RARE DISEASE
Sialidosis
Sialidosis
Sialidosis
Drug discovery
0
drugs
With orphan designations
Overview
Sialidosis is a rare autosomal recessive lysosomal storage disorder caused by NEU1 gene mutations, resulting in neuraminidase deficiency and accumulation of sialylated metabolites. It manifests as type I (late-onset, normosomatic) with myoclonus, ataxia, vision loss, and cherry-red spots, or type II (early-onset, dysmorphic) with developmental delay, organomegaly, dysostosis multiplex, and neonatal lethality in severe forms. Diagnosis relies on genetic testing and enzyme assays. Management is supportive, focusing on symptom control [1][6][13].
Burden
Type I: Progressive motor disability (wheelchair dependency) and vision impairment with preserved cognition [7][13].
Type II: High mortality (neonatal hydrops, organ failure); multisystem complications increase healthcare costs [6][10][13].
No disease-modifying treatments; lifelong multidisciplinary care required [1][8].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders
Research Papers
81 drug discovery papers about Sialidosis, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
81 drug discovery papers about Sialidosis, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-07-17 | Sialidosis type1 with cardiac malformation: A case report
Sialidosis is a rare autosomal recessive lysosomal storage disease caused by a variant in the neuraminidase 1 (NEU1) gene encoding lysosomal neuraminidase, and is a rare cause of progressive myoclonus epilepsies (PME). Sialidosis is classified into two types. Sialidosis type 1 is a relatively mild late-onset form with ataxia, myoclonus, macular cherry-red spot, seizures, and non-dysmorphic features. Sialidosis type 2 has congenital, infantile and juvenile-onset forms, and has more severe feature, including ascites, coarse facies, dysostosis multiplex, macular cherry-red spot, hepatosplenomegaly, and developmental delay than type 1. Our case, a 29-year-old male, had shown normal development up to the age of 12 years and 5 months. Subsequently, he developed ataxia and myoclonus. At age 12 years and 11 months, generalized tonic-clonic seizures occurred with ataxia, myoclonus, intentional tremor, borderline intelligence, and cherry-red macular spot. Skin fibroblast enzymological analysis of neuraminidase yielded a value below 1 nmol/h/mg protein. NEU1 gene findings were consistent with compound heterozygous missense variant c.1034C>T(p.Thr345Ile) and c.239C>T(p.Pro80Leu), while electron microscopy of skinfibroblasts showed vacuoles and dense body deposition in both neuroblasts and Schwann cells. In addition, this is the first reported case of sialidosis type 1 associated with a quadricuspid aortic valve malformation. Collectively, the above findings indicated a diagnosis of sialidosis type 1 with cardiac malformation. The involuntary movement improved temporarily in response to clonazepam but then gradually worsened. During 17 years of follow-up, his seizures were controlled with anticonvulsants, but the ataxia, myoclonus and intentional tremor gradually worsened.
2025-06-17 | A Case Report: Co-Occurrence of Wilson Disease and Lysosomal Storage Disorder Probably Sialidosis in an Iraqi Patient
Rationale: Both Wilson disease (WD) and Sialidosis are rare autosomal recessive disorders that are caused by mutations on chromosome 13 and chromosome 6, respectively. Here, we report on a patient with coexisting WD and LSD possibly Sialidosis. Patient concerns: WD is a disorder of copper metabolism. The main sites of copper accumulation are the liver and the brain, resulting in hepatic symptoms. Sialidosis belongs to a group of diseases known as the lysosomal storage disorders (LSDs). Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Sialidosis is a rare inherited metabolic disorder characterized by a deficiency of the enzyme neuraminidase (sometimes referred to as sialidase). Deficiency of neuraminidase results in the abnormal accumulation of toxic materials in the body. Sialidosis is divided into two types, type I usually becomes apparent during the second decade of life with the development of sudden involuntary muscle contractions (myoclonus), distinctive red spots (cherry-red macules) in the eyes, and sometimes additional neurological findings. Sialidosis type II is usually more severe than type I. Type II often begins during infancy or later during childhood and is characterized by cherry-red macules, mildly coarse facial features, skeletal malformations and mild cognitive impairment. Diagnosis: The diagnosis of WD was confirmed by neurological symptoms, metabolism tests, and MRI scans. Genetic analysis was subsequently conducted, and the results revealed pathogenic mutation (c.302c>A (g.52518281) P.H 1069Q (His.1069 Glu) of the ATP7B gene, confirming the diagnosis of WD. The family history was positive for WD with a 9-year-old younger sister also being diagnosed with it. His parents are negative for both Sialidosis and WD. Interventions: D-penicillamine and Zinc acetate treatment was initiated for long-term control. Outcomes: Normalize liver and spleen, control the copper level to avoid further hepatological,neurological complications. Lessons: In this study, we reported on the first case of a child who simultaneously presented WD and Sialidosis, bringing up the possibility of a presumable link between these 2 rare diseases.
2024-11-20 | Lysosomal storage diseases. Mucolipidosis
The epidemiology, clinical, biochemical and molecular genetic characteristics of mucolipidoses — autosomal recessive lysosomal storage diseases that combine the clinical manifestations of mucopolysaccharidoses and sphingolipidoses — are presented. In accordance with the modern classification, types I, II and III mucolipidoses are classified as glycoproteinoses, and type IV mucolipidoses are classified as gangliosidoses. Mucolipidoses type I, or sialidosis, is caused by the presence of inactivating mutations in the α-neuraminidase gene NEU1, and a related disease is galactosialidosis, accompanied by secondary deficiency of α-neuraminidase and β-galactosidase in the CTSA gene of the protective protein cathepsin A. Both diseases are characterized by early progressive delay in psychomotor development, muscle myoclonus, severe ophthalmopathy and early death of patients. The pathogenesis of diseases is associated with excessive accumulation of sialocontaining glycoproteins and oligosaccharides in lysosomes. Hereditary deficiency of N-acetylglucosaminyl-1-phosphotransferase, necessary for the addition of mannose-6-phosphate to the oligosaccharides of lysosomal enzymes, underlies the development of two allelic diseases caused by mutations in the GNPTAB gene mucolipidoses type II, or “I-cell” disease and mucolipidoses type III, alpha/beta or pseudopolydystrophy of Hurler. Mutations in the GNPTG gene, which encodes the gamma subunit of this enzyme, are responsible for the development of the milder type III mucolipidoses (gamma). All these diseases are characterized by impaired phosphorylation and transport of lysosomal enzymes, which is accompanied by severe growth retardation, skeletal abnormalities and early death of patients. Pathogenesis of mucolipidoses type IV, or sialolipidosis, associated with the simultaneous accumulation of phospholipids, sphingolipids, mucopolysaccharides and gangliosides, which occurs as a result of mutations in the MCOLN1 gene, encoding mucolipin 1, which forms a channel localized on the membranes of lysosomes and endosomes, involved in the regulation of lipid and protein transport. The article presents a description of clinical cases of mucolipidosis types II and IIIA. Preclinical trials have shown promise for enzyme replacement therapy, chaperone therapy, and gene therapy for the treatment of sialidosis and galactosialidosis. However, pathogenetic methods of therapy for mucolipidoses have not been described in clinical practice to date.
2021-02-03 | Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency.
Mutations in the galactosidase β 1 (GLB1) gene cause lysosomal β-galactosidase (β-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. β-Gal and neuraminidase 1 (NEU1) form a multienzyme complex in lysosomes along with the molecular chaperone, protective protein cathepsin A (PPCA). NEU1 is deficient in the neurodegenerative lysosomal storage disease sialidosis, and its targeting to and stability in lysosomes strictly depend on PPCA. In contrast, β-Gal only partially depends on PPCA, prompting us to investigate the role that β-Gal plays in the multienzyme complex. Here, we demonstrate that β-Gal negatively regulates NEU1 levels in lysosomes by competitively displacing this labile sialidase from PPCA. Chronic cellular uptake of purified recombinant human β-Gal (rhβ-Gal) or chronic lentiviral-mediated GLB1 overexpression in GM1 gangliosidosis patient fibroblasts coincides with profound secondary NEU1 deficiency. A regimen of intermittent enzyme replacement therapy dosing with rhβ-Gal, followed by enzyme withdrawal, is sufficient to augment β-Gal activity levels in GM1 gangliosidosis patient fibroblasts without promoting NEU1 deficiency. In the absence of β-Gal, NEU1 levels are elevated in the GM1 gangliosidosis mouse brain, which are restored to normal levels following weekly intracerebroventricular dosing with rhβ-Gal. Collectively, our results highlight the need to carefully titrate the dose and dosing frequency of β-Gal augmentation therapy for GM1 gangliosidosis. They further suggest that intermittent intracerebroventricular enzyme replacement therapy dosing with rhβ-Gal is a tunable approach that can safely augment β-Gal levels while maintaining NEU1 at physiological levels in the GM1 gangliosidosis brain.
2021-01-19 | Compound heterozygous mutations in the neuraminidase 1 gene in type 1 sialidosis: A case report and review of literature
BACKGROUNDType 1 sialidosis, also known as cherry-red spot-myoclonus syndrome, is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life.The most common symptoms are myoclonus, ataxia and seizure.It is rarely encountered in the Chinese mainland. CASE SUMMARYA 22-year-old male presented with complaints of progressive myoclonus, ataxia and slurred speech, without visual symptoms; the presenting symptoms began at the age of 15-year-old.Whole exome sequencing revealed two pathogenic heterozygous missense variants [c.239C>T (p.P80L) and c.544A>G (p.S182G) in the neuraminidase 1 (NEU1) gene], both of which have been identified previously in Asian patients with type 1 sialidosis.All three patients identified in Mainland China come from three unrelated families, but all three show the NEU1 mutations p.S182G and p.P80L pathogenic variants.Increasing sialidase activity through chaperones is a promising therapeutic target in sialidosis. CONCLUSIONThrough retrospective analysis and summarizing the clinical and genetic characteristics of type 1 sialidosis, we hope to raise awareness of lysosomal storage disorders among clinicians and minimize the delay in diagnosis.
small molecules
2026-02-10 | Sialidosis type I: How to alleviate disabling myoclonic seizures?-A multicenter analysis of eight cases and review of the literature.
Sialidosis type I (ST-1) is an autosomal-recessive, very rare, progressive lysosomal storage disorder caused by pathogenic variants in NEU1. It is clinically characterized by progressive ataxia, myoclonic seizures (MS), bilateral tonic-clonic seizures (BTCS), and distinctive ophthalmological findings. Given the lack of curative options, in this study, we investigated symptomatic treatment strategies, with a particular focus on the efficacy of antiseizure medications (ASMs). We describe the clinical course of a patient followed from diagnosis to 18 years of age, and review seven additional cases from our cohort. In parallel, we conducted a narrative review of the literature (PubMed, January 2010-September 2025) to identify published reports containing therapeutic data. Therapeutic responses were evaluated in a total of 33 cases (8 from our cohort, 25 from published sources). Although available data are insufficient to define standardized treatment guidelines, some ASMs, such as ACZ, PER, LEV, VPA, CZP, and ZNS, demonstrated fairly consistent efficacy in managing MS and BTCS. Sodium oxybate or deep-brain stimulation may be considered in refractory cases. Prospective documentation of clinical course and treatment outcomes-ideally through an international registry-is crucial to improve patient care and inform therapeutic strategies. Sialidosis type I (ST-1) is a very rare genetic disorder causing movement problems and seizures, with no cure available yet. We followed 8 patients and reviewed 25 published cases to assess treatments focusing on myoclonic seizure (MS) control. Some antiseizure medications showed benefit. However, we have too little data to make clear recommendations. To improve patients' treatment and to choose the most appropriate therapy, it would be important to follow patients over a longer period of time, for example, in an international registry.
2026-02-10 | Alterations in secondary lipids are associated with neuroinflammation in the brain of Neu1-deficient mice.
Neu1 (lysosomal sialidase 1) is essential for removing sialic acid from oligosaccharides and glycoconjugates. Neu1 deficiency impairs lysosomal digestion, leading to sialidosis and sialoglycoprotein accumulation. It also increases lipids, including gangliosides GM3, GD3, GM4, and LM1, in the kidney, liver, and spleen. Neu1-/- mice display symptoms resembling Type II sialidosis, including enlarged spleen and liver, kidney issues, neurological problems, spinal defects, and oligosaccharide buildup. The study examined secondary lipid alterations and inflammation in the cortex and cerebellum of these mice. Lipidomic, molecular, and immunohistochemical analyses of tissues from 2 and 5 M Neu1-/- mice revealed reduced levels of lipids, including PC, PE, PS, and CL, along with increased pro-inflammatory cytokines and loss of oligodendrocytes and neurons. Signs of astrogliosis and microgliosis emerged in specific brain regions. These results indicate that reduced levels of glycerophospholipids could serve as an indicator of inflammation in sialidosis mice. Future research should investigate therapies targeting these lipid changes, as modulating glycerophospholipids might slow disease progression in sialidosis patients.
2025-03-17 | Cathepsin B inhibition blocks amyloidogenesis in the mouse models of neurological lysosomal diseases MPS IIIC and sialidosis.
Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs), including mucopolysaccharidoses (MPS); however, the molecular mechanism underlying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3- to 5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-Geo and Hgsnat P304L ) and sialidosis (Neu1 ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC, and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing thioflavin-S+, β-amyloid+ aggregates consistent with a pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (Hgsnat P304L /Ctsb -/- ) mice as well as Hgsnat P304L and Neu1 ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor E64 showed a drastic reduction in neuronal thioflavin-S+/APP+ deposits. Neurons of Hgsnat P304L /Ctsb -/- mice and E64-treated Hgsnat P304L mice also showed reduced levels of P62+, LC3+ puncta, GM2 ganglioside, and misfolded subunit C of mitochondrial ATP synthase, consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat P304L mice, implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.
2025-01-23 | Inhibition of cathepsin B blocks amyloidogenesis in the mouse models of neurological lysosomal diseases mucopolysaccharidosis type IIIC and sialidosis
Abstract Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs) including mucopolysaccharidoses (MPS), however, the molecular mechanism underlaying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3-5-fold in the cortices of mouse models of MPS IIIC ( Hgsnat-Geo and Hgsnat P304L ) and sialidosis ( Neu1 ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing Thioflavin-S-positive, β-amyloid-positive aggregates consistent with pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC ( Hgsnat P304L /Ctsb -/- ) mice as well as Hgsnat P304L and Neu1 ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor, E64, showed a drastic reduction of neuronal Thioflavin-S-positive/APP-positive deposits. Neurons of Hgsnat P304L /Ctsb -/- mice and E64-treated Hgsnat P304L mice also showed reduced levels of P62/LC3-positive puncta, G M2 ganglioside and misfolded subunit C of mitochondrial ATP synthase (SCMAS) consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat P304L mice implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.
2025-01-16 | Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.
Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here, we examine how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival and NFAT1-mediated production of TNF-α and CCL3. Because NEU1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease and sialidosis, modulating NEU1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.
gene therapies
2026-04-01 | Lysosomal Neuraminidase 1 (NEU1): Its Unique Molecular Characters and Therapeutic Approaches for Deficiencies.
Neuraminidase 1 (NEU1) is a lysosomal sialidase that removes terminal α-bound sialic acid from sialylglycoconjugates and contributes to ubiquitous catabolism of sialylglycoconjugates and immunoregulatory functions. Different from other human sialidases, including NEU2 to NEU4, NEU1 is first produced as an N-glycosylated precursor protein, which binds to its protective protein/cathepsin A (CTSA) and then forms a lysosomal multienzyme complex (LMC) with β-galactosidase 1 (GLB1) in the rough endoplasmic reticulum (RER) lumen. NEU1 trafficking to lysosomes and intralysosomal activation under acidic pH conditions essentially requires association with CTSA, which carries terminal mannose 6-phosphate (M6P)-type N-glycan to bind with cation-dependent (CD) M6P receptor (CD-M6PR) in the Golgi apparatus via endosomes. In contrast, the single NEU1 gene overexpression in mammalian cells results in NEU1 protein crystallization in the RER owing to self-aggregation at a relatively low intrinsic CTSA level. Two NEU1 deficiencies, sialidosis (SiD) and galactosialidosis (GS), are caused by autosomal recessive NEU1 and CTSA gene mutations, respectively. These untreatable disorders are associated with excessive storage of sialylglycans in neurovisceral organs and systemic symptoms. We produced a new GS model mouse by introducing a homozygous Ctsa IVS6+1g/a mutation into the murine gene locus, leading to partial exon 6 skipping and simultaneous deficiency of Ctsa and Neu1. The GS mice exhibited clinical symptoms similar to those seen in juvenile/adult GS patients, including myoclonic seizures, suppressed behavior, a gargoyle-like face, edema, proctoptosis owing to Neu1 deficiency, and sialylglycan accumulation related to neurovisceral inflammation. Evaluating the efficacy of a novel therapy utilizing GS and SiD model mice and overcoming the human NEU1 gene product shortage will be necessary for a novel, effective treatment for NEU1 deficiencies.
2025-01-25 | Genetic Insights and Clinical Implications of NEU1 Mutations in Sialidosis
Sialidosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the NEU1 gene, resulting in deficient neuraminidase-1 activity and the subsequent accumulation of sialylated compounds in lysosomes. This review comprehensively analyzes the genetic and clinical heterogeneity associated with sialidosis, emphasizing the distinction between the milder type I form and the more severe type II form. Over 90 pathogenic NEU1 variants, predominantly missense mutations, have been identified, highlighting significant phenotypic diversity. Advancements in genomic sequencing technologies have facilitated the identification of known and novel mutations, with population-specific insights elucidating ethnic variability in symptomatology and genetic profiles. Recent case studies, including a novel compound heterozygous variant, further illustrate the complexity of the genotype–phenotype correlations. Emerging therapeutic approaches, such as enzyme replacement therapy and adeno-associated virus-mediated gene therapy, demonstrate promising potential for restoring neuraminidase-1 function and improving outcomes in preclinical models. This review emphasizes the critical role of genetic analysis in diagnosis and management while advocating for continued research into the molecular mechanisms underlying sialidosis to enable the development of targeted, personalized treatments.
2024-07-04 | AAV-mediated gene therapy for sialidosis.
Sialidosis (mucolipidosis I) is a glycoprotein storage disease, clinically characterized by a spectrum of systemic and neurological phenotypes. The primary cause of the disease is deficiency of the lysosomal sialidase NEU1, resulting in accumulation of sialylated glycoproteins/oligosaccharides in tissues and body fluids. Neu1-/- mice recapitulate the severe, early-onset forms of the disease, affecting visceral organs, muscles, and the nervous system, with widespread lysosomal vacuolization evident in most cell types. Sialidosis is considered an orphan disorder with no therapy currently available. Here, we assessed the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis. Neu1-/- mice were co-injected with two scAAV2/8 vectors, expressing human NEU1 and its chaperone PPCA. Treated mice were phenotypically indistinguishable from their WT controls. NEU1 activity was restored to different extent in most tissues, including the brain, heart, muscle, and visceral organs. This resulted in diminished/absent lysosomal vacuolization in multiple cell types and reversal of sialyl-oligosacchariduria. Lastly, normalization of lysosomal exocytosis in the cerebrospinal fluids and serum of treated mice, coupled to diminished neuroinflammation, were measures of therapeutic efficacy. These findings point to AAV-mediated gene therapy as a suitable treatment for sialidosis and possibly other diseases, associated with low NEU1 expression.
2024-05-14 | Gene therapy corrects the neurological deficits of mice with sialidosis.
Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the neuraminidase 1 (NEU1) gene. Currently, there is no treatment for sialidosis. In this study, we developed an adeno-associated virus (AAV)-mediated gene therapy for a Neu1 knockout (Neu1-/-) mouse model of sialidosis. The vector, AAV9-P3-NP, included the human NEU1 promoter, NEU1 cDNA, IRES, and CTSA cDNA. Untreated Neu1-/- mice showed astrogliosis and microglial LAMP1 accumulation in the nervous system, including brain, spinal cord, and dorsal root ganglion, together with impaired motor function. Coexpression of NEU1 and protective protein/cathepsin A (PPCA) in neonatal Neu1-/- mice by intracerebroventricular injection, and less effective by facial vein injection, decreased astrogliosis and LAMP1 accumulation in the nervous system and improved rotarod performance of the treated mice. Facial vein injection also improved the grip strength and survival of Neu1-/- mice. Therefore, cerebrospinal fluid delivery of AAV9-P3-NP, which corrects the neurological deficits of mice with sialidosis, could be a suitable treatment for patients with sialidosis type I. After intracerebroventricular or facial vein injection of AAV vectors, NEU1 and PPCA are expressed together. PPCA-protected NEU1 is then sent to lysosomes, where β-Gal binds to this complex to form a multienzyme complex in order to execute its function.
2024-01-16 | Lysosomal sialidase NEU1, its intracellular properties, deficiency, and use as a therapeutic agent.
Neuraminidase 1 (NEU1) is a lysosomal sialidase that cleaves terminal α-linked sialic acid residues from sialylglycans. NEU1 is biosynthesized in the rough endoplasmic reticulum (RER) lumen as an N-glycosylated protein to associate with its protective protein/cathepsin A (CTSA) and then form a lysosomal multienzyme complex (LMC) also containing β-galactosidase 1 (GLB1). Unlike other mammalian sialidases, including NEU2 to NEU4, NEU1 transport to lysosomes requires association of NEU1 with CTSA, binding of the CTSA carrying terminal mannose 6-phosphate (M6P)-type N-glycan with M6P receptor (M6PR), and intralysosomal NEU1 activation at acidic pH. In contrast, overexpression of the single NEU1 gene in mammalian cells causes intracellular NEU1 protein crystallization in the RER due to self-aggregation when intracellular CTSA is reduced to a relatively low level. Sialidosis (SiD) and galactosialidosis (GS) are autosomal recessive lysosomal storage diseases caused by the gene mutations of NEU1 and CTSA, respectively. These incurable diseases associate with the NEU1 deficiency, excessive accumulation of sialylglycans in neurovisceral organs, and systemic manifestations. We established a novel GS model mouse carrying homozygotic Ctsa IVS6 + 1 g/a mutation causing partial exon 6 skipping with simultaneous deficiency of Ctsa and Neu1. Symptoms developed in the GS mice like those in juvenile/adult GS patients, such as myoclonic seizures, suppressed behavior, gargoyle-like face, edema, proctoptosis due to Neu1 deficiency, and sialylglycan accumulation associated with neurovisceral inflammation. We developed a modified NEU1 (modNEU1), which does not form protein crystals but is transported to lysosomes by co-expressed CTSA. In vivo gene therapy for GS and SiD utilizing a single adeno-associated virus (AAV) carrying modNEU1 and CTSA genes under dual promoter control will be created.
cell therapies
2026-01-06 | Failure of Allogeneic Transplant to Correct Sialidosis Despite Early Diagnosis and Full Donor Engraftment of Non-Carrier Leucocytes.
Sialidosis, also known as Mucolipidosis Type I, is a rare condition caused by defects in the NEU1 gene which causes the accumulation of sialylated peptides, oligosaccharides, and glycoproteins leading to neurological decline. Haematopoetic stem cell transplantation has been performed in the symptomatic phase twice in the literature but has failed to prevent deterioration. We report on a case where a 4-year-old child was diagnosed with pre-symptomatic sialidosis due to investigation following the incidental detection of a cherry-red spot prior to the onset of neurological symptoms. We performed haematopoetic stem cell transplantation with a matched unrelated cord blood unit with optimal timing prior to clinical decline, achieving full donor engraftment with a largely uneventful post-transplant recovery followed by a period of relative clinical stability. However, subsequent neurological decline detailed by clinical history and radiological findings has occurred suggesting a lack of disease responsiveness to transplantation despite optimal timing. We go on to provide supporting laboratory investigations detailing sialidosis fibroblast culture as part of a novel cross-correction assay and compare results to other transplant responsive lysosomal storage disorders such as mucopolysaccharidosis type 1-H and detail a lack of cross-correction in concordance with our clinical findings. We conclude that conventional allogeneic haematopoetic stem cell transplantation is not a viable disease-modifying treatment option in sialidosis, even when performed optimally in the pre-symptomatic phase, and suggest that alternative treatment options must be explored to improve outcomes in this condition.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
proteins
2025-07-17 | Sialidosis type1 with cardiac malformation: A case report
Sialidosis is a rare autosomal recessive lysosomal storage disease caused by a variant in the neuraminidase 1 (NEU1) gene encoding lysosomal neuraminidase, and is a rare cause of progressive myoclonus epilepsies (PME). Sialidosis is classified into two types. Sialidosis type 1 is a relatively mild late-onset form with ataxia, myoclonus, macular cherry-red spot, seizures, and non-dysmorphic features. Sialidosis type 2 has congenital, infantile and juvenile-onset forms, and has more severe feature, including ascites, coarse facies, dysostosis multiplex, macular cherry-red spot, hepatosplenomegaly, and developmental delay than type 1. Our case, a 29-year-old male, had shown normal development up to the age of 12 years and 5 months. Subsequently, he developed ataxia and myoclonus. At age 12 years and 11 months, generalized tonic-clonic seizures occurred with ataxia, myoclonus, intentional tremor, borderline intelligence, and cherry-red macular spot. Skin fibroblast enzymological analysis of neuraminidase yielded a value below 1 nmol/h/mg protein. NEU1 gene findings were consistent with compound heterozygous missense variant c.1034C>T(p.Thr345Ile) and c.239C>T(p.Pro80Leu), while electron microscopy of skinfibroblasts showed vacuoles and dense body deposition in both neuroblasts and Schwann cells. In addition, this is the first reported case of sialidosis type 1 associated with a quadricuspid aortic valve malformation. Collectively, the above findings indicated a diagnosis of sialidosis type 1 with cardiac malformation. The involuntary movement improved temporarily in response to clonazepam but then gradually worsened. During 17 years of follow-up, his seizures were controlled with anticonvulsants, but the ataxia, myoclonus and intentional tremor gradually worsened.
2025-06-17 | A Case Report: Co-Occurrence of Wilson Disease and Lysosomal Storage Disorder Probably Sialidosis in an Iraqi Patient
Rationale: Both Wilson disease (WD) and Sialidosis are rare autosomal recessive disorders that are caused by mutations on chromosome 13 and chromosome 6, respectively. Here, we report on a patient with coexisting WD and LSD possibly Sialidosis. Patient concerns: WD is a disorder of copper metabolism. The main sites of copper accumulation are the liver and the brain, resulting in hepatic symptoms. Sialidosis belongs to a group of diseases known as the lysosomal storage disorders (LSDs). Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Sialidosis is a rare inherited metabolic disorder characterized by a deficiency of the enzyme neuraminidase (sometimes referred to as sialidase). Deficiency of neuraminidase results in the abnormal accumulation of toxic materials in the body. Sialidosis is divided into two types, type I usually becomes apparent during the second decade of life with the development of sudden involuntary muscle contractions (myoclonus), distinctive red spots (cherry-red macules) in the eyes, and sometimes additional neurological findings. Sialidosis type II is usually more severe than type I. Type II often begins during infancy or later during childhood and is characterized by cherry-red macules, mildly coarse facial features, skeletal malformations and mild cognitive impairment. Diagnosis: The diagnosis of WD was confirmed by neurological symptoms, metabolism tests, and MRI scans. Genetic analysis was subsequently conducted, and the results revealed pathogenic mutation (c.302c>A (g.52518281) P.H 1069Q (His.1069 Glu) of the ATP7B gene, confirming the diagnosis of WD. The family history was positive for WD with a 9-year-old younger sister also being diagnosed with it. His parents are negative for both Sialidosis and WD. Interventions: D-penicillamine and Zinc acetate treatment was initiated for long-term control. Outcomes: Normalize liver and spleen, control the copper level to avoid further hepatological,neurological complications. Lessons: In this study, we reported on the first case of a child who simultaneously presented WD and Sialidosis, bringing up the possibility of a presumable link between these 2 rare diseases.
2024-11-20 | Lysosomal storage diseases. Mucolipidosis
The epidemiology, clinical, biochemical and molecular genetic characteristics of mucolipidoses — autosomal recessive lysosomal storage diseases that combine the clinical manifestations of mucopolysaccharidoses and sphingolipidoses — are presented. In accordance with the modern classification, types I, II and III mucolipidoses are classified as glycoproteinoses, and type IV mucolipidoses are classified as gangliosidoses. Mucolipidoses type I, or sialidosis, is caused by the presence of inactivating mutations in the α-neuraminidase gene NEU1, and a related disease is galactosialidosis, accompanied by secondary deficiency of α-neuraminidase and β-galactosidase in the CTSA gene of the protective protein cathepsin A. Both diseases are characterized by early progressive delay in psychomotor development, muscle myoclonus, severe ophthalmopathy and early death of patients. The pathogenesis of diseases is associated with excessive accumulation of sialocontaining glycoproteins and oligosaccharides in lysosomes. Hereditary deficiency of N-acetylglucosaminyl-1-phosphotransferase, necessary for the addition of mannose-6-phosphate to the oligosaccharides of lysosomal enzymes, underlies the development of two allelic diseases caused by mutations in the GNPTAB gene mucolipidoses type II, or “I-cell” disease and mucolipidoses type III, alpha/beta or pseudopolydystrophy of Hurler. Mutations in the GNPTG gene, which encodes the gamma subunit of this enzyme, are responsible for the development of the milder type III mucolipidoses (gamma). All these diseases are characterized by impaired phosphorylation and transport of lysosomal enzymes, which is accompanied by severe growth retardation, skeletal abnormalities and early death of patients. Pathogenesis of mucolipidoses type IV, or sialolipidosis, associated with the simultaneous accumulation of phospholipids, sphingolipids, mucopolysaccharides and gangliosides, which occurs as a result of mutations in the MCOLN1 gene, encoding mucolipin 1, which forms a channel localized on the membranes of lysosomes and endosomes, involved in the regulation of lipid and protein transport. The article presents a description of clinical cases of mucolipidosis types II and IIIA. Preclinical trials have shown promise for enzyme replacement therapy, chaperone therapy, and gene therapy for the treatment of sialidosis and galactosialidosis. However, pathogenetic methods of therapy for mucolipidoses have not been described in clinical practice to date.
2021-02-03 | Intermittent enzyme replacement therapy with recombinant human β-galactosidase prevents neuraminidase 1 deficiency.
Mutations in the galactosidase β 1 (GLB1) gene cause lysosomal β-galactosidase (β-Gal) deficiency and clinical onset of the neurodegenerative lysosomal storage disease, GM1 gangliosidosis. β-Gal and neuraminidase 1 (NEU1) form a multienzyme complex in lysosomes along with the molecular chaperone, protective protein cathepsin A (PPCA). NEU1 is deficient in the neurodegenerative lysosomal storage disease sialidosis, and its targeting to and stability in lysosomes strictly depend on PPCA. In contrast, β-Gal only partially depends on PPCA, prompting us to investigate the role that β-Gal plays in the multienzyme complex. Here, we demonstrate that β-Gal negatively regulates NEU1 levels in lysosomes by competitively displacing this labile sialidase from PPCA. Chronic cellular uptake of purified recombinant human β-Gal (rhβ-Gal) or chronic lentiviral-mediated GLB1 overexpression in GM1 gangliosidosis patient fibroblasts coincides with profound secondary NEU1 deficiency. A regimen of intermittent enzyme replacement therapy dosing with rhβ-Gal, followed by enzyme withdrawal, is sufficient to augment β-Gal activity levels in GM1 gangliosidosis patient fibroblasts without promoting NEU1 deficiency. In the absence of β-Gal, NEU1 levels are elevated in the GM1 gangliosidosis mouse brain, which are restored to normal levels following weekly intracerebroventricular dosing with rhβ-Gal. Collectively, our results highlight the need to carefully titrate the dose and dosing frequency of β-Gal augmentation therapy for GM1 gangliosidosis. They further suggest that intermittent intracerebroventricular enzyme replacement therapy dosing with rhβ-Gal is a tunable approach that can safely augment β-Gal levels while maintaining NEU1 at physiological levels in the GM1 gangliosidosis brain.
2021-01-19 | Compound heterozygous mutations in the neuraminidase 1 gene in type 1 sialidosis: A case report and review of literature
BACKGROUNDType 1 sialidosis, also known as cherry-red spot-myoclonus syndrome, is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life.The most common symptoms are myoclonus, ataxia and seizure.It is rarely encountered in the Chinese mainland. CASE SUMMARYA 22-year-old male presented with complaints of progressive myoclonus, ataxia and slurred speech, without visual symptoms; the presenting symptoms began at the age of 15-year-old.Whole exome sequencing revealed two pathogenic heterozygous missense variants [c.239C>T (p.P80L) and c.544A>G (p.S182G) in the neuraminidase 1 (NEU1) gene], both of which have been identified previously in Asian patients with type 1 sialidosis.All three patients identified in Mainland China come from three unrelated families, but all three show the NEU1 mutations p.S182G and p.P80L pathogenic variants.Increasing sialidase activity through chaperones is a promising therapeutic target in sialidosis. CONCLUSIONThrough retrospective analysis and summarizing the clinical and genetic characteristics of type 1 sialidosis, we hope to raise awareness of lysosomal storage disorders among clinicians and minimize the delay in diagnosis.
small molecules
2026-02-10 | Sialidosis type I: How to alleviate disabling myoclonic seizures?-A multicenter analysis of eight cases and review of the literature.
Sialidosis type I (ST-1) is an autosomal-recessive, very rare, progressive lysosomal storage disorder caused by pathogenic variants in NEU1. It is clinically characterized by progressive ataxia, myoclonic seizures (MS), bilateral tonic-clonic seizures (BTCS), and distinctive ophthalmological findings. Given the lack of curative options, in this study, we investigated symptomatic treatment strategies, with a particular focus on the efficacy of antiseizure medications (ASMs). We describe the clinical course of a patient followed from diagnosis to 18 years of age, and review seven additional cases from our cohort. In parallel, we conducted a narrative review of the literature (PubMed, January 2010-September 2025) to identify published reports containing therapeutic data. Therapeutic responses were evaluated in a total of 33 cases (8 from our cohort, 25 from published sources). Although available data are insufficient to define standardized treatment guidelines, some ASMs, such as ACZ, PER, LEV, VPA, CZP, and ZNS, demonstrated fairly consistent efficacy in managing MS and BTCS. Sodium oxybate or deep-brain stimulation may be considered in refractory cases. Prospective documentation of clinical course and treatment outcomes-ideally through an international registry-is crucial to improve patient care and inform therapeutic strategies. Sialidosis type I (ST-1) is a very rare genetic disorder causing movement problems and seizures, with no cure available yet. We followed 8 patients and reviewed 25 published cases to assess treatments focusing on myoclonic seizure (MS) control. Some antiseizure medications showed benefit. However, we have too little data to make clear recommendations. To improve patients' treatment and to choose the most appropriate therapy, it would be important to follow patients over a longer period of time, for example, in an international registry.
2026-02-10 | Alterations in secondary lipids are associated with neuroinflammation in the brain of Neu1-deficient mice.
Neu1 (lysosomal sialidase 1) is essential for removing sialic acid from oligosaccharides and glycoconjugates. Neu1 deficiency impairs lysosomal digestion, leading to sialidosis and sialoglycoprotein accumulation. It also increases lipids, including gangliosides GM3, GD3, GM4, and LM1, in the kidney, liver, and spleen. Neu1-/- mice display symptoms resembling Type II sialidosis, including enlarged spleen and liver, kidney issues, neurological problems, spinal defects, and oligosaccharide buildup. The study examined secondary lipid alterations and inflammation in the cortex and cerebellum of these mice. Lipidomic, molecular, and immunohistochemical analyses of tissues from 2 and 5 M Neu1-/- mice revealed reduced levels of lipids, including PC, PE, PS, and CL, along with increased pro-inflammatory cytokines and loss of oligodendrocytes and neurons. Signs of astrogliosis and microgliosis emerged in specific brain regions. These results indicate that reduced levels of glycerophospholipids could serve as an indicator of inflammation in sialidosis mice. Future research should investigate therapies targeting these lipid changes, as modulating glycerophospholipids might slow disease progression in sialidosis patients.
2025-03-17 | Cathepsin B inhibition blocks amyloidogenesis in the mouse models of neurological lysosomal diseases MPS IIIC and sialidosis.
Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs), including mucopolysaccharidoses (MPS); however, the molecular mechanism underlying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3- to 5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-Geo and Hgsnat P304L ) and sialidosis (Neu1 ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC, and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing thioflavin-S+, β-amyloid+ aggregates consistent with a pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (Hgsnat P304L /Ctsb -/- ) mice as well as Hgsnat P304L and Neu1 ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor E64 showed a drastic reduction in neuronal thioflavin-S+/APP+ deposits. Neurons of Hgsnat P304L /Ctsb -/- mice and E64-treated Hgsnat P304L mice also showed reduced levels of P62+, LC3+ puncta, GM2 ganglioside, and misfolded subunit C of mitochondrial ATP synthase, consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat P304L mice, implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.
2025-01-23 | Inhibition of cathepsin B blocks amyloidogenesis in the mouse models of neurological lysosomal diseases mucopolysaccharidosis type IIIC and sialidosis
Abstract Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs) including mucopolysaccharidoses (MPS), however, the molecular mechanism underlaying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3-5-fold in the cortices of mouse models of MPS IIIC ( Hgsnat-Geo and Hgsnat P304L ) and sialidosis ( Neu1 ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing Thioflavin-S-positive, β-amyloid-positive aggregates consistent with pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC ( Hgsnat P304L /Ctsb -/- ) mice as well as Hgsnat P304L and Neu1 ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor, E64, showed a drastic reduction of neuronal Thioflavin-S-positive/APP-positive deposits. Neurons of Hgsnat P304L /Ctsb -/- mice and E64-treated Hgsnat P304L mice also showed reduced levels of P62/LC3-positive puncta, G M2 ganglioside and misfolded subunit C of mitochondrial ATP synthase (SCMAS) consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat P304L mice implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.
2025-01-16 | Neuraminidase 1 regulates neuropathogenesis by governing the cellular state of microglia via modulation of Trem2 sialylation.
Neuraminidase 1 (NEU1) cleaves terminal sialic acids from sialoglycoproteins in endolysosomes and at the plasma membrane. As such, NEU1 regulates immune cells, primarily those of the monocytic lineage. Here, we examine how Neu1 influences microglia by modulating the sialylation of full-length Trem2 (Trem2-FL), a multifunctional receptor that regulates microglial survival, phagocytosis, and cytokine production. When Neu1 is deficient/downregulated, Trem2-FL remains sialylated, accumulates intracellularly, and is excessively cleaved into a C-terminal fragment (Trem2-CTF) and an extracellular soluble domain (sTrem2), enhancing their signaling capacities. Sialylated Trem2-FL (Sia-Trem2-FL) does not hinder Trem2-FL-DAP12-Syk complex assembly but impairs signal transduction through Syk, ultimately abolishing Trem2-dependent phagocytosis. Concurrently, Trem2-CTF-DAP12 complexes dampen NF-κB signaling, while sTrem2 propagates Akt-dependent cell survival and NFAT1-mediated production of TNF-α and CCL3. Because NEU1 and Trem2 are implicated in neurodegenerative/neuroinflammatory diseases, including Alzheimer disease and sialidosis, modulating NEU1 activity represents a therapeutic approach to broadly regulate microglia-mediated neuroinflammation.
gene therapies
2026-04-01 | Lysosomal Neuraminidase 1 (NEU1): Its Unique Molecular Characters and Therapeutic Approaches for Deficiencies.
Neuraminidase 1 (NEU1) is a lysosomal sialidase that removes terminal α-bound sialic acid from sialylglycoconjugates and contributes to ubiquitous catabolism of sialylglycoconjugates and immunoregulatory functions. Different from other human sialidases, including NEU2 to NEU4, NEU1 is first produced as an N-glycosylated precursor protein, which binds to its protective protein/cathepsin A (CTSA) and then forms a lysosomal multienzyme complex (LMC) with β-galactosidase 1 (GLB1) in the rough endoplasmic reticulum (RER) lumen. NEU1 trafficking to lysosomes and intralysosomal activation under acidic pH conditions essentially requires association with CTSA, which carries terminal mannose 6-phosphate (M6P)-type N-glycan to bind with cation-dependent (CD) M6P receptor (CD-M6PR) in the Golgi apparatus via endosomes. In contrast, the single NEU1 gene overexpression in mammalian cells results in NEU1 protein crystallization in the RER owing to self-aggregation at a relatively low intrinsic CTSA level. Two NEU1 deficiencies, sialidosis (SiD) and galactosialidosis (GS), are caused by autosomal recessive NEU1 and CTSA gene mutations, respectively. These untreatable disorders are associated with excessive storage of sialylglycans in neurovisceral organs and systemic symptoms. We produced a new GS model mouse by introducing a homozygous Ctsa IVS6+1g/a mutation into the murine gene locus, leading to partial exon 6 skipping and simultaneous deficiency of Ctsa and Neu1. The GS mice exhibited clinical symptoms similar to those seen in juvenile/adult GS patients, including myoclonic seizures, suppressed behavior, a gargoyle-like face, edema, proctoptosis owing to Neu1 deficiency, and sialylglycan accumulation related to neurovisceral inflammation. Evaluating the efficacy of a novel therapy utilizing GS and SiD model mice and overcoming the human NEU1 gene product shortage will be necessary for a novel, effective treatment for NEU1 deficiencies.
2025-01-25 | Genetic Insights and Clinical Implications of NEU1 Mutations in Sialidosis
Sialidosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the NEU1 gene, resulting in deficient neuraminidase-1 activity and the subsequent accumulation of sialylated compounds in lysosomes. This review comprehensively analyzes the genetic and clinical heterogeneity associated with sialidosis, emphasizing the distinction between the milder type I form and the more severe type II form. Over 90 pathogenic NEU1 variants, predominantly missense mutations, have been identified, highlighting significant phenotypic diversity. Advancements in genomic sequencing technologies have facilitated the identification of known and novel mutations, with population-specific insights elucidating ethnic variability in symptomatology and genetic profiles. Recent case studies, including a novel compound heterozygous variant, further illustrate the complexity of the genotype–phenotype correlations. Emerging therapeutic approaches, such as enzyme replacement therapy and adeno-associated virus-mediated gene therapy, demonstrate promising potential for restoring neuraminidase-1 function and improving outcomes in preclinical models. This review emphasizes the critical role of genetic analysis in diagnosis and management while advocating for continued research into the molecular mechanisms underlying sialidosis to enable the development of targeted, personalized treatments.
2024-07-04 | AAV-mediated gene therapy for sialidosis.
Sialidosis (mucolipidosis I) is a glycoprotein storage disease, clinically characterized by a spectrum of systemic and neurological phenotypes. The primary cause of the disease is deficiency of the lysosomal sialidase NEU1, resulting in accumulation of sialylated glycoproteins/oligosaccharides in tissues and body fluids. Neu1-/- mice recapitulate the severe, early-onset forms of the disease, affecting visceral organs, muscles, and the nervous system, with widespread lysosomal vacuolization evident in most cell types. Sialidosis is considered an orphan disorder with no therapy currently available. Here, we assessed the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis. Neu1-/- mice were co-injected with two scAAV2/8 vectors, expressing human NEU1 and its chaperone PPCA. Treated mice were phenotypically indistinguishable from their WT controls. NEU1 activity was restored to different extent in most tissues, including the brain, heart, muscle, and visceral organs. This resulted in diminished/absent lysosomal vacuolization in multiple cell types and reversal of sialyl-oligosacchariduria. Lastly, normalization of lysosomal exocytosis in the cerebrospinal fluids and serum of treated mice, coupled to diminished neuroinflammation, were measures of therapeutic efficacy. These findings point to AAV-mediated gene therapy as a suitable treatment for sialidosis and possibly other diseases, associated with low NEU1 expression.
2024-05-14 | Gene therapy corrects the neurological deficits of mice with sialidosis.
Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the neuraminidase 1 (NEU1) gene. Currently, there is no treatment for sialidosis. In this study, we developed an adeno-associated virus (AAV)-mediated gene therapy for a Neu1 knockout (Neu1-/-) mouse model of sialidosis. The vector, AAV9-P3-NP, included the human NEU1 promoter, NEU1 cDNA, IRES, and CTSA cDNA. Untreated Neu1-/- mice showed astrogliosis and microglial LAMP1 accumulation in the nervous system, including brain, spinal cord, and dorsal root ganglion, together with impaired motor function. Coexpression of NEU1 and protective protein/cathepsin A (PPCA) in neonatal Neu1-/- mice by intracerebroventricular injection, and less effective by facial vein injection, decreased astrogliosis and LAMP1 accumulation in the nervous system and improved rotarod performance of the treated mice. Facial vein injection also improved the grip strength and survival of Neu1-/- mice. Therefore, cerebrospinal fluid delivery of AAV9-P3-NP, which corrects the neurological deficits of mice with sialidosis, could be a suitable treatment for patients with sialidosis type I. After intracerebroventricular or facial vein injection of AAV vectors, NEU1 and PPCA are expressed together. PPCA-protected NEU1 is then sent to lysosomes, where β-Gal binds to this complex to form a multienzyme complex in order to execute its function.
2024-01-16 | Lysosomal sialidase NEU1, its intracellular properties, deficiency, and use as a therapeutic agent.
Neuraminidase 1 (NEU1) is a lysosomal sialidase that cleaves terminal α-linked sialic acid residues from sialylglycans. NEU1 is biosynthesized in the rough endoplasmic reticulum (RER) lumen as an N-glycosylated protein to associate with its protective protein/cathepsin A (CTSA) and then form a lysosomal multienzyme complex (LMC) also containing β-galactosidase 1 (GLB1). Unlike other mammalian sialidases, including NEU2 to NEU4, NEU1 transport to lysosomes requires association of NEU1 with CTSA, binding of the CTSA carrying terminal mannose 6-phosphate (M6P)-type N-glycan with M6P receptor (M6PR), and intralysosomal NEU1 activation at acidic pH. In contrast, overexpression of the single NEU1 gene in mammalian cells causes intracellular NEU1 protein crystallization in the RER due to self-aggregation when intracellular CTSA is reduced to a relatively low level. Sialidosis (SiD) and galactosialidosis (GS) are autosomal recessive lysosomal storage diseases caused by the gene mutations of NEU1 and CTSA, respectively. These incurable diseases associate with the NEU1 deficiency, excessive accumulation of sialylglycans in neurovisceral organs, and systemic manifestations. We established a novel GS model mouse carrying homozygotic Ctsa IVS6 + 1 g/a mutation causing partial exon 6 skipping with simultaneous deficiency of Ctsa and Neu1. Symptoms developed in the GS mice like those in juvenile/adult GS patients, such as myoclonic seizures, suppressed behavior, gargoyle-like face, edema, proctoptosis due to Neu1 deficiency, and sialylglycan accumulation associated with neurovisceral inflammation. We developed a modified NEU1 (modNEU1), which does not form protein crystals but is transported to lysosomes by co-expressed CTSA. In vivo gene therapy for GS and SiD utilizing a single adeno-associated virus (AAV) carrying modNEU1 and CTSA genes under dual promoter control will be created.
cell therapies
2026-01-06 | Failure of Allogeneic Transplant to Correct Sialidosis Despite Early Diagnosis and Full Donor Engraftment of Non-Carrier Leucocytes.
Sialidosis, also known as Mucolipidosis Type I, is a rare condition caused by defects in the NEU1 gene which causes the accumulation of sialylated peptides, oligosaccharides, and glycoproteins leading to neurological decline. Haematopoetic stem cell transplantation has been performed in the symptomatic phase twice in the literature but has failed to prevent deterioration. We report on a case where a 4-year-old child was diagnosed with pre-symptomatic sialidosis due to investigation following the incidental detection of a cherry-red spot prior to the onset of neurological symptoms. We performed haematopoetic stem cell transplantation with a matched unrelated cord blood unit with optimal timing prior to clinical decline, achieving full donor engraftment with a largely uneventful post-transplant recovery followed by a period of relative clinical stability. However, subsequent neurological decline detailed by clinical history and radiological findings has occurred suggesting a lack of disease responsiveness to transplantation despite optimal timing. We go on to provide supporting laboratory investigations detailing sialidosis fibroblast culture as part of a novel cross-correction assay and compare results to other transplant responsive lysosomal storage disorders such as mucopolysaccharidosis type 1-H and detail a lack of cross-correction in concordance with our clinical findings. We conclude that conventional allogeneic haematopoetic stem cell transplantation is not a viable disease-modifying treatment option in sialidosis, even when performed optimally in the pre-symptomatic phase, and suggest that alternative treatment options must be explored to improve outcomes in this condition.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
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