RARE DISEASE
GM2 gangliosidosis
GM2 gangliosidosis
GM2 gangliosidosis
Drug discovery
14
drugs
With orphan designations
Overview
GM2 gangliosidosis is a group of autosomal recessive lysosomal storage disorders caused by deficiencies in β-hexosaminidase enzymes (A, B, or GM2 activator protein), leading to toxic GM2 ganglioside accumulation in neurons. Subtypes include Tay-Sachs (HEXA mutations), Sandhoff (HEXB mutations), and AB-variant (GM2A mutations) diseases. Infantile forms cause rapid neurodegeneration, developmental regression, and death by age 4–5, while juvenile/adult-onset variants show slower progression with motor neuron dysfunction, cerebellar atrophy, and psychiatric manifestations [1][2][5][7]. No disease-modifying therapies are currently approved [3][5].
Population
Incidence ranges from 1:222,000 (Tay-Sachs) to 1:422,000 (Sandhoff) live births, with higher carrier rates in Ashkenazi Jewish, Cajun, and French Canadian populations [2][9].
Adult-onset cases (average age 19) account for 6–7% of GM2 gangliosidoses, presenting with proximal weakness (81%), cerebellar ataxia (53%), and psychiatric disorders (30%) [1][4].
Burden
Infantile/juvenile forms: 93% require wheelchair assistance within 20 years of onset; 85% develop seizures, and 100% lose speech [2][4][11].
Adult forms: 44% develop fractures, 41% experience falls, and 30% require psychiatric care [4][11].
Caregiver impact: 100% report pervasive daily care responsibilities, with 69% managing behavioral/psychiatric crises and 45% experiencing severe emotional strain [11][14].
Therapies
Experimental approaches: Gene therapy (AAV vectors, CRISPR/Cas9), enzyme replacement therapy (intrathecal/cerebroventricular delivery), and hematopoietic stem cell transplantation (limited CNS efficacy) [5][13][17].
Symptomatic management: Gastric tube placement prolongs survival in infantile cases; anticonvulsants and mobility aids address neurological deficits [2][4][11].
Failed strategies: Substrate reduction therapy (miglustat) showed no clinical benefit in trials [8][17].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
275 drug discovery papers about GM2 gangliosidosis, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
275 drug discovery papers about GM2 gangliosidosis, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-01-10 | Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease.
Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the HEXB gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysosomal storage of GM2 triggers inflammation in the CNS and periphery. The NLRP3 inflammasome is an important coordinator of pro-inflammatory responses, and we have investigated its regulation in murine SD. The NLRP3 inflammasome requires two signals, lipopolysaccharide (LPS) and ATP, to prime and activate the complex, respectively, leading to IL-1β secretion. Peritoneal, but not bone-marrow-derived, macrophages from symptomatic SD mice, but not those from pre-symptomatic animals, secrete the cytokine following priming with LPS with no requirement for activation with ATP, suggesting that such NLRP3 deregulation is related to the extent of glycosphingolipid storage. Dysregulated production of IL-1β was dependent upon caspase activity but not cathepsin B. We investigated the role of IL-1β in SD pathology using two approaches: the creation of hexb-/-Il1r1-/- double knockout mice or by treating hexb-/- animals with anakinra, a recombinant form of the IL-1 receptor antagonist, IL-1Ra. Both resulted in modest but significant extensions in lifespan and improvement of neurological function. These data demonstrate that IL-1β actively participates in the disease process and provides proof-of-principle that blockade of the pro-inflammatory cytokine IL-1β may provide benefits to patients.
2025-01-03 | Intracerebroventricular administration of a modified hexosaminidase ameliorates late-stage neurodegeneration in a GM2 mouse model.
The GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease, are devastating neurodegenerative disorders caused by β-hexosaminidase A (HexA) deficiency. In the Sandhoff disease mouse model, rescue potential was severely reduced when HexA was introduced after disease onset. Here, we assess the effect of recombinant HexA and HexD3, a newly engineered mimetic of HexA optimized for the treatment of Tay-Sachs disease and Sandhoff disease. Enzyme replacement therapy was administered by repeat intracerebroventricular injections in Sandhoff disease model mice with dosing beginning before and after signs of neurodegeneration. As previously observed, HexA effectively increased the lifespan of Sandhoff disease mice by 3.5-fold only when treatment was started before onset of neurodegeneration. In contrast, HexD3 halted motor decline and ameliorated late-stage disease severity even when dosing began late, after neurodegeneration onset. Additionally, HexD3 had advantages over HexA in enzyme stability, distribution potential, and homodimer activity. Overall, our data indicate that advanced therapeutics may widen the treatment window for neurodegenerative disorders.
2024-07-26 | Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.
Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.
2021-09-17 | Human recombinant lysosomal β-Hexosaminidases produced in Pichia pastoris efficiently reduced lipid accumulation in Tay-Sachs fibroblasts.
GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases, are lysosomal storage disorders characterized by the lysosomal accumulation of GM2 gangliosides. This accumulation is due to deficiency in the activity of the β-hexosaminidases Hex-A or Hex-B, which are dimeric hydrolases formed by αβ or ββ subunits, respectively. These disorders show similar clinical manifestations that range from mild systemic symptoms to neurological damage and premature death. There is still no effective therapy for GM2 gangliosidoses, but some therapeutic alternatives, as enzyme replacement therapy, have being evaluated. Previously, we reported the production of active human recombinant β-hexosaminidases (rhHex-A and rhHex-B) in the methylotrophic yeast Pichia pastoris. In this study, we evaluated in vitro the cellular uptake, intracellular delivery to lysosome, and reduction of stored substrates. Both enzymes were taken-up via endocytic pathway mediated by mannose and mannose-6-phosphate receptors and delivered to lysosomes. Noteworthy, rhHex-A diminished the levels of stored lipids and lysosome mass in fibroblasts from Tay-Sachs patients. Overall, these results confirm the potential of P. pastoris as host to produce recombinant β-hexosaminidases intended to be used in the treatment of GM2 gangliosidosis.
2020-08-27 | GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies
GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.
cell therapies
2026-07-12 | Extracellular vesicles from inflammatory-primed stromal cells reduce in vitro inflammation in Sandhoff disease model.
Sandhoff disease (SD) is a fatal lysosomal storage disorder caused by β-N-acetylhexosaminidase deficiency, resulting in GM2 ganglioside accumulation, severe neurodegeneration, and chronic neuroinflammation. While enzyme-restoring therapies, such as AAV gene transfer, effectively target the primary enzymatic deficit, neuroinflammation persists and contributes to disease progression, motivating the development of anti-inflammatory adjuncts alongside disease-modifying interventions. Extracellular vesicles released by mesenchymal stromal cells (MSC-EVs) are acellular lipid nanoparticles that contain immunomodulatory molecules and can cross physical barriers, without immunogenicity issues. These features make MSC-EVs promising candidates for anti-inflammatory therapeutics targeting neuropathology. The anti-inflammatory potency of MSC-EVs is increased by priming parent MSCs with pro-inflammatory cytokines, resulting in IFEVs, as referred to in this study. Here, we evaluated the in vitro anti-inflammatory effects of IFEVs in a feline model of SD. IFEVs reduced SD neuroinflammation, lowering IL-6, TNF-α, and IL-1β protein levels in SD neuronal-mixed glia, with concordant transcriptional downregulation of NF-κB/p65 and NLRP3 components and upregulation of arginase 1 mRNA after 48 h of treatment. In SD peripheral blood mononuclear cells, IFEVs significantly increased the proportion of regulatory T cells and the Treg/T-effector cell ratio without inducing cytotoxicity. Together, these findings demonstrate that IFEVs reduced neuroinflammation and altered blood-circulating T-cell populations in an in vitro SD model, supporting their further preclinical development as a complementary immunomodulatory therapy for SD.
2024-06-26 | Evidence of Lysosomal β-Hexosaminidase Enzymatic Activity Associated with Extracellular Vesicles: Potential Applications for the Correction of Sandhoff Disease.
Extracellular vesicles (EVs) can be isolated from biological fluids and cell culture medium. Their nanometric dimension, relative stability, and biocompatibility have raised considerable interest for their therapeutic use as delivery vehicles of macromolecules, namely nucleic acids and proteins. Deficiency in lysosomal enzymes and associated proteins is at the basis of a group of genetic diseases known as lysosomal storage disorders (LSDs), characterized by the accumulation of undigested substrates into lysosomes. Among them, GM2 gangliosidoses are due to a deficiency in the activity of lysosomal enzyme β-hexosaminidase, leading to the accumulation of the GM2 ganglioside and severe neurological symptoms. Current therapeutic approaches, including enzyme replacement therapy (ERT), have proven unable to significantly treat these conditions. Here, we provide evidence that the lysosomal β-hexosaminidase enzyme is associated with EVs released by HEK cells and that the EV-associated activity can be increased by overexpressing the α-subunit of β-hexosaminidase. The delivery of EVs to β-hexosaminidase-deficient fibroblasts results in a partial cross-correction of the enzymatic defect. Overall findings indicate that EVs could be a source of β-hexosaminidase that is potentially exploitable for developing therapeutic approaches for currently untreatable LSDs.
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.
2023-07-25 | Increasing β-hexosaminidase A activity using genetically modified mesenchymal stem cells.
GM2 gangliosidoses are a group of autosomal-recessive lysosomal storage disorders. These diseases result from a deficiency of lysosomal enzyme β-hexosaminidase A (HexA), which is responsible for GM2 ganglioside degradation. HexA deficiency causes the accumulation of GM2-gangliosides mainly in the nervous system cells, leading to severe progressive neurodegeneration and neuroinflammation. To date, there is no treatment for these diseases. Cell-mediated gene therapy is considered a promising treatment for GM2 gangliosidoses. This study aimed to evaluate the ability of genetically modified mesenchymal stem cells (MSCs-HEXA-HEXB) to restore HexA deficiency in Tay-Sachs disease patient cells, as well as to analyze the functionality and biodistribution of MSCs in vivo. The effectiveness of HexA deficiency cross-correction was shown in mutant MSCs upon interaction with MSCs-HEXA-HEXB. The results also showed that the MSCs-HEXA-HEXB express the functionally active HexA enzyme, detectable in vivo, and intravenous injection of the cells does not cause an immune response in animals. These data suggest that genetically modified mesenchymal stem cells have the potentials to treat GM2 gangliosidoses.
2017-12-06 | Haematopoietic Stem Cell Transplantation Arrests the Progression of Neurodegenerative Disease in Late-Onset Tay-Sachs Disease
Tay-Sachs disease is a rare metabolic disease caused by a deficiency of hexosaminidase A that leads to accumulation of GM2 gangliosides predominantly in neural tissue. Late-onset Tay-Sachs disease variant is associated with a higher level of residual HexA activity. Treatment options are limited, and there are a few described cases who have undergone haematopoietic stem cell transplantation (HSCT) with variable outcome.We describe a case of a 23-year-old male patient who presented with a long-standing tremor since 7 years of age. He had gait ataxia, a speech stammer and swallowing problems. His condition had had a static course apart from his tremor that had been gradually deteriorating. Because of the deterioration in his neurological function, the patient had an uneventful, matched-sibling donor bone marrow transplant at the age of 15 years. Eight years post-HSCT, at the age of 23, he retains full donor engraftment, and his white cell beta-HexA of 191 nmol/mg/h is comparable to normal controls (in-assay control = 187). He continues to experience some intentional tremor that is tolerable for daily life and nonprogressive since HSCT.HSCT is a potential treatment option which might arrest neurodegeneration in patients with LOTS.
gene therapies
2026-03-26 | Tay-Sachs disease models: From cellular and animal models to treatment perspectives.
Tay-Sachs disease (TSD) is a lysosomal storage disorder caused by pathogenic variants in the HEXA gene, resulting in deficient activity of β-hexosaminidase A (Hex-A). Loss of Hex-A function leads to the intralysosomal accumulation of GM2 ganglioside, disrupting lysosomal homeostasis and triggering neurodegenerative processes, including neuronal death, demyelination, neuroinflammation, gliosis, and microglial activation. Current understanding of TSD pathophysiology, as well as the development and preclinical evaluation of therapeutic strategies, has relied heavily on a wide range of cellular and animal models. This review summarizes and critically discusses the main experimental models of TSD and their applications. Cellular models include patient-derived skin fibroblasts and induced pluripotent stem cells (iPSCs), which have been instrumental for mechanistic studies and therapeutic screening; however, their limited capacity to recapitulate tissue-level complexity highlights the need for advanced systems such as organoids and three-dimensional tissues. Animal models encompass naturally occurring TSD in species such as dogs, sheep, and deer, as well as genetically engineered mouse models, including single- and double-knockout strains. Given that mice partially bypass the Hex-A deficiency through neuraminidase-mediated GM2 degradation, double-knockout models have been crucial for dissecting the role of neuraminidases in disease modulation. Although no model fully reproduces the human disease phenotype, these systems have provided a robust foundation for pre-clinical testing and the translation of experimental therapies into clinical trials. Continued refinement and integration of these models will be essential for advancing effective treatments for Tay-Sachs disease.
2026-03-13 | Human Neuraminidase 3 reduces the severity of Tay-Sachs disease symptoms in a mouse model.
Tay-Sachs disease (TSD) is a neurodegenerative disorder caused by mutations in the HEXA gene, encoding the α-subunit of β-hexosaminidase A. HexA deficiency leads to impaired degradation and accumulation of GM2 ganglioside, causing progressive neurodegeneration in patients. Interestingly, Hexa-/- mice show a relatively mild phenotype, suggesting degradation of stored GM2 ganglioside through a 'bypass' involving a sialidase. To investigate whether sialidase Neu3 contributes to GM2 degradation, mice deficient in both HEXA and NEU3, Hexa-/-Neu3-/-, were generated. Abnormal GM2 accumulation was revealed in the brains of Hexa-/-Neu3-/- mice using thin-layer chromatography and mass spectrometric analyses. Immunohistological and histological analyses indicated astrogliosis, Purkinje cell loss, and progressive neurodegeneration. Furthermore, the mice exhibited marked neurological abnormalities, including slowed movement, ataxia, and tremors, as well as a shortened lifespan of approximately 20 weeks. Hence, Hexa-/-Neu3-/- mice, which mimic the neuropathological and clinical abnormalities observed in patients, were considered the early-onset TSD model. The role of endogenous human Neu3 in GM2 degradation remains unknown. To evaluate its therapeutic potential, we administered AAVrh10-hNeu3 intrathecally to 8-week-old Hexa-/-Neu3-/- mice, either alone or with an anti-inflammatory agent, Istradefylline. Treatment with human Neu3 and Istradefylline extended lifespan to 28 weeks, improved body weight, and reduced GM2 accumulation. Additionally, fewer lysosomal LAMP1- and TUNEL-positive cells, and higher CNPase levels were revealed. Rotarod and footprint analyses showed improvements at 20 weeks. Our results provide the first in vivo evidence that AAV-mediated human Neu3 expression and Istradefylline may slow disease progression, reduce neuropathology, and lessen motor deficits in the Hexa-/-Neu3-/- mouse model of TSD.
2026-02-25 | Intrathecal delivery of AAVrh10-mHexa combined with anti-inflammatory treatment reduces neuropathological markers and extends the lifespan of mice with early-onset Tay-Sachs disease.
Tay-Sachs disease is a lysosomal storage disorder caused by mutations in the HEXA gene, which encodes the α-subunit of β-hexosaminidase A-an enzyme that breaks down GM2 ganglioside. Recently, a mouse model of Tay-Sachs, the DKO, with deficiencies in both Hexa and Neu3 genes, showed severe neurological symptoms and neuroinflammation, surviving up to 20 weeks. In this study, we evaluated the therapeutic potential of intrathecal AAVrh10-mediated delivery of mouse Hexa, in combination with istradefylline treatment, in DKO mice. Using molecular, immunohistochemical, and behavioral methods, we found that the mice's lifespan increased to 30 weeks after receiving AAV alone or with istradefylline. Molecular analyses revealed increased Hexa activity, accompanied by reduced levels of the lysosomal marker Lamp-1 and pro-inflammatory cytokines, such as CCL2 and CCL3, in the cortex, cerebellum, and various organs, including the kidney, liver, and spleen. Immunohistochemistry revealed clearance of GM2 accumulation, fewer lysosomes, decreased active astrocytes, and improvements in neurons and oligodendrocytes in the brains of DKO mice. Correspondingly, their motor activity also improved. These results suggest that AAVrh10-based intrathecal delivery combined with istradefylline provides a promising therapeutic strategy for treating Tay-Sachs disease.
2025-09-30 | Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep.
Tay-Sachs disease (TSD) and Sandhoff disease are fatal neurodegenerative diseases without an effective therapy that are caused by mutations in the HEXA and HEXB genes, respectively. Together they encode the heterodimeric isozyme of hexosaminidase, hexosaminidase A (HexA), that degrades GM2 ganglioside. This report describes a 5-year-long study using a bidirectional adeno-associated virus 9 (AAV9) vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the TSD sheep model. Bidirectional AAV9 was delivered i.v. or through various cerebrospinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM), and lumbar intrathecal space (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV, and LIT) with treated animals that survived up to 5 years of age (untreated animals with TSD die after ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy, including MRI, magnetic resonance spectroscopy, diffusion tensor imaging, and CSF levels of GM2 ganglioside and HexA activity, was evident. Postmortem assessments showed broad HexA distribution, GM2 ganglioside clearance, and vector genome distribution, especially in deep brain structures. Therapeutic efficacy documented in this study supports translation of bidirectional vector and multipoint CSF delivery to a clinical trial in patients with TSD and Sandhoff disease.
2025-09-08 | Generation of mice with combined Hexa Gly269Ser KI or KO and Neu3 KO alleles to create new models of GM2 gangliosidoses.
The GM2 gangliosidoses are lysosomal storage disorders exhibiting a spectrum of neurological phenotypes ranging from childhood death to debilitating adult-onset neurological impairment. To date, no mouse model harbouring a specific human mutation causing GM2 gangliosidosis has been created. We used CRISPR/Cas9 to generate knockin (KI) mice with the common adult-onset Hexa Gly269Ser variant as well as knockout (KO) mice with Hexa mutations expected to cause complete HexA deficiency. We also created Neu3 KO alleles that combined with Hexa KO or KI alleles were expected to create acute and chronic models of GM2 gangliosidosis, respectively. However, both models accumulated GM2 ganglioside throughout the brain when compared to controls (CON), and exhibited progressive loss of reflexes, gait abnormalities, and premature death by 24 weeks of age. Although survival and behavioural phenotypes did not differ between KO and KI models, the KI model had substantial Hexa mRNA and evidence of GM2 turnover. This KI model will be useful for developing gene editing to correct the variant causing the Gly269Ser substitution and its novel biochemical phenotype suggests it may be suitable for testing therapies that treat partial β-hexosaminidase A deficiency.
small molecules
2026-08-28 | Intraperitoneal administration of adenosine A2A receptor antagonist reduces neuroinflammatory and antioxidant responses in GM2 gangliosidosis mouse model.
Tay-Sachs disease (TSD) is a fatal lysosomal storage disorder characterized by neuronal GM2 ganglioside accumulation and progressive neurodegeneration. Neuroinflammation and oxidative stress are increasingly seen as key factors in disease progression. In this study, we evaluated the effects of istradefylline, a selective adenosine A2A receptor antagonist, in the Hexa-/-Neu3-/- mouse model, which closely recapitulates the neuropathological features of human TSD. Istradefylline treatment reduced the expression of several proinflammatory markers, including Ccl2, Ccl3, Ccl5, Cxcl10, Il1b, and Gfap, particularly in the cortex. Immunohistochemical analysis indicated reduced astrogliosis and microgliosis and increased CNPase-positive oligodendrocytes following treatment. The two-phase regimen also modulated antioxidant-response gene expression, including Sod2, Catalase, and Ttase1, and increased cortical APE1 protein abundance. Behavioral assessment demonstrated improved rotarod performance, particularly following two-stage treatment, whereas the open-field findings did not support a significant effect on anxiety-like behavior or locomotor activity. Istradefylline did not substantially reduce GM2 accumulation or restore neuronal density, indicating that it did not correct the primary storage pathology or prevent associated neuronal loss. Overall, istradefylline attenuated selected neuroinflammatory and glial alterations and modulated antioxidant-response markers in Hexa-/-Neu3-/- mice. These findings support further investigation of A2A receptor antagonism as an adjunctive symptomatic and anti-inflammatory strategy, potentially in combination with treatments that directly target the underlying enzymatic deficiency.
2026-06-18 | The RAINBOW study: a phase 2 trial evaluating the 3-month pharmacokinetic and pharmacodynamic data and 18-month clinical and safety outcomes of nizubaglustat in GM2 gangliosidoses or Niemann-Pick type C disease.
GM2 gangliosidoses and Niemann-Pick type C disease (NPC) belong to a group of rare, progressive neurodegenerative lysosomal diseases that cause diverse neurological symptoms. Disease-modifying therapies exist for NPC, but not for GM2 gangliosidoses. Nizubaglustat is in development for both conditions. In RAINBOW, a phase 2, double-blind, placebo-controlled multicenter trial, participants with GM2 gangliosidoses or NPC were randomized 1:1:1 to receive once-daily nizubaglustat 3 mg, nizubaglustat 9 mg, or placebo for 12 weeks, after which participants could enter a double-blind extension period and receive nizubaglustat 3 mg or 9 mg. Primary outcomes were plasma pharmacokinetics, pharmacodynamics, and the safety of nizubaglustat over 12 weeks. Clinical outcomes included changes from baseline in Scale for the Assessment and Rating of Ataxia (SARA), functional SARA scores, and Inventory on Non-Ataxia Signs (INAS) count during the extension; these outcomes were evaluated separately from the double-blind, placebo-controlled analyses at 12 weeks. Among 13 participants (GM2 gangliosidoses [n = 7], NPC [n = 6]; mean age, 18.6 years; 53.8% male), nizubaglustat demonstrated rapid absorption accompanied by dose-dependent reductions in plasma C16/C18 glucosylceramides. Most adverse events were mild to moderate and manageable. Pharmacokinetics, safety, and tolerability data established an optimal nizubaglustat dose (9 mg, adjusted for weight). During the extension (n = 11), 45.5% of participants had improved by ≥1 point or stabilized in SARA, 54.6% in functional SARA, and 63.7% in INAS; seizure frequencies were reduced from baseline. Nizubaglustat demonstrated a favorable safety profile and potential clinical benefits by reducing disease progression and seizure burden in participants with GM2 gangliosidoses or NPC, supporting advancement to a phase 3 trial in a larger cohort.
2026-06-10 | An example for potentially underrated causes of recessive disease in the Greater Middle East: integrative long-read genome and transcriptome sequencing pinpoint a deep-intronic homozygous HEXB candidate founder variant in GM2-gangliosidosis
Abstract Background Consanguinity provides shortcuts to identify homozygous recessive mutations. However, deep-intronic variants escape standard sequencing (panel; exome/WES), and their pathogenicity cannot be inferred from genomic data. We applied WES, long-read genome and long-read-RNA-sequencing (LR-WGS, LR-RNA-Seq) in a Syrian patient with biochemically evident GM2-gangliosidosis. Results No exonic HEXA, HEXB and GM2A mutations were found. LR-WGS/LR-RNA-Seq revealed a homozygous HEXB variant, c.771 + 985G > A, activating a 97 bp pseudo-exon. Conclusions Integrative genome and transcriptome sequencing unlocked a deep-intronic, database-annotated HEXB mutation and proved causality. This illustrates the diagnostic challenges in patients from the Middle East with its prevalent consanguinity and hidden (candidate founder) mutations which are potential targets for splice-modulating therapies.
2026-05-20 | Sinbaglustat is efficacious in GM2 gangliosidosis primarily through inhibition of GBA2 rather than GCS.
Sinbaglustat is a brain-penetrant iminosugar under clinical investigation for glycosphingolipid (GSL) storage disorders, including GM2 gangliosidosis. It inhibits non-lysosomal glucosylceramidase (GBA2) with higher potency than glucosylceramide synthase (GCS). While efficacy of related GBA2/GCS inhibitors in mouse models of Sandhoff disease was previously demonstrated, the specific contribution of GBA2 inhibition to therapeutic outcome has remained unclear. We dissected the mechanism of Sinbaglustat in Sandhoff Hexb -/- mice using 30 or 300 mg/kg/day doses, designed to preferentially inhibit GBA2 alone or both GBA2 and GCS, respectively. Sinbaglustat's dose-dependent effects on GSLs in relation to both drug targets were consistent across enzymatic assays, patient-derived cells, and wild-type mouse brain. In Hexb -/- mice, GBA2 inhibition alone was sufficient to alter central GSL metabolism, attenuate neuroinflammatory gene expression, delay onset of motor symptoms by ≥ 2 weeks, and extend survival by 15%. High-dose treatment broadened substrate clearance via GCS inhibition and extended survival by 22%. These results reveal a therapeutic role of GBA2 inhibition in the brain and highlight sinbaglustat, an iminosugar without gastrointestinal side effects, as a promising candidate for GM2 gangliosidosis. By defining the mechanistic contribution of its dual targets, this study offers insight for dose optimization and therapeutic design in lysosomal storage disorders.
2026-04-28 | HEXA Enzyme Replacement for GM2 Gangliosidosis-Related Dementia
HEXA encodes beta-hexosaminidase A, deficiency of which causes GM2 ganglioside accumulation leading to neurodegeneration and dementia. ChEMBL compounds CHEMBL4861823 (pChEMBL: 6.69) and CHEMBL4874886 (pChEMBL: 6.90) target HEXA. These compounds could potentially enhance residual enzyme activity or serve as pharmacological chaperones.
proteins
2025-01-10 | Dysregulation of the NLRP3 Inflammasome and Promotion of Disease by IL-1β in a Murine Model of Sandhoff Disease.
Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the HEXB gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysosomal storage of GM2 triggers inflammation in the CNS and periphery. The NLRP3 inflammasome is an important coordinator of pro-inflammatory responses, and we have investigated its regulation in murine SD. The NLRP3 inflammasome requires two signals, lipopolysaccharide (LPS) and ATP, to prime and activate the complex, respectively, leading to IL-1β secretion. Peritoneal, but not bone-marrow-derived, macrophages from symptomatic SD mice, but not those from pre-symptomatic animals, secrete the cytokine following priming with LPS with no requirement for activation with ATP, suggesting that such NLRP3 deregulation is related to the extent of glycosphingolipid storage. Dysregulated production of IL-1β was dependent upon caspase activity but not cathepsin B. We investigated the role of IL-1β in SD pathology using two approaches: the creation of hexb-/-Il1r1-/- double knockout mice or by treating hexb-/- animals with anakinra, a recombinant form of the IL-1 receptor antagonist, IL-1Ra. Both resulted in modest but significant extensions in lifespan and improvement of neurological function. These data demonstrate that IL-1β actively participates in the disease process and provides proof-of-principle that blockade of the pro-inflammatory cytokine IL-1β may provide benefits to patients.
2025-01-03 | Intracerebroventricular administration of a modified hexosaminidase ameliorates late-stage neurodegeneration in a GM2 mouse model.
The GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease, are devastating neurodegenerative disorders caused by β-hexosaminidase A (HexA) deficiency. In the Sandhoff disease mouse model, rescue potential was severely reduced when HexA was introduced after disease onset. Here, we assess the effect of recombinant HexA and HexD3, a newly engineered mimetic of HexA optimized for the treatment of Tay-Sachs disease and Sandhoff disease. Enzyme replacement therapy was administered by repeat intracerebroventricular injections in Sandhoff disease model mice with dosing beginning before and after signs of neurodegeneration. As previously observed, HexA effectively increased the lifespan of Sandhoff disease mice by 3.5-fold only when treatment was started before onset of neurodegeneration. In contrast, HexD3 halted motor decline and ameliorated late-stage disease severity even when dosing began late, after neurodegeneration onset. Additionally, HexD3 had advantages over HexA in enzyme stability, distribution potential, and homodimer activity. Overall, our data indicate that advanced therapeutics may widen the treatment window for neurodegenerative disorders.
2024-07-26 | Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.
Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.
2021-09-17 | Human recombinant lysosomal β-Hexosaminidases produced in Pichia pastoris efficiently reduced lipid accumulation in Tay-Sachs fibroblasts.
GM2 gangliosidosis, Tay-Sachs and Sandhoff diseases, are lysosomal storage disorders characterized by the lysosomal accumulation of GM2 gangliosides. This accumulation is due to deficiency in the activity of the β-hexosaminidases Hex-A or Hex-B, which are dimeric hydrolases formed by αβ or ββ subunits, respectively. These disorders show similar clinical manifestations that range from mild systemic symptoms to neurological damage and premature death. There is still no effective therapy for GM2 gangliosidoses, but some therapeutic alternatives, as enzyme replacement therapy, have being evaluated. Previously, we reported the production of active human recombinant β-hexosaminidases (rhHex-A and rhHex-B) in the methylotrophic yeast Pichia pastoris. In this study, we evaluated in vitro the cellular uptake, intracellular delivery to lysosome, and reduction of stored substrates. Both enzymes were taken-up via endocytic pathway mediated by mannose and mannose-6-phosphate receptors and delivered to lysosomes. Noteworthy, rhHex-A diminished the levels of stored lipids and lysosome mass in fibroblasts from Tay-Sachs patients. Overall, these results confirm the potential of P. pastoris as host to produce recombinant β-hexosaminidases intended to be used in the treatment of GM2 gangliosidosis.
2020-08-27 | GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies
GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.
cell therapies
2026-07-12 | Extracellular vesicles from inflammatory-primed stromal cells reduce in vitro inflammation in Sandhoff disease model.
Sandhoff disease (SD) is a fatal lysosomal storage disorder caused by β-N-acetylhexosaminidase deficiency, resulting in GM2 ganglioside accumulation, severe neurodegeneration, and chronic neuroinflammation. While enzyme-restoring therapies, such as AAV gene transfer, effectively target the primary enzymatic deficit, neuroinflammation persists and contributes to disease progression, motivating the development of anti-inflammatory adjuncts alongside disease-modifying interventions. Extracellular vesicles released by mesenchymal stromal cells (MSC-EVs) are acellular lipid nanoparticles that contain immunomodulatory molecules and can cross physical barriers, without immunogenicity issues. These features make MSC-EVs promising candidates for anti-inflammatory therapeutics targeting neuropathology. The anti-inflammatory potency of MSC-EVs is increased by priming parent MSCs with pro-inflammatory cytokines, resulting in IFEVs, as referred to in this study. Here, we evaluated the in vitro anti-inflammatory effects of IFEVs in a feline model of SD. IFEVs reduced SD neuroinflammation, lowering IL-6, TNF-α, and IL-1β protein levels in SD neuronal-mixed glia, with concordant transcriptional downregulation of NF-κB/p65 and NLRP3 components and upregulation of arginase 1 mRNA after 48 h of treatment. In SD peripheral blood mononuclear cells, IFEVs significantly increased the proportion of regulatory T cells and the Treg/T-effector cell ratio without inducing cytotoxicity. Together, these findings demonstrate that IFEVs reduced neuroinflammation and altered blood-circulating T-cell populations in an in vitro SD model, supporting their further preclinical development as a complementary immunomodulatory therapy for SD.
2024-06-26 | Evidence of Lysosomal β-Hexosaminidase Enzymatic Activity Associated with Extracellular Vesicles: Potential Applications for the Correction of Sandhoff Disease.
Extracellular vesicles (EVs) can be isolated from biological fluids and cell culture medium. Their nanometric dimension, relative stability, and biocompatibility have raised considerable interest for their therapeutic use as delivery vehicles of macromolecules, namely nucleic acids and proteins. Deficiency in lysosomal enzymes and associated proteins is at the basis of a group of genetic diseases known as lysosomal storage disorders (LSDs), characterized by the accumulation of undigested substrates into lysosomes. Among them, GM2 gangliosidoses are due to a deficiency in the activity of lysosomal enzyme β-hexosaminidase, leading to the accumulation of the GM2 ganglioside and severe neurological symptoms. Current therapeutic approaches, including enzyme replacement therapy (ERT), have proven unable to significantly treat these conditions. Here, we provide evidence that the lysosomal β-hexosaminidase enzyme is associated with EVs released by HEK cells and that the EV-associated activity can be increased by overexpressing the α-subunit of β-hexosaminidase. The delivery of EVs to β-hexosaminidase-deficient fibroblasts results in a partial cross-correction of the enzymatic defect. Overall findings indicate that EVs could be a source of β-hexosaminidase that is potentially exploitable for developing therapeutic approaches for currently untreatable LSDs.
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.
2023-07-25 | Increasing β-hexosaminidase A activity using genetically modified mesenchymal stem cells.
GM2 gangliosidoses are a group of autosomal-recessive lysosomal storage disorders. These diseases result from a deficiency of lysosomal enzyme β-hexosaminidase A (HexA), which is responsible for GM2 ganglioside degradation. HexA deficiency causes the accumulation of GM2-gangliosides mainly in the nervous system cells, leading to severe progressive neurodegeneration and neuroinflammation. To date, there is no treatment for these diseases. Cell-mediated gene therapy is considered a promising treatment for GM2 gangliosidoses. This study aimed to evaluate the ability of genetically modified mesenchymal stem cells (MSCs-HEXA-HEXB) to restore HexA deficiency in Tay-Sachs disease patient cells, as well as to analyze the functionality and biodistribution of MSCs in vivo. The effectiveness of HexA deficiency cross-correction was shown in mutant MSCs upon interaction with MSCs-HEXA-HEXB. The results also showed that the MSCs-HEXA-HEXB express the functionally active HexA enzyme, detectable in vivo, and intravenous injection of the cells does not cause an immune response in animals. These data suggest that genetically modified mesenchymal stem cells have the potentials to treat GM2 gangliosidoses.
2017-12-06 | Haematopoietic Stem Cell Transplantation Arrests the Progression of Neurodegenerative Disease in Late-Onset Tay-Sachs Disease
Tay-Sachs disease is a rare metabolic disease caused by a deficiency of hexosaminidase A that leads to accumulation of GM2 gangliosides predominantly in neural tissue. Late-onset Tay-Sachs disease variant is associated with a higher level of residual HexA activity. Treatment options are limited, and there are a few described cases who have undergone haematopoietic stem cell transplantation (HSCT) with variable outcome.We describe a case of a 23-year-old male patient who presented with a long-standing tremor since 7 years of age. He had gait ataxia, a speech stammer and swallowing problems. His condition had had a static course apart from his tremor that had been gradually deteriorating. Because of the deterioration in his neurological function, the patient had an uneventful, matched-sibling donor bone marrow transplant at the age of 15 years. Eight years post-HSCT, at the age of 23, he retains full donor engraftment, and his white cell beta-HexA of 191 nmol/mg/h is comparable to normal controls (in-assay control = 187). He continues to experience some intentional tremor that is tolerable for daily life and nonprogressive since HSCT.HSCT is a potential treatment option which might arrest neurodegeneration in patients with LOTS.
gene therapies
2026-03-26 | Tay-Sachs disease models: From cellular and animal models to treatment perspectives.
Tay-Sachs disease (TSD) is a lysosomal storage disorder caused by pathogenic variants in the HEXA gene, resulting in deficient activity of β-hexosaminidase A (Hex-A). Loss of Hex-A function leads to the intralysosomal accumulation of GM2 ganglioside, disrupting lysosomal homeostasis and triggering neurodegenerative processes, including neuronal death, demyelination, neuroinflammation, gliosis, and microglial activation. Current understanding of TSD pathophysiology, as well as the development and preclinical evaluation of therapeutic strategies, has relied heavily on a wide range of cellular and animal models. This review summarizes and critically discusses the main experimental models of TSD and their applications. Cellular models include patient-derived skin fibroblasts and induced pluripotent stem cells (iPSCs), which have been instrumental for mechanistic studies and therapeutic screening; however, their limited capacity to recapitulate tissue-level complexity highlights the need for advanced systems such as organoids and three-dimensional tissues. Animal models encompass naturally occurring TSD in species such as dogs, sheep, and deer, as well as genetically engineered mouse models, including single- and double-knockout strains. Given that mice partially bypass the Hex-A deficiency through neuraminidase-mediated GM2 degradation, double-knockout models have been crucial for dissecting the role of neuraminidases in disease modulation. Although no model fully reproduces the human disease phenotype, these systems have provided a robust foundation for pre-clinical testing and the translation of experimental therapies into clinical trials. Continued refinement and integration of these models will be essential for advancing effective treatments for Tay-Sachs disease.
2026-03-13 | Human Neuraminidase 3 reduces the severity of Tay-Sachs disease symptoms in a mouse model.
Tay-Sachs disease (TSD) is a neurodegenerative disorder caused by mutations in the HEXA gene, encoding the α-subunit of β-hexosaminidase A. HexA deficiency leads to impaired degradation and accumulation of GM2 ganglioside, causing progressive neurodegeneration in patients. Interestingly, Hexa-/- mice show a relatively mild phenotype, suggesting degradation of stored GM2 ganglioside through a 'bypass' involving a sialidase. To investigate whether sialidase Neu3 contributes to GM2 degradation, mice deficient in both HEXA and NEU3, Hexa-/-Neu3-/-, were generated. Abnormal GM2 accumulation was revealed in the brains of Hexa-/-Neu3-/- mice using thin-layer chromatography and mass spectrometric analyses. Immunohistological and histological analyses indicated astrogliosis, Purkinje cell loss, and progressive neurodegeneration. Furthermore, the mice exhibited marked neurological abnormalities, including slowed movement, ataxia, and tremors, as well as a shortened lifespan of approximately 20 weeks. Hence, Hexa-/-Neu3-/- mice, which mimic the neuropathological and clinical abnormalities observed in patients, were considered the early-onset TSD model. The role of endogenous human Neu3 in GM2 degradation remains unknown. To evaluate its therapeutic potential, we administered AAVrh10-hNeu3 intrathecally to 8-week-old Hexa-/-Neu3-/- mice, either alone or with an anti-inflammatory agent, Istradefylline. Treatment with human Neu3 and Istradefylline extended lifespan to 28 weeks, improved body weight, and reduced GM2 accumulation. Additionally, fewer lysosomal LAMP1- and TUNEL-positive cells, and higher CNPase levels were revealed. Rotarod and footprint analyses showed improvements at 20 weeks. Our results provide the first in vivo evidence that AAV-mediated human Neu3 expression and Istradefylline may slow disease progression, reduce neuropathology, and lessen motor deficits in the Hexa-/-Neu3-/- mouse model of TSD.
2026-02-25 | Intrathecal delivery of AAVrh10-mHexa combined with anti-inflammatory treatment reduces neuropathological markers and extends the lifespan of mice with early-onset Tay-Sachs disease.
Tay-Sachs disease is a lysosomal storage disorder caused by mutations in the HEXA gene, which encodes the α-subunit of β-hexosaminidase A-an enzyme that breaks down GM2 ganglioside. Recently, a mouse model of Tay-Sachs, the DKO, with deficiencies in both Hexa and Neu3 genes, showed severe neurological symptoms and neuroinflammation, surviving up to 20 weeks. In this study, we evaluated the therapeutic potential of intrathecal AAVrh10-mediated delivery of mouse Hexa, in combination with istradefylline treatment, in DKO mice. Using molecular, immunohistochemical, and behavioral methods, we found that the mice's lifespan increased to 30 weeks after receiving AAV alone or with istradefylline. Molecular analyses revealed increased Hexa activity, accompanied by reduced levels of the lysosomal marker Lamp-1 and pro-inflammatory cytokines, such as CCL2 and CCL3, in the cortex, cerebellum, and various organs, including the kidney, liver, and spleen. Immunohistochemistry revealed clearance of GM2 accumulation, fewer lysosomes, decreased active astrocytes, and improvements in neurons and oligodendrocytes in the brains of DKO mice. Correspondingly, their motor activity also improved. These results suggest that AAVrh10-based intrathecal delivery combined with istradefylline provides a promising therapeutic strategy for treating Tay-Sachs disease.
2025-09-30 | Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep.
Tay-Sachs disease (TSD) and Sandhoff disease are fatal neurodegenerative diseases without an effective therapy that are caused by mutations in the HEXA and HEXB genes, respectively. Together they encode the heterodimeric isozyme of hexosaminidase, hexosaminidase A (HexA), that degrades GM2 ganglioside. This report describes a 5-year-long study using a bidirectional adeno-associated virus 9 (AAV9) vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the TSD sheep model. Bidirectional AAV9 was delivered i.v. or through various cerebrospinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM), and lumbar intrathecal space (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV, and LIT) with treated animals that survived up to 5 years of age (untreated animals with TSD die after ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy, including MRI, magnetic resonance spectroscopy, diffusion tensor imaging, and CSF levels of GM2 ganglioside and HexA activity, was evident. Postmortem assessments showed broad HexA distribution, GM2 ganglioside clearance, and vector genome distribution, especially in deep brain structures. Therapeutic efficacy documented in this study supports translation of bidirectional vector and multipoint CSF delivery to a clinical trial in patients with TSD and Sandhoff disease.
2025-09-08 | Generation of mice with combined Hexa Gly269Ser KI or KO and Neu3 KO alleles to create new models of GM2 gangliosidoses.
The GM2 gangliosidoses are lysosomal storage disorders exhibiting a spectrum of neurological phenotypes ranging from childhood death to debilitating adult-onset neurological impairment. To date, no mouse model harbouring a specific human mutation causing GM2 gangliosidosis has been created. We used CRISPR/Cas9 to generate knockin (KI) mice with the common adult-onset Hexa Gly269Ser variant as well as knockout (KO) mice with Hexa mutations expected to cause complete HexA deficiency. We also created Neu3 KO alleles that combined with Hexa KO or KI alleles were expected to create acute and chronic models of GM2 gangliosidosis, respectively. However, both models accumulated GM2 ganglioside throughout the brain when compared to controls (CON), and exhibited progressive loss of reflexes, gait abnormalities, and premature death by 24 weeks of age. Although survival and behavioural phenotypes did not differ between KO and KI models, the KI model had substantial Hexa mRNA and evidence of GM2 turnover. This KI model will be useful for developing gene editing to correct the variant causing the Gly269Ser substitution and its novel biochemical phenotype suggests it may be suitable for testing therapies that treat partial β-hexosaminidase A deficiency.
small molecules
2026-08-28 | Intraperitoneal administration of adenosine A2A receptor antagonist reduces neuroinflammatory and antioxidant responses in GM2 gangliosidosis mouse model.
Tay-Sachs disease (TSD) is a fatal lysosomal storage disorder characterized by neuronal GM2 ganglioside accumulation and progressive neurodegeneration. Neuroinflammation and oxidative stress are increasingly seen as key factors in disease progression. In this study, we evaluated the effects of istradefylline, a selective adenosine A2A receptor antagonist, in the Hexa-/-Neu3-/- mouse model, which closely recapitulates the neuropathological features of human TSD. Istradefylline treatment reduced the expression of several proinflammatory markers, including Ccl2, Ccl3, Ccl5, Cxcl10, Il1b, and Gfap, particularly in the cortex. Immunohistochemical analysis indicated reduced astrogliosis and microgliosis and increased CNPase-positive oligodendrocytes following treatment. The two-phase regimen also modulated antioxidant-response gene expression, including Sod2, Catalase, and Ttase1, and increased cortical APE1 protein abundance. Behavioral assessment demonstrated improved rotarod performance, particularly following two-stage treatment, whereas the open-field findings did not support a significant effect on anxiety-like behavior or locomotor activity. Istradefylline did not substantially reduce GM2 accumulation or restore neuronal density, indicating that it did not correct the primary storage pathology or prevent associated neuronal loss. Overall, istradefylline attenuated selected neuroinflammatory and glial alterations and modulated antioxidant-response markers in Hexa-/-Neu3-/- mice. These findings support further investigation of A2A receptor antagonism as an adjunctive symptomatic and anti-inflammatory strategy, potentially in combination with treatments that directly target the underlying enzymatic deficiency.
2026-06-18 | The RAINBOW study: a phase 2 trial evaluating the 3-month pharmacokinetic and pharmacodynamic data and 18-month clinical and safety outcomes of nizubaglustat in GM2 gangliosidoses or Niemann-Pick type C disease.
GM2 gangliosidoses and Niemann-Pick type C disease (NPC) belong to a group of rare, progressive neurodegenerative lysosomal diseases that cause diverse neurological symptoms. Disease-modifying therapies exist for NPC, but not for GM2 gangliosidoses. Nizubaglustat is in development for both conditions. In RAINBOW, a phase 2, double-blind, placebo-controlled multicenter trial, participants with GM2 gangliosidoses or NPC were randomized 1:1:1 to receive once-daily nizubaglustat 3 mg, nizubaglustat 9 mg, or placebo for 12 weeks, after which participants could enter a double-blind extension period and receive nizubaglustat 3 mg or 9 mg. Primary outcomes were plasma pharmacokinetics, pharmacodynamics, and the safety of nizubaglustat over 12 weeks. Clinical outcomes included changes from baseline in Scale for the Assessment and Rating of Ataxia (SARA), functional SARA scores, and Inventory on Non-Ataxia Signs (INAS) count during the extension; these outcomes were evaluated separately from the double-blind, placebo-controlled analyses at 12 weeks. Among 13 participants (GM2 gangliosidoses [n = 7], NPC [n = 6]; mean age, 18.6 years; 53.8% male), nizubaglustat demonstrated rapid absorption accompanied by dose-dependent reductions in plasma C16/C18 glucosylceramides. Most adverse events were mild to moderate and manageable. Pharmacokinetics, safety, and tolerability data established an optimal nizubaglustat dose (9 mg, adjusted for weight). During the extension (n = 11), 45.5% of participants had improved by ≥1 point or stabilized in SARA, 54.6% in functional SARA, and 63.7% in INAS; seizure frequencies were reduced from baseline. Nizubaglustat demonstrated a favorable safety profile and potential clinical benefits by reducing disease progression and seizure burden in participants with GM2 gangliosidoses or NPC, supporting advancement to a phase 3 trial in a larger cohort.
2026-06-10 | An example for potentially underrated causes of recessive disease in the Greater Middle East: integrative long-read genome and transcriptome sequencing pinpoint a deep-intronic homozygous HEXB candidate founder variant in GM2-gangliosidosis
Abstract Background Consanguinity provides shortcuts to identify homozygous recessive mutations. However, deep-intronic variants escape standard sequencing (panel; exome/WES), and their pathogenicity cannot be inferred from genomic data. We applied WES, long-read genome and long-read-RNA-sequencing (LR-WGS, LR-RNA-Seq) in a Syrian patient with biochemically evident GM2-gangliosidosis. Results No exonic HEXA, HEXB and GM2A mutations were found. LR-WGS/LR-RNA-Seq revealed a homozygous HEXB variant, c.771 + 985G > A, activating a 97 bp pseudo-exon. Conclusions Integrative genome and transcriptome sequencing unlocked a deep-intronic, database-annotated HEXB mutation and proved causality. This illustrates the diagnostic challenges in patients from the Middle East with its prevalent consanguinity and hidden (candidate founder) mutations which are potential targets for splice-modulating therapies.
2026-05-20 | Sinbaglustat is efficacious in GM2 gangliosidosis primarily through inhibition of GBA2 rather than GCS.
Sinbaglustat is a brain-penetrant iminosugar under clinical investigation for glycosphingolipid (GSL) storage disorders, including GM2 gangliosidosis. It inhibits non-lysosomal glucosylceramidase (GBA2) with higher potency than glucosylceramide synthase (GCS). While efficacy of related GBA2/GCS inhibitors in mouse models of Sandhoff disease was previously demonstrated, the specific contribution of GBA2 inhibition to therapeutic outcome has remained unclear. We dissected the mechanism of Sinbaglustat in Sandhoff Hexb -/- mice using 30 or 300 mg/kg/day doses, designed to preferentially inhibit GBA2 alone or both GBA2 and GCS, respectively. Sinbaglustat's dose-dependent effects on GSLs in relation to both drug targets were consistent across enzymatic assays, patient-derived cells, and wild-type mouse brain. In Hexb -/- mice, GBA2 inhibition alone was sufficient to alter central GSL metabolism, attenuate neuroinflammatory gene expression, delay onset of motor symptoms by ≥ 2 weeks, and extend survival by 15%. High-dose treatment broadened substrate clearance via GCS inhibition and extended survival by 22%. These results reveal a therapeutic role of GBA2 inhibition in the brain and highlight sinbaglustat, an iminosugar without gastrointestinal side effects, as a promising candidate for GM2 gangliosidosis. By defining the mechanistic contribution of its dual targets, this study offers insight for dose optimization and therapeutic design in lysosomal storage disorders.
2026-04-28 | HEXA Enzyme Replacement for GM2 Gangliosidosis-Related Dementia
HEXA encodes beta-hexosaminidase A, deficiency of which causes GM2 ganglioside accumulation leading to neurodegeneration and dementia. ChEMBL compounds CHEMBL4861823 (pChEMBL: 6.69) and CHEMBL4874886 (pChEMBL: 6.90) target HEXA. These compounds could potentially enhance residual enzyme activity or serve as pharmacological chaperones.
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Drug Discovery Landscape
14 orphan drug designations for GM2 gangliosidosis.
14 orphan drug designations for GM2 gangliosidosis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
(2S,3R,4R,5S)-1-[5-(2-fluoro-biphenyl-4-ylmethoxy)-pentyl]-2-hydroxymethyl-piperidine-3,4,5-triol | small molecules | EMA | Azafaros B.V. | |
N-acetyl-L-leucine | small molecules | FDA | IntraBio Inc. | |
Gemfibrozil | small molecules | FDA | — | Polaryx Therapeutics, Inc. |
Adeno-associated viral vector serotype 9 containing the human HEXA and HEXB genes | gene therapies | EMA | Raremoon Consulting Esp S.L. | |
Trans-Cinnamic Acid | small molecules | FDA | — | Polaryx Therapeutics, Inc. |
Venglustat | small molecules | EMA | Sanofi B.V. | |
venglustat malate | small molecules | FDA | Genzyme Corporation, a SANOFI COMPANY | |
adeno-associated viral vector serotype 9 (AAV9) carrying both HEXA and HEXB | gene therapies | FDA | Gencorrex Therapies Inc | |
(2S,3R,4R,5S)-2-(hydroxymethyl)-1-pentylpiperidine-3,4,5-triol | small molecules | EMA | — | Idorsia Pharmaceuticals Deutschland GmbH |
sinbaglustat | small molecules | FDA | — | Idorsia Pharmaceuticals Ltd |
N-acetyl-DL-leucine | small molecules | FDA | IntraBio Inc. | |
Recombinant adeno-associated viral vector serotype 2/1 encoding human beta-hexosaminidase alpha and beta subunits | gene therapies | EMA | — | Maria Livadiotis |
Acetylleucine | peptides | EMA | IntraBio Ireland Ltd | |
Recombinant adeno-associated virus serotype 2/1 vector encoding human beta-hexosaminidase alpha & beta subunits (rAAV2/1 Hex alpha & beta) | gene therapies | FDA | — | University of Cambridge |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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