new avenues for precise dosing of therapeutics by Sb via control over its in vivo gene expression levels and localization within the gastrointestinal tract.
2023-05-10 | Injection of Platelet Rich Plasma Intra-Ovarian to Treat Inactive Ovaries in Rabbits
In this investigation, we examined the efficiency of PRP as a therapy for inactive ovary (IO) in rabbits.IO in rabbits was induced by administration of D-galactose (200mg/kg) (dissolved in saline, 0.2mL/rabbits/day) for ten consecutive days.Rabbits divide into three groups.After preparing two concentrations of PRP solution, the PRP was injected intraovarian through surgical intervention.Then two weeks later, FSH and estrogen were measured, histopathological examination for ovaries were made according to the routine procedure, and finally, the mating trial was made to evaluate the fertility status.Ten days after D-galactose administration IO had significantly higher levels of FSH (2.30±1.32)and (2.80±0.80)and lower levels of E2 (5.55±0.78)and (5.36±0.91), in comparison to the control group (P<0.05)(1.99±0.80 and 7.16±1.195)respectively.The results after injection of PRP in two different concentrations indicated that the highest value significant (P<0.05) was in E2 levels (7.87±0.9)and (8.08±2.21),and the lowest significant (P<0.05) was in FSH levels (1.60±0.57)and (1.49±0.38)comparison with others induction D-galactose.Histopathological examination showed an increase in follicles in PRP groups compared to galactose group.It was concluded that PRP had a protective effect against galactose toxicity and improved follicular growth.
proteins
2026-05-17 | Decompensated cirrhosis in an adult revealing probable congenital galactosemia: A case report
Congenital galactosemia is an autosomal recessive inborn error of metabolism, most commonly caused by a deficiency of galactose-1-phosphate uridyltransferase (GALT). It typically presents during the neonatal period with acute liver failure, cataracts, and neurological impairment. Diagnosis in adulthood is exceptional. We report the case of a 30-year-old woman admitted for upper gastrointestinal bleeding revealing cirrhosis with portal hypertension. Medical history included bilateral cataract surgery performed twice, psychomotor delay, bilateral hearing impairment, and a history of unexplored neonatal jaundice. A comprehensive etiological workup for chronic liver disease was negative. Plasma galactose level was elevated at 1.2 mg/dL (normal < 0.7 mg/dL). In the absence of enzymatic and genetic confirmation due to socioeconomic constraints, the diagnosis of probable congenital galactosemia was retained based on a consistent set of clinical and biological findings. This case highlights the rare possibility of late presentation in adulthood and emphasizes the importance of considering a metabolic etiology in unexplained cirrhosis associated with suggestive systemic manifestations.
2026-03-20 | Hepatic and Extra-hepatic Outcomes of Classical Galactosemia in Infants: A Longitudinal Observational Study.
Classical galactosemia (CG), if untreated, can be life threatening in early infancy; however, with early galactose restriction, survival has improved markedly. Despite early diagnosis and dietary exclusion, complications may ensue. This study aimed to identify risk factors for adverse outcomes in CG. We conducted an analysis of our prospectively maintained database. Diagnosis was based on galactose-1-phosphate uridyltransferase (GALT) enzyme levels <10u/gm hemoglobin or mutation of the GALT gene. Clinical and laboratory data were retrieved from hospital electronic records and analyzed to identify potential predictors of mortality or neuro-ophthalmic morbidity (poor neurocognition, learning disability, and new-onset or persistent cataract). Fifty-nine CG patients presented with infantile cholestasis. Their median age of symptom onset and diagnosis was 16 (interquartile range [IQR]: 3-90) and 50 (IQR: 4-120) days, respectively. Among the 48 survivors, 41 had follow-up for ≥18 months and were analyzed for long-term outcomes. Complete liver recovery was documented in all 41 patients, with a median time to recovery of 5 months (IQR: 3-8) following diagnosis. On a lactose-free diet (LFD), 8 (19.5%) developed new-onset cataracts, and 21 (51.2%) patients had neurocognitive issues. The univariate analysis of non-survivors (n = 11) versus survivors (n = 48) identified risk factors: older age at diagnosis, high baseline Child-Turcotte-Pugh (CTP) and Pediatric End-Stage Liver Disease (PELD) scores, low serum sodium and albumin levels, and higher international normalized ratio values. In addition, refractory ascites, persistent coagulopathy at 4 weeks on LFD, and culture-positive sepsis were significantly associated risk factors in the non-survival group. No significant predictors were found for neurocognitive issues and cataract in follow-up. PELD and CTP scores at admission predict survival. Long-term neuro-ophthalmic morbidity is not associated with liver disease severity at onset in CG.
2025-07-08 | The Clinical Picture of Galactosemia Can Manifest Itself with Varying Intensity
Galactosemia is a rare hereditary metabolic disorder that influences a person's ability to properly metabolize galactose.Galactosemia has an autosomal recessive inheritance design that comes about in a lack of the chemical dependable for the appropriate breakdown of galactose.The clinical picture can show itself with shifting concentrated.In a normal frame, side effects show up 2-3 days after drain ingestion with heaving, expanded jaundice, diarrhea, flatulence, abdominal distension due to liver enlargement, dehydration, symptoms of hypoglycemia, and a exceptionally poor general condition.
2025-06-14 | Clinical and genetic features of Classic Galactosemia in the south of Brazil.
Classic Galactosemia (CG) is a rare metabolic disorder that leads to acute neonatal hepatic dysfunction, with striking improvement after diet treatment. However, long-term complications, such as intellectual deficits, often persist. To describe the demographic, clinical, and genetic features of CG in a cohort of patients from South Brazil. Data were retrieved through medical charts review of CG patients followed in Rio Grande do Sul, Brazil. Thirty-one patients were included (families = 29; ethnicity: white = 20, indigenous Kaingang = 9, black = 2; female = 14). Five patients were diagnosed through private NBS and began treatment at a median age of 17 days (15-30), while others presented symptoms at 5 days (1-19) starting treatment at 27 days (5-4680). Eight patients presented Cerebral Palsy, Microcephaly, and/or Epilepsy, and two had died. Notable clinical findings were the "double cap sign" in Brain MRI (n = 1), pseudohyperglycemia (n = 3), and elevated chitotriosidase activity (n = 3). GALT sequencing was performed in 25/31 patients, and the most frequent causal variant found was c.563 A > G (p.Gln188Arg). Two novel variants were detected: c.164G > T (p.Gly55Val), associated with clinical variant galactosemia; and a novel haplotype c.[90dup; 529 A > G] (p.[His31Alafs*9;Met177Val]) detected in Kaingang patients. The minimal prevalence of CG in this Indigenous population was estimated in at least 1:900 live births. This data improves the characterization of CG in symptomatic diagnosed patients and identifies a high incidence of CG in the Kaingang people due to a founder effect.
2024-07-25 | Measurement of temperature, pH and substrate levels on the activity of the Galactose-1-Phosphate Uridyltransferase enzyme
Galactose-1-phosphate uridyltransferase (GALT) is an important enzyme involved in galactose metabolism. Understanding the factors influencing GALT activity is critical to elucidate its physiological role and potential therapeutic implications in galactosemia. In developing new drugs, chicken intestine/liver powder can be used as an enzyme source, GALT, to treat galactosemia. Therefore, it is necessary to research the characterization of the GALT enzyme in chicken intestine and liver powder. In this study, we investigated the influence of temperature, pH, and substrate level on GALT enzyme activity using an experimental approach in vitro. The optimum pH extraction results show that the optimum pH for the extraction of the chicken intestine and liver GALT is pH 7, with activity values of 0.47 units/mL and 0.3953 units/mL, respectively. The optimum temperature for the extraction of chicken intestine and liver GALT is 37℃ with substrate hydrolysis capabilities of 0.48 U/mL and 0.57 U/mL, respectively. Meanwhile, the optimum substrate content is 400x. These insights provide a valuable foundation for further research aimed at comprehensively understanding GALT function, developing targeted interventions for disorders of galactose metabolism, and possible application in the development of new drugs for galactosemia
oligonucleotides
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.
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.
2022-05-09 | 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.
other
2021-11-15 | d-Galactose induced early aging in human erythrocytes: Role of band 3 protein.
Aging, a time-dependent multifaceted process, affects both cell structure and function and involves oxidative stress as well as glycation. The present investigation focuses on the role of the band 3 protein (B3p), an anion exchanger essential to red cells homeostasis, in a d-galactose ( d-Gal)-induced aging model. Anion exchange capability, measured by the rate constant of SO₄²- uptake through B3p, levels of lipid peroxidation, oxidation of membrane sulfhydryl groups, B3p expression, methemoglobin, glycated hemoglobin (Hb), and the reduced glutathione/oxidized glutathione ratio were determined after exposure of human erythrocytes to 25, 35, 50, and 100 mmol/L d-Gal for 24 h. Our results show that: (i) in vitro application of d-Gal is useful to model early aging in human erythrocytes; (ii) assessment of B3p ion transport function is a sensitive tool to monitor aging development; (iii) d-Gal leads to Hb glycation and produces substantial changes on the endogenous antioxidant system; (iv) the impact of aging on B3p function proceeds through steps, first involving Hb glycation and then oxidative events at the membrane level. These findings offer a useful tool to understand the mechanisms of aging in human erythrocytes and propose B3p as a possible target for new therapeutic strategies to counteract age-related disturbances.
1988-03-01 | Galactose inhibition of ovulation in mice
Clinical evidence suggests an association between galactosemia and premature ovarian failure. In the present study, adult female mice were fed a diet consisting of 50% galactose for either 2, 4, or 6 weeks. At all times there was a decrease in the normal ovulatory response, as evidenced by a reduction in the number of corpora lutea when compared with controls. Additionally, the exposure of galactose-treated mice to a superovulatory regimen of pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) failed to induce an increased ovulatory response. Morphologic alterations, such as the increase in interstitial tissue and the appearance of lipofuscin, coupled with the failure to respond to exogenous gonadotropins, suggest that the reduced ovulatory response may be occurring at the level of the ovary. This effect, however, is reversible with cessation of galactose treatment.
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Drug Discovery Landscape
2 orphan drug designations for Galactosemia.
2 orphan drug designations for Galactosemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-associated virus 2/9 expressing human GALT gene (AAV2/9-hGALT) | gene therapies | FDA | 2021-09-28 | — | Jaguar Gene Therapy, LLC |
2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid | small molecules | FDA | 2019-05-23 | — | Applied Therapeutics Inc. |
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