RARE DISEASE
Tay-Sachs disease
Tay-Sachs disease
Tay-Sachs disease
Synonyms: Beta-hexosaminidase subunit alpha deficiency, GM2 gangliosidosis, Tay-Sachs variant, GM2 gangliosidosis, hexosaminidase A deficiency variant, HEXA disorder
Synonyms: Beta-hexosaminidase subunit alpha deficiency, GM2 gangliosidosis, Tay-Sachs variant, GM2 gangliosidosis, hexosaminidase A deficiency variant, HEXA disorder
Synonyms: Beta-hexosaminidase subunit alpha deficiency, GM2 gangliosidosis, Tay-Sachs variant, GM2 gangliosidosis, hexosaminidase A deficiency variant, HEXA disorder
Drug discovery
2
drugs
With orphan designations
Overview
Tay-Sachs disease is a fatal autosomal recessive lysosomal storage disorder caused by HEXA gene mutations, resulting in deficient β-hexosaminidase A activity and toxic GM2 ganglioside accumulation in neurons. It manifests as infantile (neurodegeneration, death by age 4–5), juvenile (death by adolescence), or late-onset forms (variable neurological/psychiatric symptoms) [1][5][6]. Diagnostic hallmarks include cherry-red retinal spots and enzymatic/genetic testing [1][9].
Burden
Morbidity: Progressive motor/cognitive decline, seizures, blindness, and dysphagia across subtypes [1][6][17].
Mortality: Infantile form: >90% mortality by age 5; juvenile form: survival ≤15 years [6][9].
Psychosocial/cost: High caregiving demands, recurrent hospitalizations for infections, and long-term palliative needs [9][12][16].
Therapies
Supportive care: Antiepileptics, nutritional support, and palliative interventions [9][13].
Experimental therapies: Gene therapy (AAV vectors targeting CNS), substrate reduction (miglustat), pharmacological chaperones (pyrimethamine/ambroxol), and hematopoietic stem cell transplantation (limited CNS efficacy) [3][11][19].
No disease-modifying treatments approved; clinical trials focus on enzyme replacement and GM2 reduction [3][7][15].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
307 drug discovery papers about Tay-Sachs disease, with 3 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
307 drug discovery papers about Tay-Sachs disease, with 3 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-05-27 | Yeast-Produced Human Recombinant Lysosomal β-Hexosaminidase Efficiently Rescues GM2 Ganglioside Accumulation in Tay-Sachs Disease.
Background: Tay-Sachs disease (TSD) is an autosomal recessive lysosomal storage disorder characterized by the accumulation of GM2 ganglioside due to mutations in the HEXA gene, which encodes the α-subunit of β-Hexosaminidase A. This accumulation leads to significant neuropathological effects and premature death in affected individuals. No effective treatments exist, but enzyme replacement therapies are under investigation. In our previous work, we demonstrated the internalization and efficacy of human recombinant lysosomal β-hexosaminidase A (rhHex-A), produced in the methylotrophic yeast Pichia pastoris, in reducing lipids and lysosomal mass levels in fibroblasts and neural stem cells derived from patient-induced pluripotent stem cells (iPSCs). In this study, we further evaluated the potential of rhHex-A to prevent GM2 accumulation using fibroblast and neuroglia cells from a TSD patient alongside a relevant mouse model. Methods: Fibroblasts and neuroglial cell lines derived from a murine model and TSD patients were treated with 100 nM rhHexA for 72 h. After treatment, cells were stained by anti-GM2 (targeting GM2 ganglioside; KM966) and anti-LAMP1 (lysosomal-associated membrane protein 1) colocalization staining and incubated with 50 nM LysoTracker Red DND-99 to label lysosomes. In addition, GM2AP and HEXB expression were analyzed to assess whether rhHex-A treatment affected the levels of enzymes involved in GM2 ganglioside degradation. Results: Immunofluorescence staining for LysoTracker and colocalization studies of GM2 and Lamp1 indicated reduced lysosomal mass and GM2 levels. Notably, rhHex-A treatment also affected the expression of the HEXB gene, which is involved in GM2 ganglioside metabolism, highlighting a potential regulatory interaction within the metabolic pathway. Conclusions: Here, we report that rhHex-A produced in yeast can efficiently degrade GM2 ganglioside and rescue lysosomal accumulation in TSD cells.
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.
2024-08-31 | Treating late-onset Tay Sachs disease: Brain delivery with a dual trojan horse protein.
Tay-Sachs (TS) disease is a neurodegenerative disease resulting from mutations in the gene encoding the α-subunit (HEXA) of lysosomal β-hexosaminidase A (HexA). We report that (1) recombinant HEXA alone increased HexA activity and decreased GM2 content in human TS glial cells and peripheral mononuclear blood cells; 2) a recombinant chimeric protein composed of HEXA linked to two blood-brain barrier (BBB) entry elements, a transferrin receptor binding sequence and granulocyte-colony stimulating factor, associates with HEXB in vitro; reaches human cultured TS cells lysosomes and mouse brain cells, especially neurons, in vivo; lowers GM2 in cultured human TS cells; lowers whole brain GM2 concentration by approximately 40% within 6 weeks, when injected intravenously (IV) to adult TS-mutant mice mimicking the slow course of late-onset TS; and increases forelimbs grip strength. Hence, a chimeric protein equipped with dual BBB entry elements can transport a large protein such as HEXA to the brain, decrease the accumulation of GM2, and improve muscle strength, thereby providing potential treatment for late-onset TS.
2024-07-12 | Human Recombinant Lysosomal β-Hexosaminidase A produced in P.pastoris efficiently reduced GM2 ganglioside accumulation in Tay- Sachs Disease
Tay-Sachs disease is a progressive lysosomal storage disorder caused by genetic mutations in the HEXA gene encoding α-subunit of β-Hexosaminidase A, which leads to GM2 ganglioside accumulation, particularly in the central nervous system. Lysosomal GM2 ganglioside accumulation causes neuropathology and leads to premature cell death in Tay-Sachs patients, and there is no effective treatment yet. Previously, we produced the human recombinant lysosomal β-Hexosaminidase (rhHex-A) in the yeast Pichia pastoris, demonstrating the capacity to be internalized in different cell lines, and the reduction of stored GM2 gangliosides in patients´ fibroblasts and neural iPSCs. In this study, we use mouse fibroblasts and neuroglia from a novel murine model of Tay-Sachs disease and human Tay-Sachs patients’ neuroglia cells to demonstrate whether rhHex-A could reduce the GM2 accumulation. We treated the cells with rhHex-A to a final concentration of 100 nM, and the efficacy was evaluated using qRT-PCR and Immunocytochemical analysis after 24–72 h of incubation. Altogether, our results suggest that rhHex-A-produced in the yeast Pichia pastoris is a promising therapeutic to mitigate GM2 accumulation in Tay-Sachs cells.
2024-06-01 | Late-Onset Tay-Sachs Disease With a Predominantly Neuropsychiatric Presentation: Case Report and Literature Review
Aims Background: Late-onset Tay-Sachs disease (LOTS) is an autosomal recessive lysosomal storage disease due to a variety of mutations in the hexosaminidase-A gene which leads to accumulation of GM2 ganglioside in the brain. It typically presents in late adolescence with a slowly progressive spectrum of neurologic symptoms including lower-extremity weakness with muscle atrophy, dysarthria, incoordination, tremor and mild spasticity and/or dystonia. Psychiatric symptoms including mood disorder, psychosis and neurocognitive symptoms occur in around 50% of cases but are rarely the presenting feature. Methods Case Report: Patient X is a 35 year old man of Irish descent currently detained in an independent hospital locked rehabilitation unit following the breakdown of a care home placement. He first presented to mental health services at the age of 17 with psychomotor agitation, rapidly changeable moods, manic-like symptoms and sexual disinhibition. He was diagnosed with schizoaffective disorder, attention deficit hyperactivity disorder and Asperger's syndrome and he had several compulsory hospital admissions over the next five years before a prolonged period of rehabilitation and discharge to a residential home for people with autistic spectrum disorders. However, he continued to exhibit disruptive behaviour, often triggered by periods of insomnia and had further hospital admissions. When he was 31 his brother was diagnosed with LOTS and this led to him being tested and found to have the same mutation. Results Discussion: There had been no suspicion of a neuropsychiatric disorder prior to the diagnosis of the patient's brother with LOTS and he was treated with conventional psychotropic medication with limited success. However, when the case records were obtained from his first hospital admission there was evidence of dysarthria although the significance of this was not appreciated. With hindsight many of his other symptoms can be seen as indicative of a neuropsychiatric disorder. Conclusion It is important to take a family history and consider a neuropsychiatric condition in families with multiple affected individuals. There are as yet no specific treatments for LOTS, and management is aimed at symptom reduction and enhancing quality of life, but a number of disease modifying strategies are being investigated including enzyme replacement therapy, pharmaceutical chaperone therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell replacement therapy, making it even more important the condition is recognized early.
cell therapies
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.
2023-07-25 | 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.
2017-10-10 | Neural Stem Cell Transplantation and CNS Diseases.
In neurological disorders, pathological lesions in the central nervous system (CNS) may be globally dispersed throughout the brain or localized to specific regions. Although native neural stem cells (NSCs) are present in the adult mammalian brain, intrinsic self-repair of injured adult CNS tissue is inadequate or ineffective. The brain's poor regenerative ability may be due to the fact that NSCs are restricted to discrete locations, are few in number, or are surrounded by a microenvironment that does not support neuronal differentiation. Therapeutic potential of NSC transplantation in CNS diseases characterized by global degeneration requires that gene products and/or replaced cells be widely distributed. Global degenerative CNS diseases include inherited pediatric neurodegenerative diseases (inborn errors of metabolism, including lysosomal storage disorders (LSDs), such as Tay-Sachs-related Sandhoff disease), hypoxic or ischemic encephalopathy, and some adult CNS diseases (such as multiple sclerosis). Both mouse and human NSCs express many chemokines and chemokine receptors (including CXCR4 and adhesion molecules, such as integrins, selectins, and immunoglobulins) that mediate homing to sources of inflammatory chemokines, such as SDF-1α. In mammalian brains of all ages, NSCs may be attracted even at a great distance to regions of neurodegeneration. Consequently, NSC transplantation presents a promising strategy for treating many CNS diseases.
2015-12-18 | Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy.
Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.
gene therapies
2026-06-16 | Clinical Utility of Rapid Whole-Genome Sequencing in Hospitalized Adults With Unexplained Neurologic Presentations.
Adults with unexplained neurologic presentations often undergo extensive evaluations without timely diagnosis. Evidence supporting the clinical utility of rapid whole-genome sequencing (rWGS) in hospitalized adult populations remains limited. We evaluated the diagnostic yield of rWGS in adults hospitalized for unexplained neurologic manifestations and assessed clinical predictors of a phenotype-concordant genetic diagnosis. We performed a retrospective cohort analysis of adult inpatients (≥18 years) undergoing rWGS as part of a structured inpatient clinical genomics implementation at Mayo Clinic between June 2022 and September 2025. Testing was performed after primary team consultation and subsequent assessment by a clinical geneticist. We prespecified a neurologic cohort restricted to patients admitted to the neurology inpatient service in whom presenting neurologic phenotypes were the primary indication for hospitalization and genomics consultation. Patients with non-neurologic primary indications were excluded from this study. The primary outcome was a phenotype-concordant genetic diagnosis on rWGS determined by genotype-phenotype assessment. Analytic objectives included identification of clinical predictors of a phenotype-concordant genetic diagnosis, and a secondary outcome was rWGS-attributable changes in clinical management. Patients with and without phenotype-concordant diagnoses were compared using univariable logistic regression for categorical candidate predictors (odds ratios [ORs] with 95% CIs) and the t test for age. Among 96 adults who completed rWGS, 57 (59.4%) met criteria for the neurologic cohort (mean age 53.0 ± 18.0 years; 35.1% female). Thirteen of 57 (22.8%) received a phenotype-concordant genetic diagnosis involving IFIH1, CNBP, NOTCH1, C9orf72, FGF14, HUWE1, NLRP12, CCM2, PTPN11, FLNA, HEXA, PRNP, and ATXN8OS. Factors associated with a phenotype-concordant diagnosis included a family history of similar neurologic symptoms in first-degree or second-degree relatives (OR 7.4; 95% CI 1.9-31.5), multisystem involvement (OR 6.9; 95% CI 1.6-29.8), refractory psychiatric symptoms (OR 6.1; 95% CI 1.1-35.7), and unexplained ataxia (OR 4.0; 95% CI 1.1-15.1). rWGS directly altered clinical management in 2 cases, including initiation of immunotherapy for an NLRP12-associated autoinflammatory disorder and enrollment in a gene-therapy trial for adult-onset Tay-Sachs disease. In this tertiary-care inpatient cohort, rWGS identified a phenotype-concordant genetic diagnosis in nearly one-quarter of adults. Limitations include single-center design and preselection through specialized consultation, which may limit generalizability.
2026-06-12 | Cerebrospinal delivery of a bidirectional AAV9 vector improves optic nerve and retinal pathology in a sheep model of Tay-Sachs disease.
Tay-Sachs disease (TSD) is a fatal neurodegenerative lysosomal storage disease. The Jacob sheep is the only large-animal model of TSD, yet ocular pathology and the therapeutic potential of gene therapy remain poorly defined. Sheep cohorts included normal controls (n = 3); untreated TSD-affected (n = 4); intravenous AAV9-Bic_HexA/HexB-treated (n = 3); and intracerebroventricular, cisterna magna, and lumbar intrathecal AAV9- Bic_HexA/HexB-treated sheep (cerebrospinal fluid [CSF] therapy; n = 7). Retinal histopathology and immunohistochemistry, retinal whole-mount analyses for retinal ganglion cell (RGC) morphology and density, optic nerve evaluation with p-phenylenediamine (PPD )semi-thin sections, qPCR assessment for vector genomes, and RNAscope probes for transgene expression were performed. Untreated TSD sheep exhibited RGCs with abundant microvesicular cytoplasmic expansion and optic nerve spheroids, with storage material variably staining with periodic acid-Schiff. Marked astrocytosis, microgliosis, and GM2 accumulation within RGCs were present. Optic nerve axon counts and RGC density were significantly reduced, and optic nerve damage scores increased, in untreated and IV-treated sheep but were rescued with short-term CSF therapy. GM2 volume and signal intensity per RGC were significantly reduced following short-term CSF therapy. Minimal but detectable retinal vector genomes and transgene expression were observed. These findings demonstrate retinal and optic nerve pathology in Jacob sheep with TSD and AAV9 therapy.
2026-04-24 | AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models.
GM2 gangliosidoses, including Tay-Sachs (TSD) and Sandhoff (SD) diseases, are lysosomal storage disorders with neurological manifestations caused by the excessive accumulation of GM2 ganglioside due to the deficiency of the β-hexosaminidase A (HexA). Although gene therapy approaches are underway, concerns regarding efficacy and safety remain. Here, we evaluate a tyrosine-mutant adeno-associated virus serotype 9 (AAV9/3) vector encoding modified HEXB (modHEXB) wherein nine amino acid residues are substituted from HEXA. The intracerebroventricular administration of AAV9/3-modHEXB in SD mice results in modHexB expression in the brain, reduces GM2 accumulation, and attenuates neuroinflammation. Furthermore, AAV9/3-modHEXB rescues motor function, and longer lifespan in SD mice. In addition, intrathecal administration in non-human primates and rats demonstrates broad biodistribution and an overall favorable safety profile. These findings support the translational potential of AAV9/3-modHEXB as a gene therapy approach for TSD and SD.
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.
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.
2026-07-28 | Modeling Tay-Sachs Disease in Astrocyte-like Cells Reveals Significant Changes in the Transcriptomic Profile.
Tay-Sachs disease is a rare genetic disorder characterized by the accumulation of GM2 ganglioside in neuronal lysosomes due to deficient β-hexosaminidase A (HexA) activity. Progressive GM2 storage leads to severe neurodegeneration, including developmental delay, motor weakness, seizures, ataxia, and early death, typically by five years of age. Previous studies have elucidated several neuronal mechanisms, including apoptosis, endoplasmic reticulum stress, neuroinflammation, and demyelination, these investigations have focused almost exclusively on neurons. However, other components of the central nervous system, particularly astroglia, may play a critical role in disease pathophysiology as suggested by studies in related lysosomal storage disorders. To address this gap, we generated an astrocyte-like model deficient in HexA by targeted knockdown of the HEXA gene in U87MG astrocytoma cells. The resulting cell line recapitulates key pathological features, including lysosomal accumulation, increased neutral lipid content, reduced mitochondrial mass, and elevated reactive oxygen species production. Transcriptomic analysis revealed significant alterations in pathways associated with neuronal degeneration, synaptic organization, mitochondrial dysfunction, and ganglioside metabolism. In summary, this model reproduces some classical cellular alterations reported in Tay-Sachs disease and could potentially provide novel insight into astrocyte involvement in its pathophysiology. These findings support the relevance of non-neuronal cells in disease pathophysiology and establish this system as a valuable platform for screening potential novel mechanisms and therapeutic approaches. Furthermore, this approach highlights the importance of integrating cell type specific models to better understand disease heterogeneity and providing insights into the progressive neurodegeneration of Tay-Sachs disease, positioning this model as a valuable tool for studying its underlying pathophysiology.
2026-04-28 | Trehalose-Mediated Autophagy Enhancement for GM2 Clearance
Trehalose acts as an mTOR-independent autophagy inducer through TFEB activation and direct lysosomal membrane stabilization. In Tay-Sachs disease, trehalose could enhance autophagic clearance of GM2 ganglioside accumulations while also acting as a chemical chaperone to stabilize any residual HEXA enzyme function through osmolyte effects.
2026-03-10 | B4Galnt1 Deficiency Reverses Severe Neurological Symptoms in a Mouse Model of Tay-Sachs Disease.
Tay-Sachs disease is a severe neurodegenerative disorder caused by mutations in the HEXA gene, which encodes the α-subunit of the β-hexosaminidase A (HexA) enzyme. HexA deficiency leads to abnormal GM2 accumulation, eventually causing cell death and neurodegeneration. A double-knockout mouse model lacking both Hexa and Neu3 genes (Hexa-/-Neu3-/-, DKO) exhibits neuropathological and clinical features similar to those of the disease, including neuroinflammation. B4Galnt1 (ß-1,4-N-acetyl-galactosaminyltransferase 1) is involved in lipid biosynthesis in mice. We hypothesized that creating a triple knockout model (Hexa-/-Neu3-/-B4Galnt1-/-, TKO) could prevent excessive GM2 ganglioside accumulation and reduce disease symptoms. Molecular biology and immunohistochemistry analyses showed that GM2 ganglioside accumulation was halted in TKO mice. Preventing GM2 ganglioside accumulation alleviated neuroinflammation and neuronal death, extending lifespan by more than 18 months. Our findings suggest that knocking out B4Galnt1 to block GM2 ganglioside accumulation may reverse disease symptoms in the DKO mouse model, indicating a promising, safe target for substrate-reduction therapy via siRNA silencing.
2026-01-29 | Symptomatic Benefit of Acetyl-DL-Leucine for Cerebellar Ataxia in Juvenile Tay-Sachs Disease: A Pediatric Case and Literature Review.
Juvenile Tay-Sachs disease (TSD) is a GM2 gangliosidosis that commonly progresses with cerebellar ataxia, while evidence for symptomatic therapies remains limited. Acetyl-leucine has shown short-term benefit for ataxia in several lysosomal storage disorders, but pediatric data in GM2 gangliosidosis are scarce. We report a child with juvenile TSD treated off-label with racemic acetyl-dl-leucine (ADLL) and review the related literature. A six-year-old girl with previously normal early development was referred for autism spectrum features and a strong family history of metabolic disease. During follow-up, she developed seizures and neurodevelopmental regression, and juvenile TSD was diagnosed by molecular analysis and confirmed by enzymatic testing. Progressive cerebellar ataxia subsequently developed, and ADLL was initiated off-label for symptomatic treatment. After 6 months, ataxia improved clinically, with the Scale for the Assessment and Rating of Ataxia score decreasing from 29 to 25. The family reported better gait stability and increased participation in daily life, and no adverse effects were reported. Consistent with emerging data in GM2 gangliosidoses and other lysosomal storage disorders, this case supports the use of ADLL as a potential symptomatic treatment for progressive cerebellar ataxia in juvenile TSD. ADLL was well tolerated and was associated with clinically meaningful improvements in gait, daily participation, and ataxia scores. These findings add pediatric support to the growing evidence that ADLL may be used safely as symptomatic therapy in TSD-related ataxia.
proteins
2025-05-27 | Yeast-Produced Human Recombinant Lysosomal β-Hexosaminidase Efficiently Rescues GM2 Ganglioside Accumulation in Tay-Sachs Disease.
Background: Tay-Sachs disease (TSD) is an autosomal recessive lysosomal storage disorder characterized by the accumulation of GM2 ganglioside due to mutations in the HEXA gene, which encodes the α-subunit of β-Hexosaminidase A. This accumulation leads to significant neuropathological effects and premature death in affected individuals. No effective treatments exist, but enzyme replacement therapies are under investigation. In our previous work, we demonstrated the internalization and efficacy of human recombinant lysosomal β-hexosaminidase A (rhHex-A), produced in the methylotrophic yeast Pichia pastoris, in reducing lipids and lysosomal mass levels in fibroblasts and neural stem cells derived from patient-induced pluripotent stem cells (iPSCs). In this study, we further evaluated the potential of rhHex-A to prevent GM2 accumulation using fibroblast and neuroglia cells from a TSD patient alongside a relevant mouse model. Methods: Fibroblasts and neuroglial cell lines derived from a murine model and TSD patients were treated with 100 nM rhHexA for 72 h. After treatment, cells were stained by anti-GM2 (targeting GM2 ganglioside; KM966) and anti-LAMP1 (lysosomal-associated membrane protein 1) colocalization staining and incubated with 50 nM LysoTracker Red DND-99 to label lysosomes. In addition, GM2AP and HEXB expression were analyzed to assess whether rhHex-A treatment affected the levels of enzymes involved in GM2 ganglioside degradation. Results: Immunofluorescence staining for LysoTracker and colocalization studies of GM2 and Lamp1 indicated reduced lysosomal mass and GM2 levels. Notably, rhHex-A treatment also affected the expression of the HEXB gene, which is involved in GM2 ganglioside metabolism, highlighting a potential regulatory interaction within the metabolic pathway. Conclusions: Here, we report that rhHex-A produced in yeast can efficiently degrade GM2 ganglioside and rescue lysosomal accumulation in TSD cells.
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.
2024-08-31 | Treating late-onset Tay Sachs disease: Brain delivery with a dual trojan horse protein.
Tay-Sachs (TS) disease is a neurodegenerative disease resulting from mutations in the gene encoding the α-subunit (HEXA) of lysosomal β-hexosaminidase A (HexA). We report that (1) recombinant HEXA alone increased HexA activity and decreased GM2 content in human TS glial cells and peripheral mononuclear blood cells; 2) a recombinant chimeric protein composed of HEXA linked to two blood-brain barrier (BBB) entry elements, a transferrin receptor binding sequence and granulocyte-colony stimulating factor, associates with HEXB in vitro; reaches human cultured TS cells lysosomes and mouse brain cells, especially neurons, in vivo; lowers GM2 in cultured human TS cells; lowers whole brain GM2 concentration by approximately 40% within 6 weeks, when injected intravenously (IV) to adult TS-mutant mice mimicking the slow course of late-onset TS; and increases forelimbs grip strength. Hence, a chimeric protein equipped with dual BBB entry elements can transport a large protein such as HEXA to the brain, decrease the accumulation of GM2, and improve muscle strength, thereby providing potential treatment for late-onset TS.
2024-07-12 | Human Recombinant Lysosomal β-Hexosaminidase A produced in P.pastoris efficiently reduced GM2 ganglioside accumulation in Tay- Sachs Disease
Tay-Sachs disease is a progressive lysosomal storage disorder caused by genetic mutations in the HEXA gene encoding α-subunit of β-Hexosaminidase A, which leads to GM2 ganglioside accumulation, particularly in the central nervous system. Lysosomal GM2 ganglioside accumulation causes neuropathology and leads to premature cell death in Tay-Sachs patients, and there is no effective treatment yet. Previously, we produced the human recombinant lysosomal β-Hexosaminidase (rhHex-A) in the yeast Pichia pastoris, demonstrating the capacity to be internalized in different cell lines, and the reduction of stored GM2 gangliosides in patients´ fibroblasts and neural iPSCs. In this study, we use mouse fibroblasts and neuroglia from a novel murine model of Tay-Sachs disease and human Tay-Sachs patients’ neuroglia cells to demonstrate whether rhHex-A could reduce the GM2 accumulation. We treated the cells with rhHex-A to a final concentration of 100 nM, and the efficacy was evaluated using qRT-PCR and Immunocytochemical analysis after 24–72 h of incubation. Altogether, our results suggest that rhHex-A-produced in the yeast Pichia pastoris is a promising therapeutic to mitigate GM2 accumulation in Tay-Sachs cells.
2024-06-01 | Late-Onset Tay-Sachs Disease With a Predominantly Neuropsychiatric Presentation: Case Report and Literature Review
Aims Background: Late-onset Tay-Sachs disease (LOTS) is an autosomal recessive lysosomal storage disease due to a variety of mutations in the hexosaminidase-A gene which leads to accumulation of GM2 ganglioside in the brain. It typically presents in late adolescence with a slowly progressive spectrum of neurologic symptoms including lower-extremity weakness with muscle atrophy, dysarthria, incoordination, tremor and mild spasticity and/or dystonia. Psychiatric symptoms including mood disorder, psychosis and neurocognitive symptoms occur in around 50% of cases but are rarely the presenting feature. Methods Case Report: Patient X is a 35 year old man of Irish descent currently detained in an independent hospital locked rehabilitation unit following the breakdown of a care home placement. He first presented to mental health services at the age of 17 with psychomotor agitation, rapidly changeable moods, manic-like symptoms and sexual disinhibition. He was diagnosed with schizoaffective disorder, attention deficit hyperactivity disorder and Asperger's syndrome and he had several compulsory hospital admissions over the next five years before a prolonged period of rehabilitation and discharge to a residential home for people with autistic spectrum disorders. However, he continued to exhibit disruptive behaviour, often triggered by periods of insomnia and had further hospital admissions. When he was 31 his brother was diagnosed with LOTS and this led to him being tested and found to have the same mutation. Results Discussion: There had been no suspicion of a neuropsychiatric disorder prior to the diagnosis of the patient's brother with LOTS and he was treated with conventional psychotropic medication with limited success. However, when the case records were obtained from his first hospital admission there was evidence of dysarthria although the significance of this was not appreciated. With hindsight many of his other symptoms can be seen as indicative of a neuropsychiatric disorder. Conclusion It is important to take a family history and consider a neuropsychiatric condition in families with multiple affected individuals. There are as yet no specific treatments for LOTS, and management is aimed at symptom reduction and enhancing quality of life, but a number of disease modifying strategies are being investigated including enzyme replacement therapy, pharmaceutical chaperone therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell replacement therapy, making it even more important the condition is recognized early.
cell therapies
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.
2023-07-25 | 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.
2017-10-10 | Neural Stem Cell Transplantation and CNS Diseases.
In neurological disorders, pathological lesions in the central nervous system (CNS) may be globally dispersed throughout the brain or localized to specific regions. Although native neural stem cells (NSCs) are present in the adult mammalian brain, intrinsic self-repair of injured adult CNS tissue is inadequate or ineffective. The brain's poor regenerative ability may be due to the fact that NSCs are restricted to discrete locations, are few in number, or are surrounded by a microenvironment that does not support neuronal differentiation. Therapeutic potential of NSC transplantation in CNS diseases characterized by global degeneration requires that gene products and/or replaced cells be widely distributed. Global degenerative CNS diseases include inherited pediatric neurodegenerative diseases (inborn errors of metabolism, including lysosomal storage disorders (LSDs), such as Tay-Sachs-related Sandhoff disease), hypoxic or ischemic encephalopathy, and some adult CNS diseases (such as multiple sclerosis). Both mouse and human NSCs express many chemokines and chemokine receptors (including CXCR4 and adhesion molecules, such as integrins, selectins, and immunoglobulins) that mediate homing to sources of inflammatory chemokines, such as SDF-1α. In mammalian brains of all ages, NSCs may be attracted even at a great distance to regions of neurodegeneration. Consequently, NSC transplantation presents a promising strategy for treating many CNS diseases.
2015-12-18 | Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy.
Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.
gene therapies
2026-06-16 | Clinical Utility of Rapid Whole-Genome Sequencing in Hospitalized Adults With Unexplained Neurologic Presentations.
Adults with unexplained neurologic presentations often undergo extensive evaluations without timely diagnosis. Evidence supporting the clinical utility of rapid whole-genome sequencing (rWGS) in hospitalized adult populations remains limited. We evaluated the diagnostic yield of rWGS in adults hospitalized for unexplained neurologic manifestations and assessed clinical predictors of a phenotype-concordant genetic diagnosis. We performed a retrospective cohort analysis of adult inpatients (≥18 years) undergoing rWGS as part of a structured inpatient clinical genomics implementation at Mayo Clinic between June 2022 and September 2025. Testing was performed after primary team consultation and subsequent assessment by a clinical geneticist. We prespecified a neurologic cohort restricted to patients admitted to the neurology inpatient service in whom presenting neurologic phenotypes were the primary indication for hospitalization and genomics consultation. Patients with non-neurologic primary indications were excluded from this study. The primary outcome was a phenotype-concordant genetic diagnosis on rWGS determined by genotype-phenotype assessment. Analytic objectives included identification of clinical predictors of a phenotype-concordant genetic diagnosis, and a secondary outcome was rWGS-attributable changes in clinical management. Patients with and without phenotype-concordant diagnoses were compared using univariable logistic regression for categorical candidate predictors (odds ratios [ORs] with 95% CIs) and the t test for age. Among 96 adults who completed rWGS, 57 (59.4%) met criteria for the neurologic cohort (mean age 53.0 ± 18.0 years; 35.1% female). Thirteen of 57 (22.8%) received a phenotype-concordant genetic diagnosis involving IFIH1, CNBP, NOTCH1, C9orf72, FGF14, HUWE1, NLRP12, CCM2, PTPN11, FLNA, HEXA, PRNP, and ATXN8OS. Factors associated with a phenotype-concordant diagnosis included a family history of similar neurologic symptoms in first-degree or second-degree relatives (OR 7.4; 95% CI 1.9-31.5), multisystem involvement (OR 6.9; 95% CI 1.6-29.8), refractory psychiatric symptoms (OR 6.1; 95% CI 1.1-35.7), and unexplained ataxia (OR 4.0; 95% CI 1.1-15.1). rWGS directly altered clinical management in 2 cases, including initiation of immunotherapy for an NLRP12-associated autoinflammatory disorder and enrollment in a gene-therapy trial for adult-onset Tay-Sachs disease. In this tertiary-care inpatient cohort, rWGS identified a phenotype-concordant genetic diagnosis in nearly one-quarter of adults. Limitations include single-center design and preselection through specialized consultation, which may limit generalizability.
2026-06-12 | Cerebrospinal delivery of a bidirectional AAV9 vector improves optic nerve and retinal pathology in a sheep model of Tay-Sachs disease.
Tay-Sachs disease (TSD) is a fatal neurodegenerative lysosomal storage disease. The Jacob sheep is the only large-animal model of TSD, yet ocular pathology and the therapeutic potential of gene therapy remain poorly defined. Sheep cohorts included normal controls (n = 3); untreated TSD-affected (n = 4); intravenous AAV9-Bic_HexA/HexB-treated (n = 3); and intracerebroventricular, cisterna magna, and lumbar intrathecal AAV9- Bic_HexA/HexB-treated sheep (cerebrospinal fluid [CSF] therapy; n = 7). Retinal histopathology and immunohistochemistry, retinal whole-mount analyses for retinal ganglion cell (RGC) morphology and density, optic nerve evaluation with p-phenylenediamine (PPD )semi-thin sections, qPCR assessment for vector genomes, and RNAscope probes for transgene expression were performed. Untreated TSD sheep exhibited RGCs with abundant microvesicular cytoplasmic expansion and optic nerve spheroids, with storage material variably staining with periodic acid-Schiff. Marked astrocytosis, microgliosis, and GM2 accumulation within RGCs were present. Optic nerve axon counts and RGC density were significantly reduced, and optic nerve damage scores increased, in untreated and IV-treated sheep but were rescued with short-term CSF therapy. GM2 volume and signal intensity per RGC were significantly reduced following short-term CSF therapy. Minimal but detectable retinal vector genomes and transgene expression were observed. These findings demonstrate retinal and optic nerve pathology in Jacob sheep with TSD and AAV9 therapy.
2026-04-24 | AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models.
GM2 gangliosidoses, including Tay-Sachs (TSD) and Sandhoff (SD) diseases, are lysosomal storage disorders with neurological manifestations caused by the excessive accumulation of GM2 ganglioside due to the deficiency of the β-hexosaminidase A (HexA). Although gene therapy approaches are underway, concerns regarding efficacy and safety remain. Here, we evaluate a tyrosine-mutant adeno-associated virus serotype 9 (AAV9/3) vector encoding modified HEXB (modHEXB) wherein nine amino acid residues are substituted from HEXA. The intracerebroventricular administration of AAV9/3-modHEXB in SD mice results in modHexB expression in the brain, reduces GM2 accumulation, and attenuates neuroinflammation. Furthermore, AAV9/3-modHEXB rescues motor function, and longer lifespan in SD mice. In addition, intrathecal administration in non-human primates and rats demonstrates broad biodistribution and an overall favorable safety profile. These findings support the translational potential of AAV9/3-modHEXB as a gene therapy approach for TSD and SD.
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.
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.
2026-07-28 | Modeling Tay-Sachs Disease in Astrocyte-like Cells Reveals Significant Changes in the Transcriptomic Profile.
Tay-Sachs disease is a rare genetic disorder characterized by the accumulation of GM2 ganglioside in neuronal lysosomes due to deficient β-hexosaminidase A (HexA) activity. Progressive GM2 storage leads to severe neurodegeneration, including developmental delay, motor weakness, seizures, ataxia, and early death, typically by five years of age. Previous studies have elucidated several neuronal mechanisms, including apoptosis, endoplasmic reticulum stress, neuroinflammation, and demyelination, these investigations have focused almost exclusively on neurons. However, other components of the central nervous system, particularly astroglia, may play a critical role in disease pathophysiology as suggested by studies in related lysosomal storage disorders. To address this gap, we generated an astrocyte-like model deficient in HexA by targeted knockdown of the HEXA gene in U87MG astrocytoma cells. The resulting cell line recapitulates key pathological features, including lysosomal accumulation, increased neutral lipid content, reduced mitochondrial mass, and elevated reactive oxygen species production. Transcriptomic analysis revealed significant alterations in pathways associated with neuronal degeneration, synaptic organization, mitochondrial dysfunction, and ganglioside metabolism. In summary, this model reproduces some classical cellular alterations reported in Tay-Sachs disease and could potentially provide novel insight into astrocyte involvement in its pathophysiology. These findings support the relevance of non-neuronal cells in disease pathophysiology and establish this system as a valuable platform for screening potential novel mechanisms and therapeutic approaches. Furthermore, this approach highlights the importance of integrating cell type specific models to better understand disease heterogeneity and providing insights into the progressive neurodegeneration of Tay-Sachs disease, positioning this model as a valuable tool for studying its underlying pathophysiology.
2026-04-28 | Trehalose-Mediated Autophagy Enhancement for GM2 Clearance
Trehalose acts as an mTOR-independent autophagy inducer through TFEB activation and direct lysosomal membrane stabilization. In Tay-Sachs disease, trehalose could enhance autophagic clearance of GM2 ganglioside accumulations while also acting as a chemical chaperone to stabilize any residual HEXA enzyme function through osmolyte effects.
2026-03-10 | B4Galnt1 Deficiency Reverses Severe Neurological Symptoms in a Mouse Model of Tay-Sachs Disease.
Tay-Sachs disease is a severe neurodegenerative disorder caused by mutations in the HEXA gene, which encodes the α-subunit of the β-hexosaminidase A (HexA) enzyme. HexA deficiency leads to abnormal GM2 accumulation, eventually causing cell death and neurodegeneration. A double-knockout mouse model lacking both Hexa and Neu3 genes (Hexa-/-Neu3-/-, DKO) exhibits neuropathological and clinical features similar to those of the disease, including neuroinflammation. B4Galnt1 (ß-1,4-N-acetyl-galactosaminyltransferase 1) is involved in lipid biosynthesis in mice. We hypothesized that creating a triple knockout model (Hexa-/-Neu3-/-B4Galnt1-/-, TKO) could prevent excessive GM2 ganglioside accumulation and reduce disease symptoms. Molecular biology and immunohistochemistry analyses showed that GM2 ganglioside accumulation was halted in TKO mice. Preventing GM2 ganglioside accumulation alleviated neuroinflammation and neuronal death, extending lifespan by more than 18 months. Our findings suggest that knocking out B4Galnt1 to block GM2 ganglioside accumulation may reverse disease symptoms in the DKO mouse model, indicating a promising, safe target for substrate-reduction therapy via siRNA silencing.
2026-01-29 | Symptomatic Benefit of Acetyl-DL-Leucine for Cerebellar Ataxia in Juvenile Tay-Sachs Disease: A Pediatric Case and Literature Review.
Juvenile Tay-Sachs disease (TSD) is a GM2 gangliosidosis that commonly progresses with cerebellar ataxia, while evidence for symptomatic therapies remains limited. Acetyl-leucine has shown short-term benefit for ataxia in several lysosomal storage disorders, but pediatric data in GM2 gangliosidosis are scarce. We report a child with juvenile TSD treated off-label with racemic acetyl-dl-leucine (ADLL) and review the related literature. A six-year-old girl with previously normal early development was referred for autism spectrum features and a strong family history of metabolic disease. During follow-up, she developed seizures and neurodevelopmental regression, and juvenile TSD was diagnosed by molecular analysis and confirmed by enzymatic testing. Progressive cerebellar ataxia subsequently developed, and ADLL was initiated off-label for symptomatic treatment. After 6 months, ataxia improved clinically, with the Scale for the Assessment and Rating of Ataxia score decreasing from 29 to 25. The family reported better gait stability and increased participation in daily life, and no adverse effects were reported. Consistent with emerging data in GM2 gangliosidoses and other lysosomal storage disorders, this case supports the use of ADLL as a potential symptomatic treatment for progressive cerebellar ataxia in juvenile TSD. ADLL was well tolerated and was associated with clinically meaningful improvements in gait, daily participation, and ataxia scores. These findings add pediatric support to the growing evidence that ADLL may be used safely as symptomatic therapy in TSD-related ataxia.
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Drug Discovery Landscape
2 orphan drug designations for Tay-Sachs disease.
2 orphan drug designations for Tay-Sachs disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
recombinant adenovirus vector AAV2/rh8 expressing human B-hexosaminidase A & B subunits | gene therapies | FDA | — | Na't Tay-Sachs & Allied Diseases Association |
N-acetyl-glucosamine thiazoline | small molecules | FDA | — | ExSAR Corporation |
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