RARE DISEASE
Sandhoff disease
Sandhoff disease
Sandhoff disease
Drug discovery
3
drugs
With orphan designations
Overview
Sandhoff disease is an autosomal recessive lysosomal storage disorder caused by biallelic HEXB gene mutations, resulting in β-hexosaminidase A/B deficiency and toxic GM2 ganglioside accumulation. It presents as infantile (3–24 months), juvenile (2–10 years), or adult-onset forms, characterized by neurodegeneration, hypotonia, seizures, and cherry-red macular spots. Infantile cases show rapid progression to decerebration and death by age 2–4, while later-onset forms feature slower motor/cognitive decline. Diagnosis combines enzyme assays (≤15% residual activity) and genetic confirmation [1][4][9].
Burden
Infantile form: Fatal by age 2–4 years; universal pharmacoresistant epilepsy [1][4]
Adult form: Progressive disability (40+ years lifespan) with mobility loss, dysphagia, and psychiatric complications [13][19]
Economic/emotional impact: High palliative care needs and genetic counseling demands for at-risk families [11][13]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
233 drug discovery papers about Sandhoff disease, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
233 drug discovery papers about Sandhoff disease, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
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.
2024-02-16 | Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders.
Lysosomal storage disorders (LSDs), which are characterized by genetic and metabolic lysosomal dysfunctions, constitute over 60 degenerative diseases with considerable health and economic burdens. However, the mechanisms driving the progressive death of functional cells due to lysosomal defects remain incompletely understood, and broad-spectrum therapeutics against LSDs are lacking. Here, we found that various gene abnormalities that cause LSDs, including Hexb, Gla, Npc1, Ctsd and Gba, all shared mutual properties to robustly autoactivate neuron-intrinsic cGAS-STING signalling, driving neuronal death and disease progression. This signalling was triggered by excessive cytoplasmic congregation of the dsDNA and DNA sensor cGAS in neurons. Genetic ablation of cGAS or STING, digestion of neuronal cytosolic dsDNA by DNase, and repair of neuronal lysosomal dysfunction alleviated symptoms of Sandhoff disease, Fabry disease and Niemann-Pick disease, with substantially reduced neuronal loss. We therefore identify a ubiquitous mechanism mediating the pathogenesis of a variety of LSDs, unveil an inherent connection between lysosomal defects and innate immunity, and suggest a uniform strategy for curing LSDs.
2022-03-31 | HexA-Enzyme Coated Polymer Nanoparticles for the Development of a Drug-Delivery System in the Treatment of Sandhoff Lysosomal Storage Disease
Lysosomal storage disorders (LSDs) are a set of metabolic diseases caused by mutations in genes that are in charge of the production of lysosomal enzymes, resulting in the buildup of non-degraded substrates and the consequent systemic damage that mainly involves the Central Nervous System (CNS). One of the most widely used and studied treatments is Enzyme Replacement Therapy, which is based on the administration of the recombinant deficient enzyme. This strategy has often proved fallacious due to the enzyme instability in body fluids and its inability to reach adequate levels in the CNS. In this work, we developed a system based on nanotechnology that allows a stable enzyme to be obtained by its covalent immobilization on nanoparticles (NPs) of polylactic acid, subsequently administered to a cellular model of LSDs, i.e., Sandhoff disease, caused by the absence or deficiency of the β-d-N-acetyl-hexosaminidase A (HexA) enzyme. The HexA enzymes, loaded onto the polymeric NPs through an immobilization procedure that has already been investigated and validated, were found to be stable over time, maintain optimal kinetic parameters, be able to permeate the plasma membrane, hydrolyze HexA's natural substrate, and restore enzyme activity close to the levels of healthy cells. These results thus lay the foundation for testing the HexA-NPs in animal models of the disease and thus obtaining an efficient drug-delivery system.
small molecules
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.
2026-01-08 | Therapeutic Effects of Nizubaglustat in a Mouse Model of GM2 Gangliosidosis.
Nizubaglustat is a novel selective inhibitor of glucosylceramide synthase (GCS) and the non-lysosomal glucocerebrosidase (NLGase, GbA2) with brain penetrant properties. It is currently in clinical development as an oral treatment for rare lysosomal storage diseases with neurological involvement. One such disease group called GM2 gangliosidosis, to date, has no approved therapeutic treatment. To test the potential efficacy of nizubaglustat in a mouse model of GM2 gangliosidoses, we treated Sandhoff disease (SD) mice carrying a homozygous null mutation in the Hexb gene, as well as healthy heterozygous controls, to understand exposure versus effect under disease conditions. Oral doses of nizubaglustat from 0.2 to 6 mg/kg/day showed linear pharmacokinetics with plasma and brain concentrations sufficient to drive pharmacodynamic changes in markers of target engagement and efficacy. In the brain, an approximately 10-fold increase in GlcCer C16:0 and C18:0 was observed, which is consistent with NLGase inhibition. A statistically significant increase in survival (22%) was noted in SD mice treated at doses as low as 0.2 mg/kg/day compared to controls. Behavioral analyses, which included rotarod and open field tests, were also significantly improved. To understand the added potential mechanism of the improved survival, a subset of neuroinflammatory markers was also examined in specific brain regions. Gene expression studies showed an anti-inflammatory pattern with downregulation of Itgax, Trem2, Cxcl10 genes as an example. Brain immunohistochemistry for GFAP was decreased compared to vehicle treated control animals. These results provide proof-of-concept that nizubaglustat can be a promising therapeutic drug to treat patients with GM2 gangliosidoses.
2025-10-18 | Venglustat in GM2 gangliosidoses and related disorders: Results of the AMETHIST randomized controlled and basket trials.
To evaluate efficacy and safety of venglustat for GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) and cognate diseases. The AMETHIST phase 3, randomized, double-blind, placebo-controlled study evaluated oral venglustat (N = 40) vs placebo (N = 19) in adults with late-onset GM2 gangliosidoses. Coprimary endpoints were annual percent change on the 9-Hole Peg Test and percent change in cerebrospinal fluid (CSF) GM2 ganglioside from baseline to week 104. A secondary population of participants with cognate diseases (N = 16) received open-label venglustat in a "basket" trial. CSF GM2 decreased by 47.6% (90% CI: -52.6, -42.6) with venglustat versus 11.3% (90% CI: -18.3, -4.4) with placebo (difference: -36.2 [90% CI: -44.8, -27.7], P < .0001). The annual percent change in 9-Hole Peg Test was 2.49% (90% CI: 0.28, 4.74) with venglustat versus 0.95% (90% CI: -2.16, 4.15) with placebo (difference: 1.54% [90% CI: -2.33, 5.39], P = .74). Decreased CSF GM2 concentrations did not correlate with clinical endpoints. Secondary population participants remained clinically stable. The most common adverse events were fall, headache, and contusion with placebo and fall, and COVID-19 and headache with venglustat. In adults with late-onset GM2 gangliosidoses, oral venglustat decreased CSF GM2 concentrations but without clinical improvement in the endpoints assessed. No new safety findings were observed.
2025-09-04 | Characterization of Human Recombinant β1,4-GalNAc-Transferase B4GALNT1 and Inhibition by Selected Compounds
Gangliosides are essential for membrane functions, cell recognition, and maintenance of the nervous system. GM2 gangliosidosis is a group of rare genetic lysosomal storage diseases that includes Tay-Sachs disease (TSD), Sandhoff disease (SD), and AB variant. TSD and SD are characterized by deficient β-N-acetyl-hexosaminidase activity. This leads to decreased catabolism of β-N-acetyl-hexosamine-containing ganglioside GM2 in the lysosomes, damage to cells and tissues, and severe neurological symptoms. GM2 is a major ganglioside accumulating in TSD and SD, and is synthesized from GM3 by β1,4-N-acetylgalactosaminyltransferase 1 (B4GALNT1, GM2 synthase). Therapies under development for GM2 gangliosidosis include adeno-associated virus gene therapy, enzyme replacement, and substrate reduction therapy (SRT). The goal of this work was to express and purify human B4GALNT1, characterize its activity, and explore its structural features by protein modeling and substrate docking. We used a panel of synthetic compounds to study their potential inhibition of B4GALNT1 activity. This work can serve to develop SRT for GM2 gangliosidosis.
2025-04-22 | Phenotypic characterisation of human iPSC neuronal models of GM2 gangliosidoses
Gangliosides are crucial components on the outer leaflet of the plasma membrane of many cells, especially neurons. Their functions are broad and varied but their high abundance in neurons leaves these cells especially vulnerable to the effects of their accumulation in ganglioside lysosomal storage disorders (LSD). The GM2 gangliosidoses Tay-Sachs and Sandhoff disease are a type of LSD, resulting from the inability of the lysosome to catabolise the breakdown of the ganglioside GM2. This is due to a loss or mutation of either the HEXA or HEXB genes which form the two subunits of the heterodimeric β-Hexosaminidase A enzyme (βHexA). The pathology of this disease involves a period of normal growth and development, followed by a period of neurodegeneration, resulting in premature death. However, on a cellular level, how the lysosomal accumulation of GM2 leads to neuronal cell death is not well understood. I have generated a model of these diseases using an inducible, human stem cell-based neuronal cell line (i3N). This isogenic cellular system allows for rapid, large-scale growth of stem cell-derived cortical glutamatergic neurons, enabling experiments that require large amounts of input material such as mass spectrometry-based proteomic analysis. Utilising CRISPRi, I have knocked down the expression of HEXA or HEXB to disease relevant levels. Analysis of gene expression and enzyme activity validates the loss of βHexA, whilst profiling of the ganglioside repertoire indicates massive accumulation of the GM2 ganglioside, increasing over time. Further validation of these cell lines using fluorescence and electron microscopy confirms an abundance of enlarged lysosomes containing the GM2 ganglioside with multilamellar lysosomal substructures typical of these diseases. Furthermore, proteomic analysis of these cells reveals that accumulation of GM2 hugely increases abundance of a subset of lysosomal proteins, especially those involved in lysosomal exocytosis and lipid transport. Importantly, I have identified that in addition to intracellular GM2 accumulation, the ganglioside profile of the plasma membrane of these neurons also shows accumulation of GM2, likely due to fusion of the lysosomal compartment with the PM. Proteomic analysis of changes specifically at the plasma membrane has identified significant changes in abundances of synaptic proteins. Synaptic signalling deficits or changes have been implicated in other lysosomal storage disorders and may be the root cause for the neurodegeneration seen in this disease. To address this, I have measured the electrical signalling of these cells V using a Multi Electrode Array and show, for the first time, synchronous network signalling in i 3Neurons and an alteration of this signalling in GM2 gangliosidosis neurons. To address which disease phenotypes are due to specific accumulation of GM2, I have also generated a GM1 gangliosidosis i3N line and identify many shared changes between these two closely related diseases. Finally, to exemplify the usefulness of using human neurons to correctly test potential treatments for these diseases, I trial the use of ML-SA5, a drug shown to induce lysosomal exocytosis in non-neuronal cell types and proposed as a treatment for neurodegenerative lysosomal storage disorders. I show the deleterious effects that this drug has on synaptic signalling, without materially alleviating lysosomal burden, further highlighting the need to use the right model to test treatments for disease. Overall, I provide novel insights into the mechanisms of cellular dysfunction in the GM2 gangliosidoses and provide an exciting platform to test drug treatments for these diseases.
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.
2025-10-19 | Decoding the Hex-GM2-MGL2 axis in microglia-neuron crosstalk.
Neurodegeneration arises from malfunctional intercellular interactions within the central nervous system (CNS). In a recent study, Frosch et al. identified a microglia-neuron enzyme delivery system the dysfunction of which drives Sandhoff disease, but which can be corrected by hematopoietic replacement therapy, thereby revealing new therapeutic opportunities for hereditary and sporadic neurodegenerative disorders.
2025-08-29 | Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health.
Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme (Hexb). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To investigate how a microglial gene is involved in neuronal homeostasis, here we show that β-hexosaminidase is secreted by microglia and integrated into the lysosomal compartment of neurons. To assess therapeutic relevance, we treat the Hexb-/- SD mouse model with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaces Hexb-/- microglia with Hexb-sufficient cells. Microglial replacement reverses apoptotic gene signatures, improves behavior, restores β-hexosaminidase enzymatic activity and Hexb expression, prevents substrate buildup, and normalizes neuronal lysosomal phenotypes, underscoring the critical role of myeloid-derived β-hexosaminidase in maintaining neuronal health and establishing microglial replacement as a potential LSD therapy.
2025-08-07 | Microglia-neuron crosstalk through Hex-GM2-MGL2 maintains brain homeostasis.
As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses2. Here, by combining unbiased lipidomics and high-resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell-type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of β-hexosaminidase, in both mice and patients with neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner3. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin 2 receptor on microglia through N-acetylgalactosamine residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells is able to break this degenerative cycle and fully restore central nervous system homeostasis. Our results reveal a mode of bidirectional microglia-neuron communication centred around GM2 ganglioside turnover, identify a microgliopathy and offer therapeutic avenues for these maladies.
2025-08-07 | Therapeutic genetic restoration through allogeneic brain microglia replacement.
Migration of transplanted allogeneic myeloid cells into the brain following systemic haematopoietic stem and progenitor cell transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases1-3. However, the toxic myeloablation required for allogeneic HCT can cause serious, life-threatening side effects, limiting its applicability. Moreover, transplanted allogeneic myeloid cells are highly vulnerable to rejection even in an immune-privileged organ like the brain. Here we report a brain-restricted, high-efficiency microglia replacement approach without myeloablative preconditioning. Contrary to previous assumptions, we found that haematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment, and Sca1- committed progenitor cells were highly efficient in replacing microglia following intracerebral injection. This finding enabled the development of brain-restricted preconditioning and avoided long-term peripheral engraftment, thus eliminating complications such as graft-versus-host disease. Evaluating its therapeutic potential, we found that our allogeneic microglia replacement method rescued the mouse model of Sandhoff disease, a lysosomal storage disease caused by hexosaminidase B deficiency. In support of the translational relevance of this approach, we discovered that human embryonic stem cell-derived myeloid progenitor cells display a similar engraftment potential following brain-restricted conditioning. Our results overcome current limitations of conventional HCT and may pave the way for the development of allogeneic microglial cell therapies for the brain.
gene therapies
2025-09-30 | Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep.
Tay-Sachs 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 (HexA) that degrades GM2 ganglioside. This report describes a 5 year-long study using a bidirectional AAV9 vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the Tay-Sachs sheep model. Bidirectional AAV9 was delivered intravenously or through various cerebral spinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM) and lumbar delivery (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV and LIT) with treated animals survived up to 5 years of age (untreated Tay-Sachs animals die ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy including MRI, MR spectroscopy, diffusion tensor imaging as well as CSF levels of GM2 ganglioside and hexosaminidase A (HexA) activity was evident. Post-mortem 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 Tay-Sachs and Sandhoff disease patients.
2025-06-22 | Secondary accumulation of lyso-platelet activating factors in lysosomal storage diseases.
Lysosomal storage diseases (LSDs) are a group of inherited disorders caused by defects in genes that encode lysosomal enzymes, transmembrane proteins, or transport proteins. These defects typically lead to the accumulation of undegraded substrates or obstructed substances in lysosomes, serving as primary storage materials. However, in certain LSDs, secondary storage products-such as glycosphingolipids, phospholipids, and cholesterol-can also accumulate in tissues, independent of the primary enzyme or protein defect. In our recent studies, we identified lyso-platelet activating factors (lyso-PAFs) as secondary storage compounds in multiple LSDs, including Niemann-Pick disease type C1 (NPC1), GM2 activator deficiency, and GM1 gangliosidosis (GM1). Our ongoing work suggests that lyso-PAFs are also prevalent secondary storage products in Niemann-Pick disease type A (NPA), Sandhoff disease (SD), Tay-Sachs disease (TSD), and Krabbe disease (KD). We observed that elevated lyso-PAF levels were significantly correlated with the accumulation of primary storage substances in these disorders, indicating their potential as biomarkers for disease progression in these LSDs. Moreover, treatment with adeno-associated virus (AAV)-based gene therapies led to a reduction in lyso-PAF levels in the central nervous systems of TSD sheep and GM1 cats, further supporting their potential as biomarkers for therapeutic efficacy. While it remains unclear whether changes in lyso-PAFs contribute directly to disease pathology or simply reflect disease progression, further research into the enzymes involved in their synthesis and degradation is essential for uncovering their functional role in the cellular physiology and pathology of LSDs. Thus, further exploration of lyso-PAF in biofluids as prognostic and pharmacodynamic biomarkers is warranted.
2025-05-26 | Subacute Juvenile Sandhoff Disease: A Progressive Neurodegenerative Disorder.
To present a case of subacute juvenile Sandhoff disease (SD), a rare neurodegenerative disorder occurring in 1 in 4,00,000. SD is a rare neurodegenerative disorder grouped under GM2 gangliosidosis that results from a mutation in the HEXB gene, which encodes the β-subunit of β-hexosaminidase, leading to a deficiency of hexosaminidases A and B. It affects the metabolism of GM2 gangliosides, causing the enzyme to accumulate within lysosomes in visceral cells as well as the central nervous system (CNS). Depending on the age of onset, the disease presents in three different phenotypes: (1) acute infantile SD, with onset before 6 months; (2) subacute juvenile SD (SJSD), with onset at 2-5 years; and (3) late-onset SD, with onset in late teens or young adulthood. A rare case of a 10-year-old female child presented with right lower tooth pain. She had attained developmental milestones normally until about age 4 but later exhibited regressive changes around 4.5-5 years of age. She became progressively slow and unsteady. Investigations, including magnetic resonance imaging (MRI) of the brain, whole-exome sequencing, and biochemical genetic testing, led to a diagnosis of SJSD. Not much literature has been published to highlight how SJSD impacts daily life and function. However, the functional limitations resulting from neurodegeneration may adversely affect daily activities. SJSD needs multidisciplinary involvement, including a physiotherapist, speech therapist, and psychiatrist, to monitor the prognosis regularly, diagnose future manifestations requiring supportive care, and ensure adequate functioning and activity of daily living. Kadam BD, Jampanapalli SR, Ranganathan R, et al. Subacute Juvenile Sandhoff Disease: A Progressive Neurodegenerative Disorder. Int J Clin Pediatr Dent 2025;18(3):317-320.
2025-05-21 | Myotonic Discharges in Infantile Sandhoff Disease
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2025-05-08 | Characterization of Immune Responses to rAAVrh8 Gene Therapy for GM2 Gangliosidosis in Phase 1/2 Trial
Abstract Understanding how the immune system responds to adreno-associated virus (AAV) gene therapy and potentially modulating that response is vital to their safety and ultimate success. However, the immune response in the central nervous system (CNS) to AAV gene therapy is still not well understood. Here, we characterized the immune responses to AAVrh8 vectors injected into the thalamus and cerebral spinal fluid (CSF) of Tay-Sachs (TSD) and Sandhoff (SD) disease patients. Nine patients in four dose cohorts were treated with gene therapy while being immunosuppressed with rituximab, sirolimus and prednisolone. Neutralizing antibodies against AAV capsid were detected in the serum of 9/9 patients and in the CSF of 7/9 patients. Specific T-cell responses against the AAV capsid were documented in all patients, with most patients developing responses at 2–3 weeks post-injection. Flow cytometry suggested the induction of capsid-specific regulatory T-cells in the periphery. Local immune responses were detected by cytokine analysis of the CSF along with upregulation of several chemokines, including CXCL8, CXCL9 and CXCL10. These Phase I/II clinical trial data provide valuable insights into how the human immune system responds to direct administration of AAV into the CNS and important assessments on the efficacy of the immune suppression regimen which can be used to inform future AAV clinical trials.
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.
2024-02-16 | Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders.
Lysosomal storage disorders (LSDs), which are characterized by genetic and metabolic lysosomal dysfunctions, constitute over 60 degenerative diseases with considerable health and economic burdens. However, the mechanisms driving the progressive death of functional cells due to lysosomal defects remain incompletely understood, and broad-spectrum therapeutics against LSDs are lacking. Here, we found that various gene abnormalities that cause LSDs, including Hexb, Gla, Npc1, Ctsd and Gba, all shared mutual properties to robustly autoactivate neuron-intrinsic cGAS-STING signalling, driving neuronal death and disease progression. This signalling was triggered by excessive cytoplasmic congregation of the dsDNA and DNA sensor cGAS in neurons. Genetic ablation of cGAS or STING, digestion of neuronal cytosolic dsDNA by DNase, and repair of neuronal lysosomal dysfunction alleviated symptoms of Sandhoff disease, Fabry disease and Niemann-Pick disease, with substantially reduced neuronal loss. We therefore identify a ubiquitous mechanism mediating the pathogenesis of a variety of LSDs, unveil an inherent connection between lysosomal defects and innate immunity, and suggest a uniform strategy for curing LSDs.
2022-03-31 | HexA-Enzyme Coated Polymer Nanoparticles for the Development of a Drug-Delivery System in the Treatment of Sandhoff Lysosomal Storage Disease
Lysosomal storage disorders (LSDs) are a set of metabolic diseases caused by mutations in genes that are in charge of the production of lysosomal enzymes, resulting in the buildup of non-degraded substrates and the consequent systemic damage that mainly involves the Central Nervous System (CNS). One of the most widely used and studied treatments is Enzyme Replacement Therapy, which is based on the administration of the recombinant deficient enzyme. This strategy has often proved fallacious due to the enzyme instability in body fluids and its inability to reach adequate levels in the CNS. In this work, we developed a system based on nanotechnology that allows a stable enzyme to be obtained by its covalent immobilization on nanoparticles (NPs) of polylactic acid, subsequently administered to a cellular model of LSDs, i.e., Sandhoff disease, caused by the absence or deficiency of the β-d-N-acetyl-hexosaminidase A (HexA) enzyme. The HexA enzymes, loaded onto the polymeric NPs through an immobilization procedure that has already been investigated and validated, were found to be stable over time, maintain optimal kinetic parameters, be able to permeate the plasma membrane, hydrolyze HexA's natural substrate, and restore enzyme activity close to the levels of healthy cells. These results thus lay the foundation for testing the HexA-NPs in animal models of the disease and thus obtaining an efficient drug-delivery system.
small molecules
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.
2026-01-08 | Therapeutic Effects of Nizubaglustat in a Mouse Model of GM2 Gangliosidosis.
Nizubaglustat is a novel selective inhibitor of glucosylceramide synthase (GCS) and the non-lysosomal glucocerebrosidase (NLGase, GbA2) with brain penetrant properties. It is currently in clinical development as an oral treatment for rare lysosomal storage diseases with neurological involvement. One such disease group called GM2 gangliosidosis, to date, has no approved therapeutic treatment. To test the potential efficacy of nizubaglustat in a mouse model of GM2 gangliosidoses, we treated Sandhoff disease (SD) mice carrying a homozygous null mutation in the Hexb gene, as well as healthy heterozygous controls, to understand exposure versus effect under disease conditions. Oral doses of nizubaglustat from 0.2 to 6 mg/kg/day showed linear pharmacokinetics with plasma and brain concentrations sufficient to drive pharmacodynamic changes in markers of target engagement and efficacy. In the brain, an approximately 10-fold increase in GlcCer C16:0 and C18:0 was observed, which is consistent with NLGase inhibition. A statistically significant increase in survival (22%) was noted in SD mice treated at doses as low as 0.2 mg/kg/day compared to controls. Behavioral analyses, which included rotarod and open field tests, were also significantly improved. To understand the added potential mechanism of the improved survival, a subset of neuroinflammatory markers was also examined in specific brain regions. Gene expression studies showed an anti-inflammatory pattern with downregulation of Itgax, Trem2, Cxcl10 genes as an example. Brain immunohistochemistry for GFAP was decreased compared to vehicle treated control animals. These results provide proof-of-concept that nizubaglustat can be a promising therapeutic drug to treat patients with GM2 gangliosidoses.
2025-10-18 | Venglustat in GM2 gangliosidoses and related disorders: Results of the AMETHIST randomized controlled and basket trials.
To evaluate efficacy and safety of venglustat for GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) and cognate diseases. The AMETHIST phase 3, randomized, double-blind, placebo-controlled study evaluated oral venglustat (N = 40) vs placebo (N = 19) in adults with late-onset GM2 gangliosidoses. Coprimary endpoints were annual percent change on the 9-Hole Peg Test and percent change in cerebrospinal fluid (CSF) GM2 ganglioside from baseline to week 104. A secondary population of participants with cognate diseases (N = 16) received open-label venglustat in a "basket" trial. CSF GM2 decreased by 47.6% (90% CI: -52.6, -42.6) with venglustat versus 11.3% (90% CI: -18.3, -4.4) with placebo (difference: -36.2 [90% CI: -44.8, -27.7], P < .0001). The annual percent change in 9-Hole Peg Test was 2.49% (90% CI: 0.28, 4.74) with venglustat versus 0.95% (90% CI: -2.16, 4.15) with placebo (difference: 1.54% [90% CI: -2.33, 5.39], P = .74). Decreased CSF GM2 concentrations did not correlate with clinical endpoints. Secondary population participants remained clinically stable. The most common adverse events were fall, headache, and contusion with placebo and fall, and COVID-19 and headache with venglustat. In adults with late-onset GM2 gangliosidoses, oral venglustat decreased CSF GM2 concentrations but without clinical improvement in the endpoints assessed. No new safety findings were observed.
2025-09-04 | Characterization of Human Recombinant β1,4-GalNAc-Transferase B4GALNT1 and Inhibition by Selected Compounds
Gangliosides are essential for membrane functions, cell recognition, and maintenance of the nervous system. GM2 gangliosidosis is a group of rare genetic lysosomal storage diseases that includes Tay-Sachs disease (TSD), Sandhoff disease (SD), and AB variant. TSD and SD are characterized by deficient β-N-acetyl-hexosaminidase activity. This leads to decreased catabolism of β-N-acetyl-hexosamine-containing ganglioside GM2 in the lysosomes, damage to cells and tissues, and severe neurological symptoms. GM2 is a major ganglioside accumulating in TSD and SD, and is synthesized from GM3 by β1,4-N-acetylgalactosaminyltransferase 1 (B4GALNT1, GM2 synthase). Therapies under development for GM2 gangliosidosis include adeno-associated virus gene therapy, enzyme replacement, and substrate reduction therapy (SRT). The goal of this work was to express and purify human B4GALNT1, characterize its activity, and explore its structural features by protein modeling and substrate docking. We used a panel of synthetic compounds to study their potential inhibition of B4GALNT1 activity. This work can serve to develop SRT for GM2 gangliosidosis.
2025-04-22 | Phenotypic characterisation of human iPSC neuronal models of GM2 gangliosidoses
Gangliosides are crucial components on the outer leaflet of the plasma membrane of many cells, especially neurons. Their functions are broad and varied but their high abundance in neurons leaves these cells especially vulnerable to the effects of their accumulation in ganglioside lysosomal storage disorders (LSD). The GM2 gangliosidoses Tay-Sachs and Sandhoff disease are a type of LSD, resulting from the inability of the lysosome to catabolise the breakdown of the ganglioside GM2. This is due to a loss or mutation of either the HEXA or HEXB genes which form the two subunits of the heterodimeric β-Hexosaminidase A enzyme (βHexA). The pathology of this disease involves a period of normal growth and development, followed by a period of neurodegeneration, resulting in premature death. However, on a cellular level, how the lysosomal accumulation of GM2 leads to neuronal cell death is not well understood. I have generated a model of these diseases using an inducible, human stem cell-based neuronal cell line (i3N). This isogenic cellular system allows for rapid, large-scale growth of stem cell-derived cortical glutamatergic neurons, enabling experiments that require large amounts of input material such as mass spectrometry-based proteomic analysis. Utilising CRISPRi, I have knocked down the expression of HEXA or HEXB to disease relevant levels. Analysis of gene expression and enzyme activity validates the loss of βHexA, whilst profiling of the ganglioside repertoire indicates massive accumulation of the GM2 ganglioside, increasing over time. Further validation of these cell lines using fluorescence and electron microscopy confirms an abundance of enlarged lysosomes containing the GM2 ganglioside with multilamellar lysosomal substructures typical of these diseases. Furthermore, proteomic analysis of these cells reveals that accumulation of GM2 hugely increases abundance of a subset of lysosomal proteins, especially those involved in lysosomal exocytosis and lipid transport. Importantly, I have identified that in addition to intracellular GM2 accumulation, the ganglioside profile of the plasma membrane of these neurons also shows accumulation of GM2, likely due to fusion of the lysosomal compartment with the PM. Proteomic analysis of changes specifically at the plasma membrane has identified significant changes in abundances of synaptic proteins. Synaptic signalling deficits or changes have been implicated in other lysosomal storage disorders and may be the root cause for the neurodegeneration seen in this disease. To address this, I have measured the electrical signalling of these cells V using a Multi Electrode Array and show, for the first time, synchronous network signalling in i 3Neurons and an alteration of this signalling in GM2 gangliosidosis neurons. To address which disease phenotypes are due to specific accumulation of GM2, I have also generated a GM1 gangliosidosis i3N line and identify many shared changes between these two closely related diseases. Finally, to exemplify the usefulness of using human neurons to correctly test potential treatments for these diseases, I trial the use of ML-SA5, a drug shown to induce lysosomal exocytosis in non-neuronal cell types and proposed as a treatment for neurodegenerative lysosomal storage disorders. I show the deleterious effects that this drug has on synaptic signalling, without materially alleviating lysosomal burden, further highlighting the need to use the right model to test treatments for disease. Overall, I provide novel insights into the mechanisms of cellular dysfunction in the GM2 gangliosidoses and provide an exciting platform to test drug treatments for these diseases.
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.
2025-10-19 | Decoding the Hex-GM2-MGL2 axis in microglia-neuron crosstalk.
Neurodegeneration arises from malfunctional intercellular interactions within the central nervous system (CNS). In a recent study, Frosch et al. identified a microglia-neuron enzyme delivery system the dysfunction of which drives Sandhoff disease, but which can be corrected by hematopoietic replacement therapy, thereby revealing new therapeutic opportunities for hereditary and sporadic neurodegenerative disorders.
2025-08-29 | Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health.
Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme (Hexb). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To investigate how a microglial gene is involved in neuronal homeostasis, here we show that β-hexosaminidase is secreted by microglia and integrated into the lysosomal compartment of neurons. To assess therapeutic relevance, we treat the Hexb-/- SD mouse model with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaces Hexb-/- microglia with Hexb-sufficient cells. Microglial replacement reverses apoptotic gene signatures, improves behavior, restores β-hexosaminidase enzymatic activity and Hexb expression, prevents substrate buildup, and normalizes neuronal lysosomal phenotypes, underscoring the critical role of myeloid-derived β-hexosaminidase in maintaining neuronal health and establishing microglial replacement as a potential LSD therapy.
2025-08-07 | Microglia-neuron crosstalk through Hex-GM2-MGL2 maintains brain homeostasis.
As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses2. Here, by combining unbiased lipidomics and high-resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell-type-specific mutants, we identified a previously unknown mode of microglial interaction with neurons. During homeostasis, microglia deliver the lysosomal enzyme β-hexosaminidase to neurons for the degradation of the ganglioside GM2 that is integral to maintaining cell membrane organization and function. Absence of Hexb, encoding the β subunit of β-hexosaminidase, in both mice and patients with neurodegenerative Sandhoff disease leads to a massive accumulation of GM2 derivatives in a characteristic spatiotemporal manner3. In mice, neuronal GM2 gangliosides subsequently engage the macrophage galactose-type lectin 2 receptor on microglia through N-acetylgalactosamine residues, leading to lethal neurodegeneration. Notably, replacement of microglia with peripherally derived microglia-like cells is able to break this degenerative cycle and fully restore central nervous system homeostasis. Our results reveal a mode of bidirectional microglia-neuron communication centred around GM2 ganglioside turnover, identify a microgliopathy and offer therapeutic avenues for these maladies.
2025-08-07 | Therapeutic genetic restoration through allogeneic brain microglia replacement.
Migration of transplanted allogeneic myeloid cells into the brain following systemic haematopoietic stem and progenitor cell transplantation (HCT) holds great promise as a therapeutic modality to correct genetic deficiencies in the brain such as lysosomal storage diseases1-3. However, the toxic myeloablation required for allogeneic HCT can cause serious, life-threatening side effects, limiting its applicability. Moreover, transplanted allogeneic myeloid cells are highly vulnerable to rejection even in an immune-privileged organ like the brain. Here we report a brain-restricted, high-efficiency microglia replacement approach without myeloablative preconditioning. Contrary to previous assumptions, we found that haematopoietic stem cells are not required to repopulate the myeloid compartment of the brain environment, and Sca1- committed progenitor cells were highly efficient in replacing microglia following intracerebral injection. This finding enabled the development of brain-restricted preconditioning and avoided long-term peripheral engraftment, thus eliminating complications such as graft-versus-host disease. Evaluating its therapeutic potential, we found that our allogeneic microglia replacement method rescued the mouse model of Sandhoff disease, a lysosomal storage disease caused by hexosaminidase B deficiency. In support of the translational relevance of this approach, we discovered that human embryonic stem cell-derived myeloid progenitor cells display a similar engraftment potential following brain-restricted conditioning. Our results overcome current limitations of conventional HCT and may pave the way for the development of allogeneic microglial cell therapies for the brain.
gene therapies
2025-09-30 | Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep.
Tay-Sachs 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 (HexA) that degrades GM2 ganglioside. This report describes a 5 year-long study using a bidirectional AAV9 vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the Tay-Sachs sheep model. Bidirectional AAV9 was delivered intravenously or through various cerebral spinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM) and lumbar delivery (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV and LIT) with treated animals survived up to 5 years of age (untreated Tay-Sachs animals die ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy including MRI, MR spectroscopy, diffusion tensor imaging as well as CSF levels of GM2 ganglioside and hexosaminidase A (HexA) activity was evident. Post-mortem 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 Tay-Sachs and Sandhoff disease patients.
2025-06-22 | Secondary accumulation of lyso-platelet activating factors in lysosomal storage diseases.
Lysosomal storage diseases (LSDs) are a group of inherited disorders caused by defects in genes that encode lysosomal enzymes, transmembrane proteins, or transport proteins. These defects typically lead to the accumulation of undegraded substrates or obstructed substances in lysosomes, serving as primary storage materials. However, in certain LSDs, secondary storage products-such as glycosphingolipids, phospholipids, and cholesterol-can also accumulate in tissues, independent of the primary enzyme or protein defect. In our recent studies, we identified lyso-platelet activating factors (lyso-PAFs) as secondary storage compounds in multiple LSDs, including Niemann-Pick disease type C1 (NPC1), GM2 activator deficiency, and GM1 gangliosidosis (GM1). Our ongoing work suggests that lyso-PAFs are also prevalent secondary storage products in Niemann-Pick disease type A (NPA), Sandhoff disease (SD), Tay-Sachs disease (TSD), and Krabbe disease (KD). We observed that elevated lyso-PAF levels were significantly correlated with the accumulation of primary storage substances in these disorders, indicating their potential as biomarkers for disease progression in these LSDs. Moreover, treatment with adeno-associated virus (AAV)-based gene therapies led to a reduction in lyso-PAF levels in the central nervous systems of TSD sheep and GM1 cats, further supporting their potential as biomarkers for therapeutic efficacy. While it remains unclear whether changes in lyso-PAFs contribute directly to disease pathology or simply reflect disease progression, further research into the enzymes involved in their synthesis and degradation is essential for uncovering their functional role in the cellular physiology and pathology of LSDs. Thus, further exploration of lyso-PAF in biofluids as prognostic and pharmacodynamic biomarkers is warranted.
2025-05-26 | Subacute Juvenile Sandhoff Disease: A Progressive Neurodegenerative Disorder.
To present a case of subacute juvenile Sandhoff disease (SD), a rare neurodegenerative disorder occurring in 1 in 4,00,000. SD is a rare neurodegenerative disorder grouped under GM2 gangliosidosis that results from a mutation in the HEXB gene, which encodes the β-subunit of β-hexosaminidase, leading to a deficiency of hexosaminidases A and B. It affects the metabolism of GM2 gangliosides, causing the enzyme to accumulate within lysosomes in visceral cells as well as the central nervous system (CNS). Depending on the age of onset, the disease presents in three different phenotypes: (1) acute infantile SD, with onset before 6 months; (2) subacute juvenile SD (SJSD), with onset at 2-5 years; and (3) late-onset SD, with onset in late teens or young adulthood. A rare case of a 10-year-old female child presented with right lower tooth pain. She had attained developmental milestones normally until about age 4 but later exhibited regressive changes around 4.5-5 years of age. She became progressively slow and unsteady. Investigations, including magnetic resonance imaging (MRI) of the brain, whole-exome sequencing, and biochemical genetic testing, led to a diagnosis of SJSD. Not much literature has been published to highlight how SJSD impacts daily life and function. However, the functional limitations resulting from neurodegeneration may adversely affect daily activities. SJSD needs multidisciplinary involvement, including a physiotherapist, speech therapist, and psychiatrist, to monitor the prognosis regularly, diagnose future manifestations requiring supportive care, and ensure adequate functioning and activity of daily living. Kadam BD, Jampanapalli SR, Ranganathan R, et al. Subacute Juvenile Sandhoff Disease: A Progressive Neurodegenerative Disorder. Int J Clin Pediatr Dent 2025;18(3):317-320.
2025-05-21 | Myotonic Discharges in Infantile Sandhoff Disease
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2025-05-08 | Characterization of Immune Responses to rAAVrh8 Gene Therapy for GM2 Gangliosidosis in Phase 1/2 Trial
Abstract Understanding how the immune system responds to adreno-associated virus (AAV) gene therapy and potentially modulating that response is vital to their safety and ultimate success. However, the immune response in the central nervous system (CNS) to AAV gene therapy is still not well understood. Here, we characterized the immune responses to AAVrh8 vectors injected into the thalamus and cerebral spinal fluid (CSF) of Tay-Sachs (TSD) and Sandhoff (SD) disease patients. Nine patients in four dose cohorts were treated with gene therapy while being immunosuppressed with rituximab, sirolimus and prednisolone. Neutralizing antibodies against AAV capsid were detected in the serum of 9/9 patients and in the CSF of 7/9 patients. Specific T-cell responses against the AAV capsid were documented in all patients, with most patients developing responses at 2–3 weeks post-injection. Flow cytometry suggested the induction of capsid-specific regulatory T-cells in the periphery. Local immune responses were detected by cytokine analysis of the CSF along with upregulation of several chemokines, including CXCL8, CXCL9 and CXCL10. These Phase I/II clinical trial data provide valuable insights into how the human immune system responds to direct administration of AAV into the CNS and important assessments on the efficacy of the immune suppression regimen which can be used to inform future AAV clinical trials.
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Drug Discovery Landscape
3 orphan drug designations for Sandhoff disease.
3 orphan drug designations for Sandhoff disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Biphenyl-substituted L-ido configured deoxynojirimycin derivative | small molecules | FDA | 2022-01-31 | — | Azafaros BV |
recombinant adeno- associated virus vector AAV2/rh8 expressing human B-hexosaminidase A and B subunits | gene therapies | FDA | 2013-03-25 | — | Nat'l Tay-Sachs & Allied Diseases Association |
pyrimethamine | small molecules | FDA | 2011-08-16 | — | ExSAR Corporation |
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