RARE DISEASE
GM1 gangliosidosis
GM1 gangliosidosis
GM1 gangliosidosis
Synonyms: Beta-galactosidase-1 deficiency, GLB1 deficiency, Landing disease
Synonyms: Beta-galactosidase-1 deficiency, GLB1 deficiency, Landing disease
Synonyms: Beta-galactosidase-1 deficiency, GLB1 deficiency, Landing disease
Drug discovery
11
drugs
With orphan designations
Overview
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by GLB1 gene mutations, resulting in deficient β-galactosidase activity and toxic accumulation of GM1 ganglioside in neurons. It is classified into infantile (type I, severe, <6 months onset), juvenile (type II, 18 months–5 years), and adult (type III, mildest, teenage onset) forms. Key features include neurodegeneration, developmental regression, seizures, hepatosplenomegaly, skeletal dysplasia, and cherry-red maculae. Life expectancy correlates with disease severity, ranging from <3 years in type I to variable survival in type III [1][4][7][9].
Categories: rare bone diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
181 drug discovery papers about GM1 gangliosidosis, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
181 drug discovery papers about GM1 gangliosidosis, 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
cell therapies
2024-09-20 | Generation of an infantile GM1 gangliosidosis induced pluripotent stem cell line (CHOCi005-A) for disease modeling and therapeutic testing.
GM1 gangliosidosis (GM1) is a rare autosomal recessive neurogenerative lysosomal storage disease characterized by deficiency of beta-galactosidase (β-gal) and intralysosomal accumulation of GM1 ganglioside and other glycoconjugates. Resources for GM1 disease modelling are limited, and access to relevant cell lines from human patients is not possible. Generation of iPSC lines from GM1 patient-derived dermal fibroblasts allows for disease modelling and therapeutic testing in 2D and 3D cell culture models relevant to CNS disorders, including various neuronal subtypes and cerebral organoids. The iPSC line described here will be critical to therapeutic development and set the foundation for translational gene therapy work.
2023-11-23 | Lysosomal storage diseases. Sphingolipidoses — gangliosidoses
Epidemiology, clinical, biochemical and molecular genetic characteristics of gangliosidoses, genetically heterogeneous group of autosomal recessive diseases caused by hereditary deficiency of lysosomal glycohydrolases involved in the catabolism of GM1-, GM2- and GA2-gangliosides, are presented. Three clinical forms of GM1 gangliosidosis are caused by hereditary deficiency of lysosomal β-galactosidase, one of the activities of which is the release of galactose from carbohydrate complexes. As a result, GM1-ganglioside and, to a lesser extent, keratan sulfate accumulate in the lysosomes of neurons and other cells. Three genetically heterogeneous forms of GM2-gangliosidosis are associated with dysfunction of hexosaminidase activity. Tay–Sachs disease, or GM2 ganglioside variant B, is caused by mutations in the hexosaminidase alpha chain HEXA gene. Sandhoff’s disease is associated with mutations in the HEXB gene for the hexosaminidase beta chain. In this case, there is a deficiency of the A and B components of the enzyme — the null variant of GM2 gangliosidosis. In variant AB, or juvenile GM2 gangliosidosis, all hexosaminidase components are present, but the activating factor is defective due to mutations in the GM2A gene. All types of gangliosidosis are characterized by progressive retardation of psychomotor development and early death of patients, most often under the age of 3 years. The frequency of various types of gangliosidoses in different populations does not exceed 1 : 300,000. An exception is the ethic group of Ashkenazi Jews, in which the incidence of Tay–Sachs disease, reaches 1 : 3000, which makes total screening of heterozygotes and prenatal diagnosis of the disease in high-risk families economically justified. The article highlights the importance of experimental models for studying the molecular basis of pathogenesis and developing various therapeutic approaches, such as bone marrow transplantation, enzyme replacement therapy and substrate reducing therapy, gene therapy, and genome editing. Clinical examples of patients with gangliosidosis are given to improve the efficiency of diagnostics of these rare diseases by clinicians.
2009-01-02 | Intracerebral cell transplantation therapy for murine GM1 gangliosidosis
We performed a cell transplantation study to treat the brain involvement in lysosomal storage diseases. We used acid beta-galactosidase knock-out mice (BKO) from C57BL/6 as recipients. To minimize immune responses, we used cells derived from transgenic mice of C57BL/6 overexpressing the normal human beta-galactosidase. Fetal brain cells (FBC), bone marrow-derived mesenchymal stem cells (MSC), and mixed FBC and MSC cells were prepared and injected into the ventricle of newborn BKO mouse brain. The mice were examined at 1, 2, 4, and 8 weeks and 6 months after injection. In each experiment, the injected cells migrated into the whole brain effectively and survived for at least 8 weeks. Decrease in ganglioside GM1 level was also observed. FBC could survive for 6 months in recipient brain. However, the number of transplanted FBC decreased. In the brains of MSC- or mixed cell-treated mice, no grafted cells could be found at 6 months. To achieve sufficient long-term effects on the brain, a method of steering the immune response away from cytotoxic responses or of inducing tolerance to the products of therapeutic genes must be developed.
2006-01-01 | 408. Safety of Lysosomal Enzymes Over-Expression in HSC for Gene Therapy of Storage Disorders
In the past years we worked extensively on the development of HSC gene therapy for two fatal demyelinating lysosomal storage disorders, Metachromatic (MLD) and Globoid Cell (GLD) leukodystrophies. We recently demonstrated that transplantation of lentiviral vector-transduced Hematopoietic Stem Cells (HSC) prevented and corrected functional and pathological manifestations of MLD in the mouse model (Biffi A. et al., JCI 2004; Biffi A. et al, submitted for publication). Moreover, we proved the critical role of Arylsulfatase A (ARSA) over-expression to attain therapeutic efficacy. Similarly, promising preliminary results were obtained in the murine model of GLD. ARSA and galactocerebrosidase (GALC), the defective enzymes in MLD and GLD, respectively, catalyze two consecutive steps of sulfatide metabolism, leading to ceramide production. Both enzymes are poorly expressed in most tissues. In the perspective of future clinical applications of the HSC gene therapy, we assessed the safety of ARSA and GALC over-expression. We challenged murine and human HSC with LV encoding ARSA or GALC and tested their long-term repopulating potential and differentiation. Both human and murine HSC after gene transfer over-expressed ARSA up to 10-15 fold above normal levels and retained their capability to proliferate and differentiate in vitro, as assessed by CFC and LT-CIC assays. Murine cells efficiently repopulated transplanted hosts long-term. Interestingly, when transplanted in xenograft models (NOD-SCID and γchain-/-RAG-/- mice), human CD34+ HSC over-expressing ARSA repopulated long-term chimeric mice, both primary and secondary recipients, in which transduced cells were detected up to 20 weeks after the transplant, and showed a normal differentiation in B, T cells and monocytes. On the contrary, when GALC over-expressing murine HSC were transplanted into both wild type and homozygous defective irradiated mice, they failed to rescue transplanted animals from lethal conditioning. Transduced cells demonstrated a significantly reduced capability to proliferate and differentiate in vitro, as assessed by CFC assay, and underwent apoptosis, as assessed by TUNEL and activated caspase III stainings. Interestingly, these findings were completely reverted upon treatment of transduced cells with anti-apoptotic molecules, such as IGF1. Preliminary quantification of ceramide in both ARSA and GALC transduced HSC demonstrated an increase only upon GALC over-expression, indicating the critical role of this enzyme in controlling ceramide production and intracellular homeostasis. Overall, these data underline the safety of ARSA over-expression for future clinical testing and the requirement of regulated GALC expression for efficacious and safe HSC gene therapy, thus indicating a dramatic difference in the safety profile of these lysosomal enzymes.
2005-11-28 | Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology.
Bone marrow cells (BMCs) could correct some pathologic conditions of the central nervous system (CNS) if these cells would effectively repopulate the brain. One such condition is G(M1)-gangliosidosis, a neurodegenerative glycosphingolipidosis due to deficiency of lysosomal beta-galactosidase (beta-gal). In this disease, abnormal build up of G(M1)-ganglioside in the endoplasmic reticulum of brain cells results in calcium imbalance, induction of an unfolded protein response (UPR), and neuronal apoptosis. These processes are accompanied by the activation/proliferation of microglia and the production of inflammatory cytokines. Here we demonstrate that local neuroinflammation promotes the selective activation of chemokines, such as stromal-cell-derived factor 1 (SDF-1), macrophage inflammatory protein 1-alpha (MIP-1alpha), and MIP-1beta, which chemoattract genetically modified BMCs into the CNS. Mice that underwent bone marrow transplantation showed increased beta-gal activity in different brain regions and reduced lysosomal storage. Decreased production of chemokines and effectors of the UPR as well as restoration of neurologic functions accompanied this phenotypic reversion. Our results suggest that beta-gal-expressing bone marrow (BM)-derived cells selectively migrate to the CNS under a gradient of chemokines and become a source of correcting enzyme to deficient neurons. Thus, a disease condition such as G(M1)-gangliosidosis, which is characterized by neurodegeneration and neuroinflammation, may influence the response of the CNS to ex vivo gene therapy.
proteins
2023-10-21 | Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 gangliosidosis
GM1 gangliosidosis is a neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes lysosomal β-galactosidase. The enzyme deficiency blocks GM1 ganglioside catabolism, leading to accumulation of GM1 ganglioside and asialo-GM1 ganglioside (GA1 glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residual β-galactosidase activity primarily determining the clinical course. Glb1 null mouse models, which completely lack β-galactosidase expression, exhibit a less severe form of the disease than expected from the comparable deficiency in humans, suggesting a potential species difference in the GM1 ganglioside degradation pathway. We hypothesized this difference may involve the sialidase NEU3, which acts on GM1 ganglioside to produce GA1 glycolipid. To test this hypothesis, we generated Glb1/Neu3 double KO (DKO) mice. These mice had a significantly shorter lifespan, increased neurodegeneration, and more severe ataxia than Glb1 KO mice. Glb1/Neu3 DKO mouse brains exhibited an increased GM1 ganglioside to GA1 glycolipid ratio compared with Glb1 KO mice, indicating that NEU3 mediated GM1 ganglioside to GA1 glycolipid conversion in Glb1 KO mice. The expression of genes associated with neuroinflammation and glial responses were enhanced in Glb1/Neu3 DKO mice compared with Glb1 KO mice. Mouse NEU3 more efficiently converted GM1 ganglioside to GA1 glycolipid than human NEU3 did. Our findings highlight NEU3’s role in ameliorating the consequences of Glb1 deletion in mice, provide insights into NEU3’s differential effects between mice and humans in GM1 gangliosidosis, and offer a potential therapeutic approach for reducing toxic GM1 ganglioside accumulation in GM1 gangliosidosis patients.
2022-08-29 | Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis.
GM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase (β-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis present with massive and progressive accumulation of GM1 in the central nervous system (CNS), which leads to mental and motor decline, progressive neurodegeneration, and early death. No therapy is currently available for this lysosomal storage disease. Here, we describe a proof-of-concept preclinical study toward the development of enzyme replacement therapy (ERT) for GM1-gangliosidosis using a recombinant murine β-Gal fused to the plant lectin subunit B of ricin (mβ-Gal:RTB). We show that long-term, bi-weekly systemic injection of mβ-Gal:RTB in the β-Gal-/- mouse model resulted in widespread internalization of the enzyme by cells of visceral organs, with consequent restoration of enzyme activity. Most importantly, β-Gal activity was detected in several brain regions. This was accompanied by a reduction of accumulated GM1, reversal of neuroinflammation, and decrease in the apoptotic marker caspase 3. These results indicate that the RTB lectin delivery module enhances both the CNS-biodistribution pattern and the therapeutic efficacy of the β-Gal ERT, with the potential to translate to a clinical setting for the treatment of GM1-gangliosidosis.
2021-02-05 | Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice.
Autosomal recessive mutations in the galactosidase β1 (GLB1) gene cause lysosomal β-gal deficiency, resulting in accumulation of galactose-containing substrates and onset of the progressive and fatal neurodegenerative lysosomal storage disease, GM1 gangliosidosis. Here, an enzyme replacement therapy (ERT) approach in fibroblasts from GM1 gangliosidosis patients with recombinant human β-gal (rhβ-gal) produced in Chinese hamster ovary cells enabled direct and precise rhβ-gal delivery to acidified lysosomes. A single, low dose (3 nm) of rhβ-gal was sufficient for normalizing β-gal activity and mediating substrate clearance for several weeks. We found that rhβ-gal uptake by the fibroblasts is dose-dependent and saturable and can be competitively inhibited by mannose 6-phosphate, suggesting cation-independent, mannose 6-phosphate receptor-mediated endocytosis from the cell surface. A single intracerebroventricularly (ICV) administered dose of rhβ-gal (100 μg) resulted in broad bilateral biodistribution of rhβ-gal to critical regions of pathology in a mouse model of GM1 gangliosidosis. Weekly ICV dosing of rhβ-gal for 8 weeks substantially reduced brain levels of ganglioside and oligosaccharide substrates and reversed well-established secondary neuropathology. Of note, unlike with the ERT approach, chronic lentivirus-mediated GLB1 overexpression in the GM1 gangliosidosis patient fibroblasts caused accumulation of a prelysosomal pool of β-gal, resulting in activation of the unfolded protein response and endoplasmic reticulum stress. This outcome was unsurprising in light of our in vitro biophysical findings for rhβ-gal, which include pH-dependent and concentration-dependent stability and dynamic self-association. Collectively, our results highlight that ICV-ERT is an effective therapeutic intervention for managing GM1 gangliosidosis potentially more safely than with gene therapy approaches.
2021-02-03 | Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency.
Mutations in the galactosidase β 1 (GLB1) gene cause lysosomal β-galactosidase (β-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. β-Gal and neuraminidase 1 (NEU1) form a multienzyme complex in lysosomes along with the molecular chaperone, protective protein cathepsin A (PPCA). NEU1 is deficient in the neurodegenerative lysosomal storage disease sialidosis, and its targeting to and stability in lysosomes strictly depend on PPCA. In contrast, β-Gal only partially depends on PPCA, prompting us to investigate the role that β-Gal plays in the multienzyme complex. Here, we demonstrate that β-Gal negatively regulates NEU1 levels in lysosomes by competitively displacing this labile sialidase from PPCA. Chronic cellular uptake of purified recombinant human β-Gal (rhβ-Gal) or chronic lentiviral-mediated GLB1 overexpression in GM1 gangliosidosis patient fibroblasts coincides with profound secondary NEU1 deficiency. A regimen of intermittent enzyme replacement therapy dosing with rhβ-Gal, followed by enzyme withdrawal, is sufficient to augment β-Gal activity levels in GM1 gangliosidosis patient fibroblasts without promoting NEU1 deficiency. In the absence of β-Gal, NEU1 levels are elevated in the GM1 gangliosidosis mouse brain, which are restored to normal levels following weekly intracerebroventricular dosing with rhβ-Gal. Collectively, our results highlight the need to carefully titrate the dose and dosing frequency of β-Gal augmentation therapy for GM1 gangliosidosis. They further suggest that intermittent intracerebroventricular enzyme replacement therapy dosing with rhβ-Gal is a tunable approach that can safely augment β-Gal levels while maintaining NEU1 at physiological levels in the GM1 gangliosidosis brain.
2020-02-01 | Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery
The greatest challenges for therapeutic efficacy of many macromolecular drugs that act on intracellular are delivery to key organs and tissues and delivery into cells and subcellular compartments. Transport of drugs into critical cells associated with disease, including those in organs protected by restrictive biological barriers such as central nervous system (CNS), bone, and eye remains a significant hurdle to drug efficacy and impacts commercial risk and incentives for drug development for many diseases. These limitations expose a significant need for the development of novel strategies for macromolecule delivery. RTB lectin is the non-toxic carbohydrate-binding subunit B of ricin toxin with high affinity for galactose/galactosamine-containing glycolipids and glycoproteins common on human cell surfaces. RTB mediates endocytic uptake into mammalian cells by multiple routes exploiting both adsorptive-mediated and receptor-mediated mechanisms. In vivo biodistribution studies in lysosomal storage disease models provide evidence for the theory that the RTB-lectin transports corrective doses of enzymes across the blood-brain barrier to treat CNS pathologies. These results encompass significant implications for protein-based therapeutic approaches to address lysosomal and other diseases having strong CNS involvement.
small molecules
2026-06-26 | Infantile GM1 Gangliosidosis with Epilepsy Associated with a Same-Codon GLB1 Variant (c.808T>G/c.808T>C).
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by a deficiency of β-galactosidase due to pathogenic variants in the GLB1 gene. Almost 300 pathogenic or likely pathogenic variants have been identified, associated with a phenotypic spectrum ranging from GM1 gangliosidosis to mucopolysaccharidosis type IVB. Disease severity is largely determined by the extent to which specific variants impair enzymatic catalytic activity, particularly through disruption of substrate recognition and binding within the active site. We report a patient with GM1 gangliosidosis type I harboring two pathogenic missense variants, c.808T>G (p.Tyr270Asp) and c.808T>C (p.Tyr270His), in a compound heterozygous state. To the best of our knowledge, this specific allelic combination has not been previously described. Both variants affect the same codon, resulting in distinct amino acid substitutions at position 270, a residue critically involved in maintaining the structural and functional integrity of the catalytic domain of β-galactosidase. Disruption at this site is expected to severely compromise enzymatic activity. Comparative analysis with previously reported cases carrying variants at the same residue, in either homozygous or compound heterozygous states, demonstrates a possible consistent association with the infantile form of GM1 gangliosidosis, characterized by a rapidly progressive neurodegenerative course and multisystem involvement. Collectively, these findings provide additional support for the hypothesis that codon 270 can be regarded as a critical functional hotspot within GLB1, where even distinct amino acid substitutions can result in profound enzymatic dysfunction and a severe early-onset phenotype.
2026-06-08 | Identification of novel compound heterozygous mutations in the GLB1 gene by whole-exome sequencing in a case of infantile GM1 gangliosidosis: a case report.
GM1 gangliosidosis was a rare, fatal autosomal recessive lysosomal storage disorder caused by biallelic mutations in the GLB1 gene. Whole-exome sequencing (WES) was increasingly utilized to identify novel pathogenic variants in the GLB1 gene among undiagnosed pediatric cases. We reported a 9-month-old male infant with developmental delay, hepatomegaly, extensive Mongolian spots, and hypotonia. WES identified two novel compound heterozygous GLB1 variants: a paternal c.792 + 1G > A splice-site mutation and a maternal c.1572_1573insC(p.Gly525Argfs*7) frameshift mutation. Both were classified as pathogenic by ACMG guidelines. β-galactosidase activity was markedly deficient, confirming the diagnosis. The family received genetic counseling and opted for prenatal diagnosis in a subsequent pregnancy. At age 2 years, the patient exhibited an inability to speak or walk and had a history of recurrent severe pneumonia requiring multiple hospitalizations, with his overall condition currently managed supportively. Two novel pathogenic GLB1 mutations expanded the mutational spectrum of infantile GM1 gangliosidosis. WES with enzymatic validation enabled precise diagnosis, genetic counseling, and prenatal management. The development of targeted therapies remained imperative to alter the disease's natural course.
2026-03-28 | Impact of Sinbaglustat on Neurons of the Medial Nucleus of the Trapezoid Body in a Murine Model of Human GM1-Gangliosidosis.
Background: GM1-gangliosidosis (GM1) is a lysosomal storage disorder caused by mutations in the Glb1 gene, resulting in reduced β-galactosidase activity and accumulation of GM1 gangliosides in neuronal lysosomes. Effective therapeutic strategies for this disease remain limited. Substrate reduction therapy using small molecules targeting glucosylceramide synthase (GCS) and non-lysosomal glucosylceramidase (GBA2), such as sinbaglustat, represents a promising approach. Methods: Structural and electrophysiological properties of principal neurons of the medial nucleus of the trapezoid body (MNTB) were investigated in 7-month-old Glb1-/- mice. Animals received long-term treatment with either low (LD; 10 mg/kg) or high (HD; 300 mg/kg) doses of sinbaglustat and were compared with untreated Glb1-/- (KO) and untreated wild-type (WT) mice. Results: Sinbaglustat treatment reduced lysosomal storage material in MNTB neurons. Basal membrane properties were largely unchanged across groups. However, action potential halfwidth was significantly increased in untreated KO and LD mice compared to untreated WT animals but was normalized in HD mice. After-hyperpolarization duration was prolonged in Glb1-/- mice relative to WT. Temporal precision during high-frequency stimulation was reduced in untreated KO mice and improved following sinbaglustat treatment. Conclusions: These findings indicate that GM1-gangliosidosis is associated with functional alterations in MNTB neurons and suggest that long-term sinbaglustat treatment can partially restore neuronal electrophysiological properties, supporting its therapeutic potential in GM1.
2025-07-29 | β-Galactosidase inhibition explored by biochemical methods and in silico studies for plant polyphenols.
β-Galactosidase is a lysosomal enzyme whose deficiency is associated with genetic disorders such as GM1 gangliosidosis, prompting the search for novel enzyme modulators with therapeutic potential. The current study evaluated the inhibitory potential of selected natural polyphenols against β-galactosidase using a combined approach of biochemical assays and computational modeling. Sixteen plant-derived compounds were initially screened through molecular docking against Aspergillus oryzae β-galactosidase. Among these, hesperidin, rutin, and chlorogenic acid exhibited the most favorable interactions and were subsequently assessed through in vitro enzyme inhibition assays and MM/GBSA binding energy calculations. These compounds showed potential inhibitory effects and stable binding within the enzyme's active site. Although classical pharmacological chaperone activity was not directly demonstrated, the observed modulation of enzyme function suggests potential for further development of these polyphenols as structurally distinct β-galactosidase inhibitors. The findings provide a basis for future investigations aimed at natural product-based strategies to manage lysosomal storage disorders such as GM1 gangliosidosis.
2025-04-19 | Sinbaglustat ameliorates disease pathology in a murine model of GM1 gangliosidosis without affecting CNS ganglioside levels.
Sinbaglustat is a brain-penetrating small molecule that inhibits the non-lysosomal glucocerebrosidase (GBA2) and, with lower potency, glucosylceramide synthase (GCS). Sinbaglustat has passed clinical phase I. Our preclinical study assessed its efficacy in a transgenic mouse model of GM1 gangliosidosis, lacking a functional β-galactosidase enzyme (Glb1-/-). Starting at 4 weeks of age, mice were either treated with a nominal dose of 10 or 300 mg/kg/day of sinbaglustat or remained untreated. Wild-type (WT) mice served as control. Body weight, clinical and neurological signs, and motor function was assessed until 17-18 weeks (4 months) and 30 weeks (7 months) of age when mice were euthanized for ex vivo assessments. In comparison to WT, Glb1-/- mice showed the expected accumulation of GM1 gangliosidosis-related sphingolipids, neuropathology, and behavioral deficits. Both dosages of sinbaglustat left GM1 and lyso GM1 levels in the brain unaffected but delayed the onset of motor impairment and progression of clinical disease in Glb1-/- mice with the higher dose being more efficacious. Histologically and immunohistochemically, both treatment groups of Glb1-/- mice displayed reduced neuronal vacuolation. Only the higher dose of sinbaglustat decreased axonal damage and astrogliosis, which was also associated with a decrease of the axonal/neuronal damage marker plasma neurofilament light at 4 months (17-18 weeks). Both doses of sinbaglustat increased the GBA2 substrate glucosylceramide (GluCer) in the brain, while only the high dose reduced GluCer and other glycosphingolipids (GSLs) in the periphery indicating additional inhibition of GCS. We conclude that sinbaglustat had a therapeutic-like effect in the GM1 gangliosidosis mouse model.
gene therapies
2025-09-16 | MRI brain volumetric analysis of type II GM1 gangliosidosis patients treated with gene therapy
Motivation: Type II GM1 gangliosidosis is a rare disease that lacks reliable quantitative neural biomarkers to monitor disease progression. Goal(s): With the advent of gene therapy in treating GM1, we sought to quantify volumetrics of different brain regions known to be affected in GM1 patients. Approach: We quantified and tracked brain volumetric changes longitudinally on specific brain structures at different timepoints using MRI to evaluate disease progression/regression in GM1 patients treated with gene therapy and compared them to untreated patients and healthy controls. Results: We demonstrated the utility of brain volumetrics in assessing longitudinal brain region changes in gene therapy treated GM1 patients. Impact: Our study addressed the need for quantitative neural biomarkers in type II GM1 gangliosidosis which correlated with clinical markers. Through longitudinal brain volumetric analysis using MRI, we demonstrated the efficacy of gene therapy in monitoring disease progression/regression in GM1 patients.
2024-11-26 | Diffusion tensor imaging quantification of brain matter tracts in gene therapy treated GM1 gangliosidosis patients
Motivation: Type II GM1 gangliosidosis is a rare disease that lacks reliable quantitative biomarkers to assess neuronal health. Goal(s): We sought to quantify diffusion tensor imaging (DTI) parameters of different brain regions known to be affected in GM1 to track neuronal changes especially with the advent of gene therapy in treating GM1. Approach: We quantified fractional anisotropy and radial diffusivity changes at different timepoints using DTI-MRI to evaluate myelination changes in GM1 patients treated with gene therapy and compared them to untreated patients and healthy controls. Results: DTI can be used to demonstrate efficacy of gene therapy in monitoring disease progression/regression in GM1 patients. Impact: This study addressed the need for reliable biomarkers in assessing neuronal health in type II GM1 gangliosidosis. Using DTI parameters, we demonstrated the efficacy of gene therapy in reliably monitoring myelination changes in GM1 patients.
2024-09-20 | Base editing of the GLB1 gene is therapeutic in GM1 gangliosidosis patient-derived cells.
GM1 gangliosidosis is an autosomal recessive neurodegenerative lysosomal storage disease caused by pathogenic variants in the GLB1 gene, limiting the production of active lysosomal β-galactosidase. Phenotypic heterogeneity is due in part to variant type, location within GLB1, and the amount of residual enzyme activity; in the most severe form, death occurs in infancy. With no FDA approved therapeutics, development of efficacious strategies for the disease is pivotal. CRISPR/Cas based approaches have revolutionized precision medicine and have been indispensable to the development of treatments for several monogenic disorders with bespoke strategies central to current research pipelines. We used CRISPR/Cas-adenine base editing to correct the GLB1 c.380G>A (p.Cys127Tyr) variant in patient-derived dermal fibroblasts compound heterozygous with the GLB1 c.481T>G (p.Trp161Gly) pathogenic variant. Nucleofection of plasmids encoding the target sgRNA and ABEmax restored the canonical guanine (32.2 ± 2.2 % of the target allele) and synthesis of active β-galactosidase. Analysis of cellular markers of pathology revealed normalization of both primary glycoconjugate storage and lysosomal pathology. Furthermore, analysis of off-target sites nominated by the in silico tools Cas-OFFinder and/or CRISTA revealed no significant editing or indels. This study supports the use of CRISPR/Cas-based approaches for the treatment of GM1 gangliosidosis, and provides foundational data for future translational studies.
2024-08-31 | Establishment of iPS cell line (SDQLCHi080-A) from a patient with GM1 gangliosidosis due to GLB1 mutation.
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by defects in the beta-galactosidase (GLB1) gene, which results in accumulation of GM1 gangliosides and related glycoconjugates in the lysosomes leading to lysosomal swelling, cellular damage, and organ dysfunction. We generated SDQLCHi080-A cell line from a patient with GM1 gangliosidosis carrying mutations of c.523C > T and c.574T > C > T in the GLB1 gene. The cell line exhibited typical iPSC morphology, expressed high levels of stemness markers, exhibited normal karyotype, and has the capability to differentiate into three germ layers. This cell line could provide a useful GM1 gangliosidosis model in vitro for further study.
2024-04-26 | Therapeutic developments for neurodegenerative GM1 gangliosidosis
GM1 gangliosidosis (GM1) is a rare but fatal neurodegenerative disease caused by dysfunction or lack of production of lysosomal enzyme, β-galactosidase, leading to accumulation of substrates. The most promising treatments for GM1, include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), stem cell therapy and gene editing. However, effectiveness is limited for neuropathic GM1 due to the restrictive nature of the blood-brain barrier (BBB). ERT and SRT alleviate substrate accumulation through exogenous supplementation over the patient's lifetime, while gene editing could be curative, fixing the causative gene,
cell therapies
2024-09-20 | Generation of an infantile GM1 gangliosidosis induced pluripotent stem cell line (CHOCi005-A) for disease modeling and therapeutic testing.
GM1 gangliosidosis (GM1) is a rare autosomal recessive neurogenerative lysosomal storage disease characterized by deficiency of beta-galactosidase (β-gal) and intralysosomal accumulation of GM1 ganglioside and other glycoconjugates. Resources for GM1 disease modelling are limited, and access to relevant cell lines from human patients is not possible. Generation of iPSC lines from GM1 patient-derived dermal fibroblasts allows for disease modelling and therapeutic testing in 2D and 3D cell culture models relevant to CNS disorders, including various neuronal subtypes and cerebral organoids. The iPSC line described here will be critical to therapeutic development and set the foundation for translational gene therapy work.
2023-11-23 | Lysosomal storage diseases. Sphingolipidoses — gangliosidoses
Epidemiology, clinical, biochemical and molecular genetic characteristics of gangliosidoses, genetically heterogeneous group of autosomal recessive diseases caused by hereditary deficiency of lysosomal glycohydrolases involved in the catabolism of GM1-, GM2- and GA2-gangliosides, are presented. Three clinical forms of GM1 gangliosidosis are caused by hereditary deficiency of lysosomal β-galactosidase, one of the activities of which is the release of galactose from carbohydrate complexes. As a result, GM1-ganglioside and, to a lesser extent, keratan sulfate accumulate in the lysosomes of neurons and other cells. Three genetically heterogeneous forms of GM2-gangliosidosis are associated with dysfunction of hexosaminidase activity. Tay–Sachs disease, or GM2 ganglioside variant B, is caused by mutations in the hexosaminidase alpha chain HEXA gene. Sandhoff’s disease is associated with mutations in the HEXB gene for the hexosaminidase beta chain. In this case, there is a deficiency of the A and B components of the enzyme — the null variant of GM2 gangliosidosis. In variant AB, or juvenile GM2 gangliosidosis, all hexosaminidase components are present, but the activating factor is defective due to mutations in the GM2A gene. All types of gangliosidosis are characterized by progressive retardation of psychomotor development and early death of patients, most often under the age of 3 years. The frequency of various types of gangliosidoses in different populations does not exceed 1 : 300,000. An exception is the ethic group of Ashkenazi Jews, in which the incidence of Tay–Sachs disease, reaches 1 : 3000, which makes total screening of heterozygotes and prenatal diagnosis of the disease in high-risk families economically justified. The article highlights the importance of experimental models for studying the molecular basis of pathogenesis and developing various therapeutic approaches, such as bone marrow transplantation, enzyme replacement therapy and substrate reducing therapy, gene therapy, and genome editing. Clinical examples of patients with gangliosidosis are given to improve the efficiency of diagnostics of these rare diseases by clinicians.
2009-01-02 | Intracerebral cell transplantation therapy for murine GM1 gangliosidosis
We performed a cell transplantation study to treat the brain involvement in lysosomal storage diseases. We used acid beta-galactosidase knock-out mice (BKO) from C57BL/6 as recipients. To minimize immune responses, we used cells derived from transgenic mice of C57BL/6 overexpressing the normal human beta-galactosidase. Fetal brain cells (FBC), bone marrow-derived mesenchymal stem cells (MSC), and mixed FBC and MSC cells were prepared and injected into the ventricle of newborn BKO mouse brain. The mice were examined at 1, 2, 4, and 8 weeks and 6 months after injection. In each experiment, the injected cells migrated into the whole brain effectively and survived for at least 8 weeks. Decrease in ganglioside GM1 level was also observed. FBC could survive for 6 months in recipient brain. However, the number of transplanted FBC decreased. In the brains of MSC- or mixed cell-treated mice, no grafted cells could be found at 6 months. To achieve sufficient long-term effects on the brain, a method of steering the immune response away from cytotoxic responses or of inducing tolerance to the products of therapeutic genes must be developed.
2006-01-01 | 408. Safety of Lysosomal Enzymes Over-Expression in HSC for Gene Therapy of Storage Disorders
In the past years we worked extensively on the development of HSC gene therapy for two fatal demyelinating lysosomal storage disorders, Metachromatic (MLD) and Globoid Cell (GLD) leukodystrophies. We recently demonstrated that transplantation of lentiviral vector-transduced Hematopoietic Stem Cells (HSC) prevented and corrected functional and pathological manifestations of MLD in the mouse model (Biffi A. et al., JCI 2004; Biffi A. et al, submitted for publication). Moreover, we proved the critical role of Arylsulfatase A (ARSA) over-expression to attain therapeutic efficacy. Similarly, promising preliminary results were obtained in the murine model of GLD. ARSA and galactocerebrosidase (GALC), the defective enzymes in MLD and GLD, respectively, catalyze two consecutive steps of sulfatide metabolism, leading to ceramide production. Both enzymes are poorly expressed in most tissues. In the perspective of future clinical applications of the HSC gene therapy, we assessed the safety of ARSA and GALC over-expression. We challenged murine and human HSC with LV encoding ARSA or GALC and tested their long-term repopulating potential and differentiation. Both human and murine HSC after gene transfer over-expressed ARSA up to 10-15 fold above normal levels and retained their capability to proliferate and differentiate in vitro, as assessed by CFC and LT-CIC assays. Murine cells efficiently repopulated transplanted hosts long-term. Interestingly, when transplanted in xenograft models (NOD-SCID and γchain-/-RAG-/- mice), human CD34+ HSC over-expressing ARSA repopulated long-term chimeric mice, both primary and secondary recipients, in which transduced cells were detected up to 20 weeks after the transplant, and showed a normal differentiation in B, T cells and monocytes. On the contrary, when GALC over-expressing murine HSC were transplanted into both wild type and homozygous defective irradiated mice, they failed to rescue transplanted animals from lethal conditioning. Transduced cells demonstrated a significantly reduced capability to proliferate and differentiate in vitro, as assessed by CFC assay, and underwent apoptosis, as assessed by TUNEL and activated caspase III stainings. Interestingly, these findings were completely reverted upon treatment of transduced cells with anti-apoptotic molecules, such as IGF1. Preliminary quantification of ceramide in both ARSA and GALC transduced HSC demonstrated an increase only upon GALC over-expression, indicating the critical role of this enzyme in controlling ceramide production and intracellular homeostasis. Overall, these data underline the safety of ARSA over-expression for future clinical testing and the requirement of regulated GALC expression for efficacious and safe HSC gene therapy, thus indicating a dramatic difference in the safety profile of these lysosomal enzymes.
2005-11-28 | Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology.
Bone marrow cells (BMCs) could correct some pathologic conditions of the central nervous system (CNS) if these cells would effectively repopulate the brain. One such condition is G(M1)-gangliosidosis, a neurodegenerative glycosphingolipidosis due to deficiency of lysosomal beta-galactosidase (beta-gal). In this disease, abnormal build up of G(M1)-ganglioside in the endoplasmic reticulum of brain cells results in calcium imbalance, induction of an unfolded protein response (UPR), and neuronal apoptosis. These processes are accompanied by the activation/proliferation of microglia and the production of inflammatory cytokines. Here we demonstrate that local neuroinflammation promotes the selective activation of chemokines, such as stromal-cell-derived factor 1 (SDF-1), macrophage inflammatory protein 1-alpha (MIP-1alpha), and MIP-1beta, which chemoattract genetically modified BMCs into the CNS. Mice that underwent bone marrow transplantation showed increased beta-gal activity in different brain regions and reduced lysosomal storage. Decreased production of chemokines and effectors of the UPR as well as restoration of neurologic functions accompanied this phenotypic reversion. Our results suggest that beta-gal-expressing bone marrow (BM)-derived cells selectively migrate to the CNS under a gradient of chemokines and become a source of correcting enzyme to deficient neurons. Thus, a disease condition such as G(M1)-gangliosidosis, which is characterized by neurodegeneration and neuroinflammation, may influence the response of the CNS to ex vivo gene therapy.
proteins
2023-10-21 | Sialidase NEU3 action on GM1 ganglioside is neuroprotective in GM1 gangliosidosis
GM1 gangliosidosis is a neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes lysosomal β-galactosidase. The enzyme deficiency blocks GM1 ganglioside catabolism, leading to accumulation of GM1 ganglioside and asialo-GM1 ganglioside (GA1 glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residual β-galactosidase activity primarily determining the clinical course. Glb1 null mouse models, which completely lack β-galactosidase expression, exhibit a less severe form of the disease than expected from the comparable deficiency in humans, suggesting a potential species difference in the GM1 ganglioside degradation pathway. We hypothesized this difference may involve the sialidase NEU3, which acts on GM1 ganglioside to produce GA1 glycolipid. To test this hypothesis, we generated Glb1/Neu3 double KO (DKO) mice. These mice had a significantly shorter lifespan, increased neurodegeneration, and more severe ataxia than Glb1 KO mice. Glb1/Neu3 DKO mouse brains exhibited an increased GM1 ganglioside to GA1 glycolipid ratio compared with Glb1 KO mice, indicating that NEU3 mediated GM1 ganglioside to GA1 glycolipid conversion in Glb1 KO mice. The expression of genes associated with neuroinflammation and glial responses were enhanced in Glb1/Neu3 DKO mice compared with Glb1 KO mice. Mouse NEU3 more efficiently converted GM1 ganglioside to GA1 glycolipid than human NEU3 did. Our findings highlight NEU3’s role in ameliorating the consequences of Glb1 deletion in mice, provide insights into NEU3’s differential effects between mice and humans in GM1 gangliosidosis, and offer a potential therapeutic approach for reducing toxic GM1 ganglioside accumulation in GM1 gangliosidosis patients.
2022-08-29 | Preclinical Enzyme Replacement Therapy with a Recombinant β-Galactosidase-Lectin Fusion for CNS Delivery and Treatment of GM1-Gangliosidosis.
GM1-gangliosidosis is a catastrophic, neurodegenerative lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase (β-Gal). The primary substrate of the enzyme is GM1-ganglioside (GM1), a sialylated glycosphingolipid abundant in nervous tissue. Patients with GM1-gangliosidosis present with massive and progressive accumulation of GM1 in the central nervous system (CNS), which leads to mental and motor decline, progressive neurodegeneration, and early death. No therapy is currently available for this lysosomal storage disease. Here, we describe a proof-of-concept preclinical study toward the development of enzyme replacement therapy (ERT) for GM1-gangliosidosis using a recombinant murine β-Gal fused to the plant lectin subunit B of ricin (mβ-Gal:RTB). We show that long-term, bi-weekly systemic injection of mβ-Gal:RTB in the β-Gal-/- mouse model resulted in widespread internalization of the enzyme by cells of visceral organs, with consequent restoration of enzyme activity. Most importantly, β-Gal activity was detected in several brain regions. This was accompanied by a reduction of accumulated GM1, reversal of neuroinflammation, and decrease in the apoptotic marker caspase 3. These results indicate that the RTB lectin delivery module enhances both the CNS-biodistribution pattern and the therapeutic efficacy of the β-Gal ERT, with the potential to translate to a clinical setting for the treatment of GM1-gangliosidosis.
2021-02-05 | Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice.
Autosomal recessive mutations in the galactosidase β1 (GLB1) gene cause lysosomal β-gal deficiency, resulting in accumulation of galactose-containing substrates and onset of the progressive and fatal neurodegenerative lysosomal storage disease, GM1 gangliosidosis. Here, an enzyme replacement therapy (ERT) approach in fibroblasts from GM1 gangliosidosis patients with recombinant human β-gal (rhβ-gal) produced in Chinese hamster ovary cells enabled direct and precise rhβ-gal delivery to acidified lysosomes. A single, low dose (3 nm) of rhβ-gal was sufficient for normalizing β-gal activity and mediating substrate clearance for several weeks. We found that rhβ-gal uptake by the fibroblasts is dose-dependent and saturable and can be competitively inhibited by mannose 6-phosphate, suggesting cation-independent, mannose 6-phosphate receptor-mediated endocytosis from the cell surface. A single intracerebroventricularly (ICV) administered dose of rhβ-gal (100 μg) resulted in broad bilateral biodistribution of rhβ-gal to critical regions of pathology in a mouse model of GM1 gangliosidosis. Weekly ICV dosing of rhβ-gal for 8 weeks substantially reduced brain levels of ganglioside and oligosaccharide substrates and reversed well-established secondary neuropathology. Of note, unlike with the ERT approach, chronic lentivirus-mediated GLB1 overexpression in the GM1 gangliosidosis patient fibroblasts caused accumulation of a prelysosomal pool of β-gal, resulting in activation of the unfolded protein response and endoplasmic reticulum stress. This outcome was unsurprising in light of our in vitro biophysical findings for rhβ-gal, which include pH-dependent and concentration-dependent stability and dynamic self-association. Collectively, our results highlight that ICV-ERT is an effective therapeutic intervention for managing GM1 gangliosidosis potentially more safely than with gene therapy approaches.
2021-02-03 | Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency.
Mutations in the galactosidase β 1 (GLB1) gene cause lysosomal β-galactosidase (β-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. β-Gal and neuraminidase 1 (NEU1) form a multienzyme complex in lysosomes along with the molecular chaperone, protective protein cathepsin A (PPCA). NEU1 is deficient in the neurodegenerative lysosomal storage disease sialidosis, and its targeting to and stability in lysosomes strictly depend on PPCA. In contrast, β-Gal only partially depends on PPCA, prompting us to investigate the role that β-Gal plays in the multienzyme complex. Here, we demonstrate that β-Gal negatively regulates NEU1 levels in lysosomes by competitively displacing this labile sialidase from PPCA. Chronic cellular uptake of purified recombinant human β-Gal (rhβ-Gal) or chronic lentiviral-mediated GLB1 overexpression in GM1 gangliosidosis patient fibroblasts coincides with profound secondary NEU1 deficiency. A regimen of intermittent enzyme replacement therapy dosing with rhβ-Gal, followed by enzyme withdrawal, is sufficient to augment β-Gal activity levels in GM1 gangliosidosis patient fibroblasts without promoting NEU1 deficiency. In the absence of β-Gal, NEU1 levels are elevated in the GM1 gangliosidosis mouse brain, which are restored to normal levels following weekly intracerebroventricular dosing with rhβ-Gal. Collectively, our results highlight the need to carefully titrate the dose and dosing frequency of β-Gal augmentation therapy for GM1 gangliosidosis. They further suggest that intermittent intracerebroventricular enzyme replacement therapy dosing with rhβ-Gal is a tunable approach that can safely augment β-Gal levels while maintaining NEU1 at physiological levels in the GM1 gangliosidosis brain.
2020-02-01 | Targeting Macromolecules to CNS and Other Hard-to-Treat Organs Using Lectin-Mediated Delivery
The greatest challenges for therapeutic efficacy of many macromolecular drugs that act on intracellular are delivery to key organs and tissues and delivery into cells and subcellular compartments. Transport of drugs into critical cells associated with disease, including those in organs protected by restrictive biological barriers such as central nervous system (CNS), bone, and eye remains a significant hurdle to drug efficacy and impacts commercial risk and incentives for drug development for many diseases. These limitations expose a significant need for the development of novel strategies for macromolecule delivery. RTB lectin is the non-toxic carbohydrate-binding subunit B of ricin toxin with high affinity for galactose/galactosamine-containing glycolipids and glycoproteins common on human cell surfaces. RTB mediates endocytic uptake into mammalian cells by multiple routes exploiting both adsorptive-mediated and receptor-mediated mechanisms. In vivo biodistribution studies in lysosomal storage disease models provide evidence for the theory that the RTB-lectin transports corrective doses of enzymes across the blood-brain barrier to treat CNS pathologies. These results encompass significant implications for protein-based therapeutic approaches to address lysosomal and other diseases having strong CNS involvement.
small molecules
2026-06-26 | Infantile GM1 Gangliosidosis with Epilepsy Associated with a Same-Codon GLB1 Variant (c.808T>G/c.808T>C).
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by a deficiency of β-galactosidase due to pathogenic variants in the GLB1 gene. Almost 300 pathogenic or likely pathogenic variants have been identified, associated with a phenotypic spectrum ranging from GM1 gangliosidosis to mucopolysaccharidosis type IVB. Disease severity is largely determined by the extent to which specific variants impair enzymatic catalytic activity, particularly through disruption of substrate recognition and binding within the active site. We report a patient with GM1 gangliosidosis type I harboring two pathogenic missense variants, c.808T>G (p.Tyr270Asp) and c.808T>C (p.Tyr270His), in a compound heterozygous state. To the best of our knowledge, this specific allelic combination has not been previously described. Both variants affect the same codon, resulting in distinct amino acid substitutions at position 270, a residue critically involved in maintaining the structural and functional integrity of the catalytic domain of β-galactosidase. Disruption at this site is expected to severely compromise enzymatic activity. Comparative analysis with previously reported cases carrying variants at the same residue, in either homozygous or compound heterozygous states, demonstrates a possible consistent association with the infantile form of GM1 gangliosidosis, characterized by a rapidly progressive neurodegenerative course and multisystem involvement. Collectively, these findings provide additional support for the hypothesis that codon 270 can be regarded as a critical functional hotspot within GLB1, where even distinct amino acid substitutions can result in profound enzymatic dysfunction and a severe early-onset phenotype.
2026-06-08 | Identification of novel compound heterozygous mutations in the GLB1 gene by whole-exome sequencing in a case of infantile GM1 gangliosidosis: a case report.
GM1 gangliosidosis was a rare, fatal autosomal recessive lysosomal storage disorder caused by biallelic mutations in the GLB1 gene. Whole-exome sequencing (WES) was increasingly utilized to identify novel pathogenic variants in the GLB1 gene among undiagnosed pediatric cases. We reported a 9-month-old male infant with developmental delay, hepatomegaly, extensive Mongolian spots, and hypotonia. WES identified two novel compound heterozygous GLB1 variants: a paternal c.792 + 1G > A splice-site mutation and a maternal c.1572_1573insC(p.Gly525Argfs*7) frameshift mutation. Both were classified as pathogenic by ACMG guidelines. β-galactosidase activity was markedly deficient, confirming the diagnosis. The family received genetic counseling and opted for prenatal diagnosis in a subsequent pregnancy. At age 2 years, the patient exhibited an inability to speak or walk and had a history of recurrent severe pneumonia requiring multiple hospitalizations, with his overall condition currently managed supportively. Two novel pathogenic GLB1 mutations expanded the mutational spectrum of infantile GM1 gangliosidosis. WES with enzymatic validation enabled precise diagnosis, genetic counseling, and prenatal management. The development of targeted therapies remained imperative to alter the disease's natural course.
2026-03-28 | Impact of Sinbaglustat on Neurons of the Medial Nucleus of the Trapezoid Body in a Murine Model of Human GM1-Gangliosidosis.
Background: GM1-gangliosidosis (GM1) is a lysosomal storage disorder caused by mutations in the Glb1 gene, resulting in reduced β-galactosidase activity and accumulation of GM1 gangliosides in neuronal lysosomes. Effective therapeutic strategies for this disease remain limited. Substrate reduction therapy using small molecules targeting glucosylceramide synthase (GCS) and non-lysosomal glucosylceramidase (GBA2), such as sinbaglustat, represents a promising approach. Methods: Structural and electrophysiological properties of principal neurons of the medial nucleus of the trapezoid body (MNTB) were investigated in 7-month-old Glb1-/- mice. Animals received long-term treatment with either low (LD; 10 mg/kg) or high (HD; 300 mg/kg) doses of sinbaglustat and were compared with untreated Glb1-/- (KO) and untreated wild-type (WT) mice. Results: Sinbaglustat treatment reduced lysosomal storage material in MNTB neurons. Basal membrane properties were largely unchanged across groups. However, action potential halfwidth was significantly increased in untreated KO and LD mice compared to untreated WT animals but was normalized in HD mice. After-hyperpolarization duration was prolonged in Glb1-/- mice relative to WT. Temporal precision during high-frequency stimulation was reduced in untreated KO mice and improved following sinbaglustat treatment. Conclusions: These findings indicate that GM1-gangliosidosis is associated with functional alterations in MNTB neurons and suggest that long-term sinbaglustat treatment can partially restore neuronal electrophysiological properties, supporting its therapeutic potential in GM1.
2025-07-29 | β-Galactosidase inhibition explored by biochemical methods and in silico studies for plant polyphenols.
β-Galactosidase is a lysosomal enzyme whose deficiency is associated with genetic disorders such as GM1 gangliosidosis, prompting the search for novel enzyme modulators with therapeutic potential. The current study evaluated the inhibitory potential of selected natural polyphenols against β-galactosidase using a combined approach of biochemical assays and computational modeling. Sixteen plant-derived compounds were initially screened through molecular docking against Aspergillus oryzae β-galactosidase. Among these, hesperidin, rutin, and chlorogenic acid exhibited the most favorable interactions and were subsequently assessed through in vitro enzyme inhibition assays and MM/GBSA binding energy calculations. These compounds showed potential inhibitory effects and stable binding within the enzyme's active site. Although classical pharmacological chaperone activity was not directly demonstrated, the observed modulation of enzyme function suggests potential for further development of these polyphenols as structurally distinct β-galactosidase inhibitors. The findings provide a basis for future investigations aimed at natural product-based strategies to manage lysosomal storage disorders such as GM1 gangliosidosis.
2025-04-19 | Sinbaglustat ameliorates disease pathology in a murine model of GM1 gangliosidosis without affecting CNS ganglioside levels.
Sinbaglustat is a brain-penetrating small molecule that inhibits the non-lysosomal glucocerebrosidase (GBA2) and, with lower potency, glucosylceramide synthase (GCS). Sinbaglustat has passed clinical phase I. Our preclinical study assessed its efficacy in a transgenic mouse model of GM1 gangliosidosis, lacking a functional β-galactosidase enzyme (Glb1-/-). Starting at 4 weeks of age, mice were either treated with a nominal dose of 10 or 300 mg/kg/day of sinbaglustat or remained untreated. Wild-type (WT) mice served as control. Body weight, clinical and neurological signs, and motor function was assessed until 17-18 weeks (4 months) and 30 weeks (7 months) of age when mice were euthanized for ex vivo assessments. In comparison to WT, Glb1-/- mice showed the expected accumulation of GM1 gangliosidosis-related sphingolipids, neuropathology, and behavioral deficits. Both dosages of sinbaglustat left GM1 and lyso GM1 levels in the brain unaffected but delayed the onset of motor impairment and progression of clinical disease in Glb1-/- mice with the higher dose being more efficacious. Histologically and immunohistochemically, both treatment groups of Glb1-/- mice displayed reduced neuronal vacuolation. Only the higher dose of sinbaglustat decreased axonal damage and astrogliosis, which was also associated with a decrease of the axonal/neuronal damage marker plasma neurofilament light at 4 months (17-18 weeks). Both doses of sinbaglustat increased the GBA2 substrate glucosylceramide (GluCer) in the brain, while only the high dose reduced GluCer and other glycosphingolipids (GSLs) in the periphery indicating additional inhibition of GCS. We conclude that sinbaglustat had a therapeutic-like effect in the GM1 gangliosidosis mouse model.
gene therapies
2025-09-16 | MRI brain volumetric analysis of type II GM1 gangliosidosis patients treated with gene therapy
Motivation: Type II GM1 gangliosidosis is a rare disease that lacks reliable quantitative neural biomarkers to monitor disease progression. Goal(s): With the advent of gene therapy in treating GM1, we sought to quantify volumetrics of different brain regions known to be affected in GM1 patients. Approach: We quantified and tracked brain volumetric changes longitudinally on specific brain structures at different timepoints using MRI to evaluate disease progression/regression in GM1 patients treated with gene therapy and compared them to untreated patients and healthy controls. Results: We demonstrated the utility of brain volumetrics in assessing longitudinal brain region changes in gene therapy treated GM1 patients. Impact: Our study addressed the need for quantitative neural biomarkers in type II GM1 gangliosidosis which correlated with clinical markers. Through longitudinal brain volumetric analysis using MRI, we demonstrated the efficacy of gene therapy in monitoring disease progression/regression in GM1 patients.
2024-11-26 | Diffusion tensor imaging quantification of brain matter tracts in gene therapy treated GM1 gangliosidosis patients
Motivation: Type II GM1 gangliosidosis is a rare disease that lacks reliable quantitative biomarkers to assess neuronal health. Goal(s): We sought to quantify diffusion tensor imaging (DTI) parameters of different brain regions known to be affected in GM1 to track neuronal changes especially with the advent of gene therapy in treating GM1. Approach: We quantified fractional anisotropy and radial diffusivity changes at different timepoints using DTI-MRI to evaluate myelination changes in GM1 patients treated with gene therapy and compared them to untreated patients and healthy controls. Results: DTI can be used to demonstrate efficacy of gene therapy in monitoring disease progression/regression in GM1 patients. Impact: This study addressed the need for reliable biomarkers in assessing neuronal health in type II GM1 gangliosidosis. Using DTI parameters, we demonstrated the efficacy of gene therapy in reliably monitoring myelination changes in GM1 patients.
2024-09-20 | Base editing of the GLB1 gene is therapeutic in GM1 gangliosidosis patient-derived cells.
GM1 gangliosidosis is an autosomal recessive neurodegenerative lysosomal storage disease caused by pathogenic variants in the GLB1 gene, limiting the production of active lysosomal β-galactosidase. Phenotypic heterogeneity is due in part to variant type, location within GLB1, and the amount of residual enzyme activity; in the most severe form, death occurs in infancy. With no FDA approved therapeutics, development of efficacious strategies for the disease is pivotal. CRISPR/Cas based approaches have revolutionized precision medicine and have been indispensable to the development of treatments for several monogenic disorders with bespoke strategies central to current research pipelines. We used CRISPR/Cas-adenine base editing to correct the GLB1 c.380G>A (p.Cys127Tyr) variant in patient-derived dermal fibroblasts compound heterozygous with the GLB1 c.481T>G (p.Trp161Gly) pathogenic variant. Nucleofection of plasmids encoding the target sgRNA and ABEmax restored the canonical guanine (32.2 ± 2.2 % of the target allele) and synthesis of active β-galactosidase. Analysis of cellular markers of pathology revealed normalization of both primary glycoconjugate storage and lysosomal pathology. Furthermore, analysis of off-target sites nominated by the in silico tools Cas-OFFinder and/or CRISTA revealed no significant editing or indels. This study supports the use of CRISPR/Cas-based approaches for the treatment of GM1 gangliosidosis, and provides foundational data for future translational studies.
2024-08-31 | Establishment of iPS cell line (SDQLCHi080-A) from a patient with GM1 gangliosidosis due to GLB1 mutation.
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by defects in the beta-galactosidase (GLB1) gene, which results in accumulation of GM1 gangliosides and related glycoconjugates in the lysosomes leading to lysosomal swelling, cellular damage, and organ dysfunction. We generated SDQLCHi080-A cell line from a patient with GM1 gangliosidosis carrying mutations of c.523C > T and c.574T > C > T in the GLB1 gene. The cell line exhibited typical iPSC morphology, expressed high levels of stemness markers, exhibited normal karyotype, and has the capability to differentiate into three germ layers. This cell line could provide a useful GM1 gangliosidosis model in vitro for further study.
2024-04-26 | Therapeutic developments for neurodegenerative GM1 gangliosidosis
GM1 gangliosidosis (GM1) is a rare but fatal neurodegenerative disease caused by dysfunction or lack of production of lysosomal enzyme, β-galactosidase, leading to accumulation of substrates. The most promising treatments for GM1, include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), stem cell therapy and gene editing. However, effectiveness is limited for neuropathic GM1 due to the restrictive nature of the blood-brain barrier (BBB). ERT and SRT alleviate substrate accumulation through exogenous supplementation over the patient's lifetime, while gene editing could be curative, fixing the causative gene,
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Drug Discovery Landscape
11 orphan drug designations for GM1 gangliosidosis.
11 orphan drug designations for GM1 gangliosidosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Autologous peripheral blood-derived CD34+ haematopoietic stem and progenitor cells transduced with a lentiviral vector containing the murine Glb1 gene | gene therapies | EMA | 2025-10-22 | — | Fondazione Telethon Ets |
biphenyl-substituted L-ido configured deoxynojirimycin derivative or Fluorobiphenyl-Piperidinetriol | small molecules | FDA | 2024-11-25 | — | Azafaros BV |
Nizubaglustat | small molecules | EMA | 2024-06-28 | — | Azafaros B.V. |
Acetylleucine | small molecules | EMA | 2022-10-11 | — | IntraBio Ireland Limited |
Aloxistatin | gene therapies | FDA | 2022-05-10 | — | DORPHAN SA |
N-Acetyl-Leucine | gene therapies | FDA | 2022-04-13 | — | IntraBio Inc. |
Adeno-associated virus serotype hu68 containing the human GLB1 gene | gene therapies | EMA | 2020-10-19 | — | FGK Representative Service GmbH |
non-replicating recombinant adeno-associated virus serotype hu68 vector, which contains human GLB1 transgene encoding the galactosidase beta 1 enzyme | gene therapies | FDA | 2020-04-16 | — | GEMMA Biotherapeutics |
Single stranded adeno-associated virus vector encoding beta-galactosidase-1 | gene therapies | FDA | 2019-11-14 | — | UMass Chan Medical School |
Adeno-associated viral vector serotype rh.10 expressing beta-galactosidase | gene therapies | EMA | 2017-03-20 | — | LYSOGENE |
adeno-associated virus (AAV) serotype rh.10 expressing beta-galactosidase | gene therapies | FDA | 2017-01-30 | — | Lysogene, Inc. |
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