RARE DISEASE
Sanfilippo syndrome type C
Sanfilippo syndrome type C
Sanfilippo syndrome type C
Synonyms: HGSNAT deficiency, Heparan-alpha-glucosaminide N-acetyltransferase deficiency, MPS3C, MPSIIIC, Mucopolysaccharidosis type 3C, Mucopolysaccharidosis type IIIC
Synonyms: HGSNAT deficiency, Heparan-alpha-glucosaminide N-acetyltransferase deficiency, MPS3C, MPSIIIC, Mucopolysaccharidosis type 3C, Mucopolysaccharidosis type IIIC
Synonyms: HGSNAT deficiency, Heparan-alpha-glucosaminide N-acetyltransferase deficiency, MPS3C, MPSIIIC, Mucopolysaccharidosis type 3C, Mucopolysaccharidosis type IIIC
Drug discovery
2
drugs
With orphan designations
Overview
Sanfilippo syndrome type C (MPS IIIC) is a rare autosomal recessive lysosomal storage disorder caused by HGSNAT gene mutations, leading to deficient heparan-alpha-glucosaminide N-acetyltransferase enzyme activity [6][11][14]. This results in heparan sulfate accumulation, causing progressive neurodegeneration [9][19]. Key features include developmental regression, hyperactivity, sleep disturbances, seizures, and severe cognitive decline [6][11][19]. Life expectancy typically extends to adolescence or early adulthood, with death often due to respiratory complications [6][14].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
113 drug discovery papers about Sanfilippo syndrome type C, with 6 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
113 drug discovery papers about Sanfilippo syndrome type C, with 6 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-11 | NDST1 as a substrate-reduction target in Mucopolysaccharidosis type IIIC: virtual screening, microsecond molecular dynamics, and peptide design
ABSTRACT Mucopolysaccharidosis IIIC (Sanfilippo syndrome type C) is a rare lysosomal storage disorder caused by loss-of-function mutations in HGSNAT , which encodes an enzyme involved in heparan sulfate (HS) degradation, leading to impaired HS catabolism, lysosomal accumulation, and progressive neurodegeneration. Because enzyme replacement therapies have limited penetration across the blood–brain barrier, substrate-reduction therapy represents an alternative therapeutic strategy. Here, N-deacetylase/N-sulfotransferase 1 (NDST1), a key enzyme responsible for HS biosynthesis, was investigated as a potential substrate-reduction target. A structure-based computational pipeline was used to identify and evaluate inhibitors targeting the NDST1 sulfotransferase domain. Approximately 4.1 million drug-like compounds and FDA-approved drugs were screened by molecular docking, followed by pharmacokinetic filtering, molecular dynamics simulations, and MM/PBSA binding free energy calculations. In parallel, peptide binders targeting the same site were generated using diffusion-based protein design and evaluated using molecular dynamics and MM/GBSA analysis. Four chemically distinct small-molecule scaffolds and three peptide candidates were identified as stable binders to the NDST1 active site. The lead small-molecule candidate exhibited a predicted binding free energy of −13.36 ± 5.87 kcal mol −1 . These provide a focused set of candidates for further investigation and support the feasibility of targeting NDST1 as a substrate-reduction strategy for MPS IIIC.
2026-04-29 | Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III.
Mucopolysaccharidosis type III (MPS III) is a group of autosomal recessive neurodegenerative lysosomal storage disorders that causes progressive cognitive and physical impairment, predominantly in child/early adulthood. The median age of death is 17 years as there is no safe, effective treatment approved. Using faithful Drosophila and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up-regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down-regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short-term studies, food enriched with 5 mM spermidine improved overall fly activity and climbing ability. A 4-week study in pre-symptomatic MPS IIIA mice (3- or 6-mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer-term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.
2026-01-01 | Mucopolysaccharidosis III: Using Mouse and Human Neuronal Models for Biomarker Discovery and Therapeutic Development
Sanfilippo Disease, or Mucopolysaccharidosis (MPS) III, is a spectrum (MPS IIIA to D) of rare inherited neurological lysosomal diseases caused by deficiencies in one of four lysosomal enzymes that catabolize heparan sulphate (HS). Sanfilippo causes a severe neurocognitive decline in affected children and progressively leads to dementia and premature death before the third decade of life. MPS III still lacks effective therapeutic strategies in the central nervous system (CNS), as both enzyme replacement and AAV9-mediated systemic gene therapy have limited efficacy in the CNS. Previously, our research identified several neuron-specific biomarkers of pathogenesis in the MPS IIIC mouse models, including defects in the excitatory and inhibitory synapses and decreased levels of brain-derived neurotrophic factor (BDNF). However, these deficits have yet to be confirmed in a human-relevant neuronal model of Sanfilippo disease. My PhD research aimed to develop human-relevant in vitro neuronal models from induced pluripotent stem cells (iPSCs) of MPS III patients to characterize the disease. iPSCs in combination with mouse models for MPS III would then be used to evaluate the therapeutic efficacy of a small neurotrophic molecule, “AVP6”. In my second chapter, I investigated the therapeutic potential of extracellular vesicles (EV) for the neuronal delivery of heparan-α-glucosaminide-N-acetyltransferase (HGSNAT) deficient in MPS IIIC. The first chapter I characterized MPS IIIA, B, and C iPSC-derived cortical neurons (iCNs) and tested them with AVP6. We demonstrated that MPS III iCNs retained disease-specific primary enzymatic deficits and lysosomal storage phenotype (increased LAMP2+ area). MPS III iCNs revealed significantly reduced levels of BDNF, and protein markers for glutamatergic (VGLUT1/PSD-95) and GABA-ergic (VGAT/Gephyrin) synapses. AVP6 treatments restored or significantly increased levels of all synaptic proteins and BDNF. Using the MPS IIIA mouse model (Sgshmps3a) I studied the long-term (7 months) behavioural and histopathological effects of daily intranasal administration of AVP6. Unlike untreated, AVP6-treated MPS IIIA mice did not display behavioural deficits including the loss of working and spatial memory, or inability to socialize. Our histopathological analysis revealed that the major hallmarks of the disease in the CNS did not develop in the AVP6-treated groups. This included a decrease in the levels of the excitatory synaptic markers (VGLUT1/PSD95), microgliosis (CD68+ cells), astrocytosis (GFAP+ cells), myelin loss (MBP levels), and autophagy block (LC3B levels). These results paralleled those demonstrated by other lab members for the MPS IIIB and MPS IIIC mice; showing the versatility of AVP6. In the second chapter, I investigated whether EV can be used for the therapeutic delivery of HGSNAT to MPS IIIC iCN. We demonstrated that EV isolated from lentivirus-transduced cell lines overexpressing the GFP-tagged human HGSNAT (HGSNAT-GFP) contained high levels of the enzyme (> 100-fold increase compared to EV from non-transduced cells). MPS IIIC iCNs treated with HGSNAT-loaded EVs for three days showed a complete rescue of the reduced levels of VGLUT1+, VGAT+ and BDNF+ puncta, with the inhibitory synaptic marker Gephyrin+ puncta significantly increased but remaining below control levels. We further generated iPSC-derived microglia (iMGL) overexpressing HGSNAT-GFP and cocultured them for seven days with MPS IIIC iCNs. MPS IIIC iCNs cocultured with iMGLs overexpressing HGSNAT-GFP showed a recovery of all disease biomarkers, including a recovery of the reduced PSD-95+ and Gephyrin+ puncta levels. Overall, in my PhD research project, I developed human-relevant models of Sanfilippo diseases that allowed for the characterization and effective testing of novel therapeutics.
2025-04-28 | Substrate reduction using a glucosamine analogue in Drosophila melanogaster and mouse models of Sanfilippo syndrome.
Mucopolysaccharidosis (MPS) types III A and C are inherited neurodegenerative disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism, leading to the accumulation of partially-degraded HS fragments. At present, there are no approved treatments and death is commonly in the second decade of life. Several therapies have undergone pre-clinical evaluation for these conditions, including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, findings from a Phase III clinical trial demonstrated that high dose oral genistein did not significantly improve neurodevelopmental outcomes in patients with MPS III (Sanfilippo syndrome). Here, we have tested an N-acetylglucosamine analogue, 4-deoxy-N-acetylglucosamine peracetate, as a novel substrate reduction therapy for HS-storing lysosomal storage disorders such as MPS III. Treatment with this compound significantly reduced HS levels in cultured MPS IIIA patient and mouse fibroblasts in a time- and dose-dependent manner. MPS IIIC Drosophila fed 4-deoxy-N-acetylglucosamine peracetate contained significantly less HS relative to those raised on control diets. Likewise, improvements in HS load within the MPS IIIA mouse brain suggests that the compound crossed the blood-brain barrier after oral administration. Although long-term studies are needed, these findings indicate that 4-deoxy-GlcNAc peracetate may be beneficial in slowing the accumulation of HS and may represent a novel substrate reduction therapeutic for MPS III and potentially other HS-storing disorders.
2025-04-02 | Identification of a neuron-specific ferroptosis in the neurodegenerative mucopolysaccharidosis III model.
Sanfilippo syndrome (MPSIII) is a neurodegenerative disorder caused by enzyme deficiencies, leading to the toxic accumulation of heparan sulfate oligosaccharides in the brain. Emerging evidence suggests that ferroptosis, an iron-dependent form of cell death, contribute to neurodegeneration. To investigate ferroptosis in MPSIIIB, we examined its regulatory mechanisms and markers in MPSIIIB brains. Our results showed elevated iron levels, decreased mRNA expression of TFR1 and ZIP14 (involved in iron uptake) at 9 months of age, and increased protein levels of FTH (which stores intracellular iron) in MPSIIIB brains, indicating a potential link to ferroptosis. We also observed diminished levels of ferroptosis-neutralizing proteins (xc-/GPX4), while the protective pathway (Keap1-Nrf2) was activated. Oxidative homeostasis disruption was revealed by increased expression of genes encoding SOD2, SIRT3, iNOS, and nNOS enzymes. Increased expression of lipid peroxidation genes (ascl4 and lpcat3) further supported ferroptosis involvement. Furthermore, we analyzed protein abundance and brain immunostaining of the iron exporter FPN. Despite its high expression levels, this protein appeared misfolded and was insufficiently targeted to cellular plasma membrane, which might contribute to cellular iron retention. The co-localization of FPN with NeuN, a marker of neurons, demonstrates that only neurons are affected by this targeting defect, suggesting neuronal ferroptosis specifically in MPSIIIB. Overall, our findings evidenced of the involvement of ferroptosis in MPSIIIB pathogenesis, highlighting dysregulation in iron homeostasis, antioxidant defenses, and lipid peroxidation as key features of the disease.
cell therapies
2025-11-19 | Allogeneic hematopoietic stem cell transplantation modulates neurodevelopmental trajectories in mucopolysaccharidosis: a longitudinal study of subtype-specific outcomes and age-dependent efficacy.
Mucopolysaccharidosis (MPS) involves neurodevelopmental decline due to lysosomal dysfunction. Hematopoietic stem cell transplantation (HSCT) may modify disease progression, but subtype-specific outcomes remain unclear. Fifty-seven MPS patients (aged 1-8 years) undergoing HSCT in Shanghai (2019-2024) were assessed longitudinally using Griffiths Mental Development Scales-Chinese (GDS-C) pre-HSCT and at 3, 12, and 24 months post-HSCT. Linear mixed models evaluated timepoint, age, and subtype effects. HSCT significantly improved locomotor function (F = 111.57, p < 0.001), with greatest gains in MPS III (β = 59.57) and age-dependent decline (β = - 2.46/year). Personal-social function improved modestly (F = 4.44, p = 0.039), while language/eye-hand coordination showed progressive gains (p ≤ 0.001). Subtype influenced language (F = 3.75) and coordination (F = 2.89), with attenuated responses in MPS II. No Timepoint × Subtype interactions suggested uniform temporal effects. HSCT stabilizes/improves neurodevelopment in MPS, modulated by subtype and transplant age. Early intervention optimizes outcomes, particularly for MPS III. Culturally adapted GDS-C enables precise monitoring, guiding HSCT timing and rehabilitation.
2025-10-18 | The Neuroimmune Landscape of the Lysosomal Storage Disorder Sanfilippo Syndrome.
Lysosomal storage disorders (LSDs) such as Sanfilippo syndrome (Mucopolysaccharidosis type III) are characterized by impaired lysosomal degradation due to inherited in lysosomal proteins. This dysfunction leads to the accumulation of undegraded substrates, such as heparan sulfate, ultimately leading to progressive neuroinflammation and neurodegeneration. Despite well-defined genetic causes, no disease-modifying therapies exist for Sanfilippo syndrome. While microglia, the brain's resident immune cells, can play both protective and pathogenic roles, the contribution of neuroinflammation to LSD pathology remains underexplored. This review examines the contribution of neuroinflammation to Sanfilippo syndrome, emphasizing emerging mechanisms involving TLR4 signaling, inflammasome activation, the cGAS-STING pathway, and lysosomal biogenesis regulators such as TFE family transcription factors. We also discuss the potential of cellular therapies to modulate neuroimmune responses and offer new therapeutic avenues. By integrating insights from neuroimmunology and lysosomal biology, we aim to identify shared mechanisms and therapeutic targets across Sanfilippo syndrome and related LSDs.
2025-03-24 | Transplantation of Wild-Type Hematopoietic Stem and Progenitor Cells Improves Disease Phenotypes in a Mucopolysaccharidosis IIIC Mouse Model.
Mucopolysaccharidosis type IIIC (MPS IIIC) is a severe neurodegenerative lysosomal storage disease caused by the loss-of-function of the lysosomal transmembrane protein acetyl-CoA: heparan-α-glucosamine N-acetyltransferase. MPS IIIC is characterized by the accumulation of the glycosaminoglycan (GAG) heparan sulfate. There is no treatment for this disease. We generated a new MPS IIIC mouse model and confirmed disease phenotypes such as GAG accumulation, splenomegaly, neurological defects, and presence of disease-specific non-reducing end carbohydrates. To explore a new therapeutic strategy for this condition, we transplanted wild-type (WT) hematopoietic stem and progenitor cells (HSPCs) into lethally irradiated 2-month-old Hgsnat-/- mice and analyzed the resulting impact 6 months later. Transplanted HSPCs differentiated into macrophages in tissues and microglia-like cells in the brain. This resulted in a partial restoration of Hgsnat expression and enzymatic activity along with a significant reduction of the MPS IIIC-specific non-reducing end carbohydrate in the treated Hgsnat-/- mice compared to untreated Hgsnat-/- mice or Hgsnat-/- mice transplanted with Hgsnat-/- HPSCs. In addition, WT HSPC transplant resulted in improved neurological defects, reduction in splenomegaly, and urine retention in the Hgsnat-/- mice. Furthermore, presence of glomerular hyaline bodies with focal fibrosis and sclerosis was observed in the kidney of the disease controls, whereas these abnormalities were improved in the Hgsnat-/- mice treated with WT HSPCs. These data support that HSPC transplantation presents a promising therapeutic avenue for MPS IIIC and represents the first step toward the clinical translation of an HSPC-mediated therapy strategy for MPS IIIC.
2025-03-19 | Allogeneic hematopoietic stem cell transplantation for mucopolysaccharidosis patients: a single-center experience and assessment of quality of life.
Allogeneic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for patients with mucopolysaccharidoses (MPS). We investigate the efficacy and improvements in the quality of life of HSCT in pediatric patients with MPS. A retrospective analysis of transplantation data from 46 cases of MPS from a single institution in China was conducted. The cohort of 46 patients included 9 cases of MPS I, 16 cases of MPS II, 15 cases of MPS IVA and 6 cases of MPS VI. The median age at diagnosis was 2.59 years. The median age at transplantation was 3.80 years. The median follow-up time was 3.1 years (range, 0.8-8.1 years) and 43 patients were alive. The incidence of grades II to IV aGVHD was 17.4%, wherein the incidence of grades III and IV aGVHD was 4.3%. The incidence of moderate-to-severe cGVHD was 6.5%. GAGs urinary excretion decreased and enzyme activity levels reached normal. After HSCT, multiple bone dysplasia, upper-airway obstruction and recurrent otitis media were significantly improved; vision, corneal clouding, cardiovascular disease, hepatosplenomegaly and hydrocephalus were improved or remained stable; neurological symptoms were improved or remained stable in most patients but progressed in others; the patients with MPS IH/S and MPS II reached nearly normal growth rate of height and weight. Meanwhile, the patients with MPS IH, MPS IVA and MPS VI remained poor growth after HSCT. The Activities of Daily Living (ADL) scores were improved in most patients with MPS. ADL scores in patients with severe phenotypes were lower than health control subjects and patients with attenuated phenotypes. HSCT is a good therapeutic option for MPS and improves the quality of life of patients. MPS patients with attenuated phenotypes provide a better outcome in ADL after HSCT.
2024-04-05 | Heterologous HSPC transplantation rescues neuroinflammation and ameliorates peripheral manifestations in the mouse model of lysosomal transmembrane enzyme deficiency, MPS IIIC
Abstract Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme uncapable of free diffusion between the cells and their cross-correction which limits development of therapies based on the enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC ( Hgsnat P304L ) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied by behaviour test battery staring from the age of 6 months. At the age of ∼8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage and other biomarkers of the disease. We found that the treatment corrected several behaviour deficits including hyperactivity and reduction of socialization, but not a memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1β, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with the cells from normal healthy donor. They also suggest, that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology.
proteins
2025-10-01 | Sanfilippo Syndrome: Brain Clinical Picture
This case involves a 20-year-old female patient who experienced three episodes of tonic–clonic seizures after becoming agitated upon waking up at home. The patient has exhibited behavioral abnormalities and speech impairment since childhood and was diagnosed with mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome) at the age of 14 years. The diagnosis was confirmed through chromatography of glycosaminoglycans, revealing the presence of heparan sulfate with greater mobility in urine and a concentration of 25 mg/mmol creatinine in urine. The patient has been under the care of a multidisciplinary team. Computed tomography revealed typical findings of Sanfilippo syndrome, including diffuse cortical thickening of the bone structures evaluated, volumetric reduction of brain parenchyma, accentuation of furrows between cortical gyri and Sylvian fissures, and compensatory dilation of the ventricular system [Figure 1].Figure 1: (a) A computed tomography (CT) scan of the bone window demonstrates diffuse bone thickening. (b) CT in the soft-tissue window shows the widening of the sulci between the cortical gyri and Sylvian fissures and compensatory dilation of the ventricular system. (c) CT in the soft-tissue window reveals volumetric reduction of the brain parenchyma.Sanfilippo syndrome is an autosomal recessive disease characterized by an enzymatic disorder affecting the degradation of heparan sulfate, an intra- and extracellular proteoglycan found in various cells.[1,2] In the United States, its incidence is approximately 1 in 70,000 live births.[3] The syndrome is categorized into four subtypes based on the specific enzymatic deficiency, with MPS IIIA and IIB being the most prevalent.[1] This condition is a progressive neurodegenerative disorder, and its symptoms arise from the accumulation of heparan sulfate in the central nervous system, leading to cognitive decline, motor dysfunction, and behavioral abnormalities.[4,5] The most significant neuroradiological features include abnormal white matter signal intensity, dilation of periventricular spaces, widening of cortical sulci, cerebral atrophy, enlargement of extraventricular spaces, and spinal cord compression,[6] as evidenced in this case. Concerning the skeletal system, key radiological findings consist of dysostosis multiplex, which encompasses various bone malformations found in the skull, hands, legs, arms, and spine.[7] Abnormal storage of glycosaminoglycans leads to hepatomegaly and splenomegaly while also causing damage to cartilage and synovial recesses in joints.[7] As of now, there is no approved treatment for MPS III. However, various treatments are under investigation, including enzyme replacement therapies, substrate reduction therapies, and gene and cell therapies. According to Kong et al., it is anticipated that an approved treatment will become available in the near future.[8] Ethics statement This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its amendments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and that due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2024-07-26 | Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.
Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.
2021-06-23 | Evaluation of artificial signal peptides for secretion of two lysosomal enzymes in CHO cells
Enzyme replacement therapy (ERT) is a scientifically rational and clinically proven treatment for lysosomal storage diseases. Most enzymes used for ERT are purified from the culture supernatant of mammalian cells. However, it is challenging to purify lysosomal enzymes with sufficient quality and quantity for clinical use due to their low secretion levels in mammalian cell systems. To improve the secretion efficiency of recombinant lysosomal enzymes, we evaluated the impact of artificial signal peptides on the production of recombinant lysosomal enzymes in Chinese hamster ovary (CHO) cell lines. We engineered two recombinant human lysosomal enzymes, N-acetyl-α-glucosaminidase (rhNAGLU) and glucosamine (N-acetyl)-6-sulfatase (rhGNS), by replacing their native signal peptides with nine different signal peptides derived from highly secretory proteins and expressed them in CHO K1 cells. When comparing the native signal peptides, we found that rhGNS was secreted into media at higher levels than rhNAGLU. The secretion of rhNAGLU and rhGNS can, however, be carefully controlled by altering signal peptides. The secretion of rhNAGLU was relatively higher with murine Igκ light chain and human chymotrypsinogen B1 signal peptides, whereas Igκ light chain signal peptide 1 and human chymotrypsinogen B1 signal peptides were more effective for rhGNS secretion, suggesting that human chymotrypsinogen B1 signal peptide is the most appropriate for increasing lysosomal enzyme secretion. Collectively, our results indicate that altering signal peptide can modulate the secretion of recombinant lysosome enzymes and will enable lysosomal enzyme production for clinical use.
2021-05-17 | Update of treatment for mucopolysaccharidosis type III (sanfilippo syndrome).
Mucopolysaccharidosis III (Sanfilippo syndrome, MPS III) is caused by lysosomal enzyme deficiency, which is a rare autosomal recessive hereditary disease. For now, there is no approved treatment for MPS III despite lots of efforts providing new vision of its molecular basis, as well as governments providing regulatory and economic incentives to stimulate the development of specific therapies. Those efforts and incentives attract academic institutions and industry to provide potential therapies for MPS III, including enzyme replacement therapies, substrate reduction therapies, gene and cell therapies, and so on, which were discussed in this paper.
2018-06-18 | Targeting Heparan Sulfate Proteoglycans as a Novel Therapeutic Strategy for Mucopolysaccharidoses
Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS). We demonstrate that this protein is able to reduce lysosomal defects in primary fibroblasts from MPS I and MPS IIIB patients. We also show that, by masking the excess of extracellular accumulated HS in MPS fibroblasts, fibroblast growth factor (FGF) signal transduction can be positively modulated. We, therefore, suggest the use of a competitive binding molecule for HS in MPSs as an alternative strategy to prevent the detrimental extracellular substrate storage. Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS). We demonstrate that this protein is able to reduce lysosomal defects in primary fibroblasts from MPS I and MPS IIIB patients. We also show that, by masking the excess of extracellular accumulated HS in MPS fibroblasts, fibroblast growth factor (FGF) signal transduction can be positively modulated. We, therefore, suggest the use of a competitive binding molecule for HS in MPSs as an alternative strategy to prevent the detrimental extracellular substrate storage.
gene therapies
2026-08-01 | A Rare Septuagenarian Patient with a Mild Form of Mucopolysaccharidosis Type IIIC with Ocular Manifestations, a Case Report
Purpose: We present an atypical case of mucopolysaccharidosis (MPS) type IIIC to contribute to the growing understanding of its clinical heterogeneity and expand the known phenotypic spectrum of the disorder. This report describes one of the oldest known patients with genetically confirmed MPS IIIC. Case presentation: The patient received genetic testing in her seventies, revealing variations in the HGSNAT and NAGLU genes, two genes associated with MPS III. Her clinical presentation consisted primarily of retinal dystrophy, diagnosed via clinical presentation in addition to OCT and ERG. The patient also showed signs of peripheral neuropathy which were initially presumed to be idiopathic. She did not exhibit the typical behavioral involvement and craniofacial abnormalities expected of MPS type IIIC. Conclusions: This presentation broadens the recognized clinical spectrum of MPS IIIC and may facilitate earlier diagnosis in adults with similar, seemingly idiopathic findings. Improved recognition of such atypical cases may support timely genetic testing and potential therapeutic options.
2026-07-23 | Extracellular vesicles derived from cells overexpressing HGSNAT rescue defects in Mucopolysaccharidosis IIIC neurons
Summary Mucopolysaccharidosis III type C (MPS IIIC) is a rare neurological lysosomal storage disorder caused by genetic deficiency of the lysosomal membrane enzyme, heparan-α-glucosaminide N-acetyltransferase (HGSNAT). To assess the feasibility of therapeutic strategies based on cross-correction of neurons by HGSNAT secreted from transplanted cells overexpressing the enzyme, we generated induced cortical neurons (iCN) from induced pluripotent stem cells (iPSCs) derived from MPS IIIC patients. The neurons were treated with extracellular vesicles (EV) purified from the culture medium conditioned by human endothelial cells transduced with a lentiviral vector encoding EGFP-tagged HGSNAT (LV-HGSNAT-EGFP). The isolated EV showed supraphysiologic HGSNAT activity levels and efficiently delivered the enzyme to the lysosomes of MPS IIIC iCN reducing lysosomal size and restoring normal synaptic protein levels. EV-mediated delivery of HGSNAT to neurons was further confirmed by the analysis of MPS IIIC iCN either co-cultured with iPSC-derived MPS IIIC microglia (iMGL) transduced with LV-HGSNAT-EGFP or treated with the iMGL conditioned medium. MPS IIIC iCN co-cultured with iMGL overexpressing HGSNAT achieved a complete phenotypic rescue, including normalization of lysosomal size, and the levels of heparan sulfate, G M2 -ganglioside, synaptic proteins and brain-derived neurotropic factor. Treatment of MPS IIIC iCNs with conditioned medium led to a partial defects correction. Our findings reveal the translational potential of EV-mediated enzyme delivery in MPS IIIC patients treated with LV-mediated haematopoietic progenitor stem cell gene therapy.
2026-06-26 | Pathogenic Variants in HGSNAT associated with Autosomal Recessive Retinitis Pigmentosa without Overt Sanfilippo Syndrome.
Biallelic variants in the HGSNAT gene are associated with Sanfilippo syndrome, a rare lysosomal storage disorder caused by deficiency of heparan acetyl CoA glucosamine N-Acetyl-transferase enzyme(HGSNAT). The syndrome is characterized by multiple systemic findings, including progressive neurological and retinal degeneration. Retinitis pigmentosa due to HGSNAT gene variants are rarely reported without systemic manifestations. Here we describe two patients with retinitis pigmentosa and reduced enzymatic activity. One of our patients also had hearing loss. We also present a review of the literature for cases of non-syndromic retinal dystrophy associated with HGSNAT variants in the discussion. The first patient with retinitis pigmentosa and hearing loss has two variants of uncertain significance in the HGSNAT gene(p.Thr522Met and p.Cys79Arg). HGSNAT enzyme activity was 0.43nmol/17hr/mg(normal:5.8-45nmol/17hr/mg protein). Our second patient with isolated retinitis pigmentosa has two heterozygous pathogenic variants in HGSNAT (p.Arg124Trp and p.Ala615Thr). HGSNAT enzyme activity was 1.13nmol/17hr/mg(normal:5.8-45nmol/17hr/mg protein). The retinal findings are consistent with HGSNAT-related disease. The first case is the second report of retinitis pigmentosa and hearing loss linked to HGSNAT-related disease. Both cases showed reduced HGSNAT enzyme activity in blood. Although more evidence is needed to definitively link adult-onset hearing loss to HGSNAT variants, it may be due to reduced enzyme activity.
2026-01-27 | Unveiling Mucopolysaccharidosis IIIC in Brazil: Diagnostic Journey and Clinical Features of Brazilian Patients Identified Through the MPS Brazil Network.
Mucopolysaccharidosis type IIIC (MPS IIIC) is a rare lysosomal storage disorder caused by pathogenic variants in the HGSNAT gene. Data from large patient cohorts remain scarce, particularly in Latin America. We retrospectively analyzed clinical, biochemical, and genetic data from patients diagnosed with MPS IIIC through the MPS Brazil Network. Diagnosis was based on reduced activity of acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), elevated urinary glycosaminoglycans (uGAGs), and/or molecular genetics tests. A total of 101 patients were confirmed with MPS IIIC, representing one of the largest cohorts worldwide. Females accounted for 60% of cases. The mean age at symptom onset was 5.4 ± 3.9 years, while the mean age at diagnosis was 11.7 ± 6.9 years, reflecting a 6-year diagnostic delay. Most patients initially presented with developmental delay (82%) and facial dysmorphism (80%), whereas behavioral manifestations were less frequently identified (25%), suggesting a milder phenotype than previously reported. Genetic information was available for 28% of patients, showing recurrent alleles (c.372-2A>G, c.252dupT) and several novel mutations, which expand the mutational spectrum of the disease. Genotype-phenotype similarities with Portuguese, Italian, and Chinese cases suggest shared ancestry contributions. Regional differences included earlier diagnoses in the North of Brazil and high consanguinity rates in the Northeast region. This study describes the largest Brazilian cohort of MPS IIIC, documenting novel variants and regional heterogeneity. Findings highlight diagnostic delays, ancestry influences, and the urgent need for disease-modifying therapies.
2026-01-01 | Mucopolysaccharidosis type IIIC diagnosed at the age of 12 years: Why was the disease diagnosed so late?
Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases associated with impaired lysosomal degradation of glycosaminoglycans.The aim of this manuscript is to report a case of a patient with mucopolysaccharidosis type IIIC (MPS IIIC) diagnosed at 12 years of age -to raise awareness among pediatricians, pediatric neurologists, and endocrinologists about the possible misdiagnosis.The patient was initially diagnosed with autism spectrum disorder and hyperactivity with normal motor development.During follow-up, psychomotor regression with moderate intellectual disability was observed.The patient was referred for further metabolic work-up only after the results of molecular analysis suggesting MPS IIIC.The final diagnosis was established based on clinical, biochemical, and molecular analyses.
other
2025-11-27 | Neuroinflammation as a Novel Therapeutic Frontier for Sanfilippo Syndrome.
Glycosaminoglycans (GAGs), also named 'mucopolysaccharides', are nodal constituents of the connective tissue matrix which go through synthesis, demolition, and reconstruction within several cellular structures: an abnormal GAG catabolism is the basis of progressive intra-lysosomal accumulation of non-metabolized GAGs, defining all mucopolysaccharidoses (MPS), protean disorders characterized by physical abnormalities and multi-organ failure depending on the specific site of non-renewable GAGs stored. A severe cognitive decline is typically observed in the Sanfilippo syndrome, which corresponds to MPS type III, a group of four inherited neurodegenerative diseases resulting from the lack of specific enzymes involved in heparan sulfate (HS) metabolism. As a consequence, the storage of partially degraded HS fragments within lysosomes of the central nervous system elicits chain inflammatory reactions involving the NLRP3-inflammasome in microglia and astrocytes, which cease their homeostatic and immune functions and finally compromise neuron survival. This article provides an overview of the neuroinflammatory picture observed in children with MPS type III, postulating a role of HS accumulation to prime innate immunity responses which culminate with pro-inflammatory cytokine release in the brain and highlighting the relevance of interleukin-1 as a main contributor to neuroinflammation.
2025-10-01 | A case report on the treatment of autoimmune hemolytic anemia after CBT by daratumumab in a mucopolysaccharidosis type III patient.
Mucopolysaccharidosis type III, also referred to as Sanfilippo disease, is a rare hereditary lysosomal storage illness and one of the more common variants. The illness can affect all tissues and organs of the body, with the central nervous system being the most profoundly impacted. Autoimmune hemolytic anemia (AIHA) is a rare, diverse, antibody-mediated disorder characterized by the production of antibodies that target and destroy red blood cells, leading to their rapid destruction. AIHA is a prevalent and notable complication in recipients following umbilical cord blood stem cell transplantation. Immunosuppressive treatments, including intravenous immunoglobulin and rituximab, have been the primary therapeutic modalities. There is no consensus on the appropriate treatment for post-transplant severe AIHA. This article details a 5-year-old male diagnosed with mucopolysaccharidosis type III. He developed AIHA + 144 days after umbilical cord blood stem cell transplantation. Genetic testing, cranial CT, blood cell analysis, direct/indirect antihuman globulin test. Treatment encompasses red blood cell transfusion to rectify anemia, intravenous administration of methylprednisolone, calcium gluconate, alkaline solutions, plasma exchange, rituximab, gamma globulin, and more symptomatic therapies. The symptoms of hemolysis were inadequately managed throughout the disease progression and were alleviated upon therapy with daratumumab. The treatment was conducted without adverse effects, and the problem was well managed. A telephonic follow-up with the patient was conducted by our department 546 days post-discharge. The child's cognitive ability, linguistic skills, and other neurological processes remained stable without further decline. This report discusses a child with MPS III, a rare disorder characterized by complex and varied phenotypes, including distinctive facial features, short stature, cognitive regression, varying degrees of skeletal deformities, and hepatosplenomegaly. The patient has autoimmune hemolysis after umbilical cord blood transplantation. For patients who do not respond to rituximab and gamma globulin, daratumumab may be considered.
2025-02-01 | mRNA Degradation as a Therapeutic Solution for Mucopolysaccharidosis Type IIIC: Use of Antisense Oligonucleotides to Promote Downregulation of Heparan Sulfate Synthesis
Mucopolysaccharidosis type IIIC is a neurodegenerative lysosomal storage disorder (LSD) characterized by the accumulation of undegraded heparan sulfate (HS) due to the lack of an enzyme responsible for its degradation: acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). Classical treatments are ineffective. Here, we attempt a new approach in genetic medicine, genetic substrate reduction therapy (gSRT), to counteract this neurological disorder. Briefly, we used synthetic oligonucleotides, particularly gapmer antisense oligonucleotides (ASOs), to target the synthesis of the accumulated compounds at the molecular level, downregulating a specific gene involved in the first step of HS biosynthesis, XYLT1. Our goal was to reduce HS production and, consequently, its accumulation. Initially, five gapmer ASOs were designed and their potential to decrease XYLT1 mRNA levels were tested in patient-derived fibroblasts. Subsequent analyses focused on the two best performing molecules alone. The results showed a high inhibition of the XYLT1 gene mRNA (around 90%), a decrease in xylosyltransferase I (XT-I) protein levels and a reduction in HS storage 6 and 10 days after transfection (up to 21% and 32%, respectively). Overall, our results are highly promising and may represent the initial step towards the development of a potential therapeutic option not only for MPS IIIC, but virtually for every other MPS III form. Ultimately, the same principle may also apply to other neuropathic MPS.
2024-11-22 | Development of a novel tool for individual treatment trials in mucopolysaccharidosis.
Mucopolysaccharidosis (MPS) encompasses a group of genetic lysosomal storage disorders, linked to reduced life expectancy and a significant lack of effective treatment options. Immunomodulatory drugs could have the potential to be a relevant medical approach, as the accumulation of undegraded substances initiates an innate immune response, which leads to inflammation and clinical deterioration. However, immunomodulators are not licensed for this indication. Consequently, we aim to provide evidence advocating fast access to innovative individual treatment trials (ITTs) with immunomodulatory drugs and high-quality evaluation of drug effects by implementing a risk-benefit model tailored for MPS. The iterative methodology of our novel decision analysis framework (DAF) involves three key steps: (i) literature review on promising treatment targets and immunomodulators in MPS; (ii) quantitative risk-benefit assessment (RBA) of selected molecules; (iii) assigning phenotypic profiles and quantitative evaluations. The results facilitate a personalized application of the model and are based on published evidence as well as interdisciplinary experts' consensus and patient perspectives. Four promising immunomodulators have been identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra is anticipated as a treatment of choice for neuronopathic MPS patients. Nevertheless, a comprehensive RBA should always be completed on an individual basis. Our evidence-based DAF tool for ITTs directly addresses the substantial unmet medical need in MPS and characterizes an initial stride toward precision medicine with immunomodulators.
2024-01-18 | Drosophila melanogaster models of MPS IIIC (Hgsnat‐deficiency) highlight the role of glia in disease presentation
Abstract Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan‐α‐glucosaminide N ‐acetyltransferase ( HGSNAT ; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep–wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As HGSNAT is conserved in Drosophila melanogaster , we now describe the creation and characterisation of the first Drosophila models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi‐mediated knockdown of hgsnat were confirmed to have a reduced level of HGSNAT transcripts and age‐dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre‐synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in hgsnat neuronal knockdown lines. Further, when hgsnat was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that hgsnat function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.
small molecules
2026-08-11 | NDST1 as a substrate-reduction target in Mucopolysaccharidosis type IIIC: virtual screening, microsecond molecular dynamics, and peptide design
ABSTRACT Mucopolysaccharidosis IIIC (Sanfilippo syndrome type C) is a rare lysosomal storage disorder caused by loss-of-function mutations in HGSNAT , which encodes an enzyme involved in heparan sulfate (HS) degradation, leading to impaired HS catabolism, lysosomal accumulation, and progressive neurodegeneration. Because enzyme replacement therapies have limited penetration across the blood–brain barrier, substrate-reduction therapy represents an alternative therapeutic strategy. Here, N-deacetylase/N-sulfotransferase 1 (NDST1), a key enzyme responsible for HS biosynthesis, was investigated as a potential substrate-reduction target. A structure-based computational pipeline was used to identify and evaluate inhibitors targeting the NDST1 sulfotransferase domain. Approximately 4.1 million drug-like compounds and FDA-approved drugs were screened by molecular docking, followed by pharmacokinetic filtering, molecular dynamics simulations, and MM/PBSA binding free energy calculations. In parallel, peptide binders targeting the same site were generated using diffusion-based protein design and evaluated using molecular dynamics and MM/GBSA analysis. Four chemically distinct small-molecule scaffolds and three peptide candidates were identified as stable binders to the NDST1 active site. The lead small-molecule candidate exhibited a predicted binding free energy of −13.36 ± 5.87 kcal mol −1 . These provide a focused set of candidates for further investigation and support the feasibility of targeting NDST1 as a substrate-reduction strategy for MPS IIIC.
2026-04-29 | Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III.
Mucopolysaccharidosis type III (MPS III) is a group of autosomal recessive neurodegenerative lysosomal storage disorders that causes progressive cognitive and physical impairment, predominantly in child/early adulthood. The median age of death is 17 years as there is no safe, effective treatment approved. Using faithful Drosophila and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up-regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down-regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short-term studies, food enriched with 5 mM spermidine improved overall fly activity and climbing ability. A 4-week study in pre-symptomatic MPS IIIA mice (3- or 6-mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer-term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.
2026-01-01 | Mucopolysaccharidosis III: Using Mouse and Human Neuronal Models for Biomarker Discovery and Therapeutic Development
Sanfilippo Disease, or Mucopolysaccharidosis (MPS) III, is a spectrum (MPS IIIA to D) of rare inherited neurological lysosomal diseases caused by deficiencies in one of four lysosomal enzymes that catabolize heparan sulphate (HS). Sanfilippo causes a severe neurocognitive decline in affected children and progressively leads to dementia and premature death before the third decade of life. MPS III still lacks effective therapeutic strategies in the central nervous system (CNS), as both enzyme replacement and AAV9-mediated systemic gene therapy have limited efficacy in the CNS. Previously, our research identified several neuron-specific biomarkers of pathogenesis in the MPS IIIC mouse models, including defects in the excitatory and inhibitory synapses and decreased levels of brain-derived neurotrophic factor (BDNF). However, these deficits have yet to be confirmed in a human-relevant neuronal model of Sanfilippo disease. My PhD research aimed to develop human-relevant in vitro neuronal models from induced pluripotent stem cells (iPSCs) of MPS III patients to characterize the disease. iPSCs in combination with mouse models for MPS III would then be used to evaluate the therapeutic efficacy of a small neurotrophic molecule, “AVP6”. In my second chapter, I investigated the therapeutic potential of extracellular vesicles (EV) for the neuronal delivery of heparan-α-glucosaminide-N-acetyltransferase (HGSNAT) deficient in MPS IIIC. The first chapter I characterized MPS IIIA, B, and C iPSC-derived cortical neurons (iCNs) and tested them with AVP6. We demonstrated that MPS III iCNs retained disease-specific primary enzymatic deficits and lysosomal storage phenotype (increased LAMP2+ area). MPS III iCNs revealed significantly reduced levels of BDNF, and protein markers for glutamatergic (VGLUT1/PSD-95) and GABA-ergic (VGAT/Gephyrin) synapses. AVP6 treatments restored or significantly increased levels of all synaptic proteins and BDNF. Using the MPS IIIA mouse model (Sgshmps3a) I studied the long-term (7 months) behavioural and histopathological effects of daily intranasal administration of AVP6. Unlike untreated, AVP6-treated MPS IIIA mice did not display behavioural deficits including the loss of working and spatial memory, or inability to socialize. Our histopathological analysis revealed that the major hallmarks of the disease in the CNS did not develop in the AVP6-treated groups. This included a decrease in the levels of the excitatory synaptic markers (VGLUT1/PSD95), microgliosis (CD68+ cells), astrocytosis (GFAP+ cells), myelin loss (MBP levels), and autophagy block (LC3B levels). These results paralleled those demonstrated by other lab members for the MPS IIIB and MPS IIIC mice; showing the versatility of AVP6. In the second chapter, I investigated whether EV can be used for the therapeutic delivery of HGSNAT to MPS IIIC iCN. We demonstrated that EV isolated from lentivirus-transduced cell lines overexpressing the GFP-tagged human HGSNAT (HGSNAT-GFP) contained high levels of the enzyme (> 100-fold increase compared to EV from non-transduced cells). MPS IIIC iCNs treated with HGSNAT-loaded EVs for three days showed a complete rescue of the reduced levels of VGLUT1+, VGAT+ and BDNF+ puncta, with the inhibitory synaptic marker Gephyrin+ puncta significantly increased but remaining below control levels. We further generated iPSC-derived microglia (iMGL) overexpressing HGSNAT-GFP and cocultured them for seven days with MPS IIIC iCNs. MPS IIIC iCNs cocultured with iMGLs overexpressing HGSNAT-GFP showed a recovery of all disease biomarkers, including a recovery of the reduced PSD-95+ and Gephyrin+ puncta levels. Overall, in my PhD research project, I developed human-relevant models of Sanfilippo diseases that allowed for the characterization and effective testing of novel therapeutics.
2025-04-28 | Substrate reduction using a glucosamine analogue in Drosophila melanogaster and mouse models of Sanfilippo syndrome.
Mucopolysaccharidosis (MPS) types III A and C are inherited neurodegenerative disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism, leading to the accumulation of partially-degraded HS fragments. At present, there are no approved treatments and death is commonly in the second decade of life. Several therapies have undergone pre-clinical evaluation for these conditions, including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, findings from a Phase III clinical trial demonstrated that high dose oral genistein did not significantly improve neurodevelopmental outcomes in patients with MPS III (Sanfilippo syndrome). Here, we have tested an N-acetylglucosamine analogue, 4-deoxy-N-acetylglucosamine peracetate, as a novel substrate reduction therapy for HS-storing lysosomal storage disorders such as MPS III. Treatment with this compound significantly reduced HS levels in cultured MPS IIIA patient and mouse fibroblasts in a time- and dose-dependent manner. MPS IIIC Drosophila fed 4-deoxy-N-acetylglucosamine peracetate contained significantly less HS relative to those raised on control diets. Likewise, improvements in HS load within the MPS IIIA mouse brain suggests that the compound crossed the blood-brain barrier after oral administration. Although long-term studies are needed, these findings indicate that 4-deoxy-GlcNAc peracetate may be beneficial in slowing the accumulation of HS and may represent a novel substrate reduction therapeutic for MPS III and potentially other HS-storing disorders.
2025-04-02 | Identification of a neuron-specific ferroptosis in the neurodegenerative mucopolysaccharidosis III model.
Sanfilippo syndrome (MPSIII) is a neurodegenerative disorder caused by enzyme deficiencies, leading to the toxic accumulation of heparan sulfate oligosaccharides in the brain. Emerging evidence suggests that ferroptosis, an iron-dependent form of cell death, contribute to neurodegeneration. To investigate ferroptosis in MPSIIIB, we examined its regulatory mechanisms and markers in MPSIIIB brains. Our results showed elevated iron levels, decreased mRNA expression of TFR1 and ZIP14 (involved in iron uptake) at 9 months of age, and increased protein levels of FTH (which stores intracellular iron) in MPSIIIB brains, indicating a potential link to ferroptosis. We also observed diminished levels of ferroptosis-neutralizing proteins (xc-/GPX4), while the protective pathway (Keap1-Nrf2) was activated. Oxidative homeostasis disruption was revealed by increased expression of genes encoding SOD2, SIRT3, iNOS, and nNOS enzymes. Increased expression of lipid peroxidation genes (ascl4 and lpcat3) further supported ferroptosis involvement. Furthermore, we analyzed protein abundance and brain immunostaining of the iron exporter FPN. Despite its high expression levels, this protein appeared misfolded and was insufficiently targeted to cellular plasma membrane, which might contribute to cellular iron retention. The co-localization of FPN with NeuN, a marker of neurons, demonstrates that only neurons are affected by this targeting defect, suggesting neuronal ferroptosis specifically in MPSIIIB. Overall, our findings evidenced of the involvement of ferroptosis in MPSIIIB pathogenesis, highlighting dysregulation in iron homeostasis, antioxidant defenses, and lipid peroxidation as key features of the disease.
cell therapies
2025-11-19 | Allogeneic hematopoietic stem cell transplantation modulates neurodevelopmental trajectories in mucopolysaccharidosis: a longitudinal study of subtype-specific outcomes and age-dependent efficacy.
Mucopolysaccharidosis (MPS) involves neurodevelopmental decline due to lysosomal dysfunction. Hematopoietic stem cell transplantation (HSCT) may modify disease progression, but subtype-specific outcomes remain unclear. Fifty-seven MPS patients (aged 1-8 years) undergoing HSCT in Shanghai (2019-2024) were assessed longitudinally using Griffiths Mental Development Scales-Chinese (GDS-C) pre-HSCT and at 3, 12, and 24 months post-HSCT. Linear mixed models evaluated timepoint, age, and subtype effects. HSCT significantly improved locomotor function (F = 111.57, p < 0.001), with greatest gains in MPS III (β = 59.57) and age-dependent decline (β = - 2.46/year). Personal-social function improved modestly (F = 4.44, p = 0.039), while language/eye-hand coordination showed progressive gains (p ≤ 0.001). Subtype influenced language (F = 3.75) and coordination (F = 2.89), with attenuated responses in MPS II. No Timepoint × Subtype interactions suggested uniform temporal effects. HSCT stabilizes/improves neurodevelopment in MPS, modulated by subtype and transplant age. Early intervention optimizes outcomes, particularly for MPS III. Culturally adapted GDS-C enables precise monitoring, guiding HSCT timing and rehabilitation.
2025-10-18 | The Neuroimmune Landscape of the Lysosomal Storage Disorder Sanfilippo Syndrome.
Lysosomal storage disorders (LSDs) such as Sanfilippo syndrome (Mucopolysaccharidosis type III) are characterized by impaired lysosomal degradation due to inherited in lysosomal proteins. This dysfunction leads to the accumulation of undegraded substrates, such as heparan sulfate, ultimately leading to progressive neuroinflammation and neurodegeneration. Despite well-defined genetic causes, no disease-modifying therapies exist for Sanfilippo syndrome. While microglia, the brain's resident immune cells, can play both protective and pathogenic roles, the contribution of neuroinflammation to LSD pathology remains underexplored. This review examines the contribution of neuroinflammation to Sanfilippo syndrome, emphasizing emerging mechanisms involving TLR4 signaling, inflammasome activation, the cGAS-STING pathway, and lysosomal biogenesis regulators such as TFE family transcription factors. We also discuss the potential of cellular therapies to modulate neuroimmune responses and offer new therapeutic avenues. By integrating insights from neuroimmunology and lysosomal biology, we aim to identify shared mechanisms and therapeutic targets across Sanfilippo syndrome and related LSDs.
2025-03-24 | Transplantation of Wild-Type Hematopoietic Stem and Progenitor Cells Improves Disease Phenotypes in a Mucopolysaccharidosis IIIC Mouse Model.
Mucopolysaccharidosis type IIIC (MPS IIIC) is a severe neurodegenerative lysosomal storage disease caused by the loss-of-function of the lysosomal transmembrane protein acetyl-CoA: heparan-α-glucosamine N-acetyltransferase. MPS IIIC is characterized by the accumulation of the glycosaminoglycan (GAG) heparan sulfate. There is no treatment for this disease. We generated a new MPS IIIC mouse model and confirmed disease phenotypes such as GAG accumulation, splenomegaly, neurological defects, and presence of disease-specific non-reducing end carbohydrates. To explore a new therapeutic strategy for this condition, we transplanted wild-type (WT) hematopoietic stem and progenitor cells (HSPCs) into lethally irradiated 2-month-old Hgsnat-/- mice and analyzed the resulting impact 6 months later. Transplanted HSPCs differentiated into macrophages in tissues and microglia-like cells in the brain. This resulted in a partial restoration of Hgsnat expression and enzymatic activity along with a significant reduction of the MPS IIIC-specific non-reducing end carbohydrate in the treated Hgsnat-/- mice compared to untreated Hgsnat-/- mice or Hgsnat-/- mice transplanted with Hgsnat-/- HPSCs. In addition, WT HSPC transplant resulted in improved neurological defects, reduction in splenomegaly, and urine retention in the Hgsnat-/- mice. Furthermore, presence of glomerular hyaline bodies with focal fibrosis and sclerosis was observed in the kidney of the disease controls, whereas these abnormalities were improved in the Hgsnat-/- mice treated with WT HSPCs. These data support that HSPC transplantation presents a promising therapeutic avenue for MPS IIIC and represents the first step toward the clinical translation of an HSPC-mediated therapy strategy for MPS IIIC.
2025-03-19 | Allogeneic hematopoietic stem cell transplantation for mucopolysaccharidosis patients: a single-center experience and assessment of quality of life.
Allogeneic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for patients with mucopolysaccharidoses (MPS). We investigate the efficacy and improvements in the quality of life of HSCT in pediatric patients with MPS. A retrospective analysis of transplantation data from 46 cases of MPS from a single institution in China was conducted. The cohort of 46 patients included 9 cases of MPS I, 16 cases of MPS II, 15 cases of MPS IVA and 6 cases of MPS VI. The median age at diagnosis was 2.59 years. The median age at transplantation was 3.80 years. The median follow-up time was 3.1 years (range, 0.8-8.1 years) and 43 patients were alive. The incidence of grades II to IV aGVHD was 17.4%, wherein the incidence of grades III and IV aGVHD was 4.3%. The incidence of moderate-to-severe cGVHD was 6.5%. GAGs urinary excretion decreased and enzyme activity levels reached normal. After HSCT, multiple bone dysplasia, upper-airway obstruction and recurrent otitis media were significantly improved; vision, corneal clouding, cardiovascular disease, hepatosplenomegaly and hydrocephalus were improved or remained stable; neurological symptoms were improved or remained stable in most patients but progressed in others; the patients with MPS IH/S and MPS II reached nearly normal growth rate of height and weight. Meanwhile, the patients with MPS IH, MPS IVA and MPS VI remained poor growth after HSCT. The Activities of Daily Living (ADL) scores were improved in most patients with MPS. ADL scores in patients with severe phenotypes were lower than health control subjects and patients with attenuated phenotypes. HSCT is a good therapeutic option for MPS and improves the quality of life of patients. MPS patients with attenuated phenotypes provide a better outcome in ADL after HSCT.
2024-04-05 | Heterologous HSPC transplantation rescues neuroinflammation and ameliorates peripheral manifestations in the mouse model of lysosomal transmembrane enzyme deficiency, MPS IIIC
Abstract Mucopolysaccharidosis III type C (MPS IIIC) is an untreatable neuropathic lysosomal storage disease caused by a genetic deficiency of the lysosomal N-acetyltransferase, HGSNAT, catalyzing a transmembrane acetylation of heparan sulfate. HGSNAT is a transmembrane enzyme uncapable of free diffusion between the cells and their cross-correction which limits development of therapies based on the enzyme replacement and gene correction. Since our previous work identified neuroinflammation as a hallmark of the CNS pathology in MPS IIIC, we tested whether it can be corrected by replacement of activated brain microglia with neuroprotective macrophages/microglia derived from a heterologous HSPC transplant. Eight-week-old MPS IIIC ( Hgsnat P304L ) mice were transplanted with HSPC from congenic wild type mice after myeloablation with Busulfan and studied by behaviour test battery staring from the age of 6 months. At the age of ∼8 months, mice were sacrificed to study pathological changes in the brain, heparan sulfate storage and other biomarkers of the disease. We found that the treatment corrected several behaviour deficits including hyperactivity and reduction of socialization, but not a memory decline. It also improved several features of CNS pathology such as microastroglyosis, expression of pro-inflammatory cytokine IL-1β, and accumulation of misfolded amyloid aggregates in cortical neurons. At the periphery, the treatment delayed development of terminal urinary retention, potentially increasing longevity, and reduced blood levels of heparan sulfate. However, we did not observe correction of lysosomal storage phenotype in neurons and heparan sulfate brain levels. Together, our results demonstrate that neuroinflammation in a neurological lysosomal storage disease, caused by defects in a transmembrane enzyme, can be effectively ameliorated by replacement of microglia bearing the genetic defect with the cells from normal healthy donor. They also suggest, that heterologous HSPC transplant, if used together with other methods, such as chaperone therapy or substrate reduction therapy, may constitute an effective combination therapy for MPS IIIC and other disorders with a similar etiology.
proteins
2025-10-01 | Sanfilippo Syndrome: Brain Clinical Picture
This case involves a 20-year-old female patient who experienced three episodes of tonic–clonic seizures after becoming agitated upon waking up at home. The patient has exhibited behavioral abnormalities and speech impairment since childhood and was diagnosed with mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome) at the age of 14 years. The diagnosis was confirmed through chromatography of glycosaminoglycans, revealing the presence of heparan sulfate with greater mobility in urine and a concentration of 25 mg/mmol creatinine in urine. The patient has been under the care of a multidisciplinary team. Computed tomography revealed typical findings of Sanfilippo syndrome, including diffuse cortical thickening of the bone structures evaluated, volumetric reduction of brain parenchyma, accentuation of furrows between cortical gyri and Sylvian fissures, and compensatory dilation of the ventricular system [Figure 1].Figure 1: (a) A computed tomography (CT) scan of the bone window demonstrates diffuse bone thickening. (b) CT in the soft-tissue window shows the widening of the sulci between the cortical gyri and Sylvian fissures and compensatory dilation of the ventricular system. (c) CT in the soft-tissue window reveals volumetric reduction of the brain parenchyma.Sanfilippo syndrome is an autosomal recessive disease characterized by an enzymatic disorder affecting the degradation of heparan sulfate, an intra- and extracellular proteoglycan found in various cells.[1,2] In the United States, its incidence is approximately 1 in 70,000 live births.[3] The syndrome is categorized into four subtypes based on the specific enzymatic deficiency, with MPS IIIA and IIB being the most prevalent.[1] This condition is a progressive neurodegenerative disorder, and its symptoms arise from the accumulation of heparan sulfate in the central nervous system, leading to cognitive decline, motor dysfunction, and behavioral abnormalities.[4,5] The most significant neuroradiological features include abnormal white matter signal intensity, dilation of periventricular spaces, widening of cortical sulci, cerebral atrophy, enlargement of extraventricular spaces, and spinal cord compression,[6] as evidenced in this case. Concerning the skeletal system, key radiological findings consist of dysostosis multiplex, which encompasses various bone malformations found in the skull, hands, legs, arms, and spine.[7] Abnormal storage of glycosaminoglycans leads to hepatomegaly and splenomegaly while also causing damage to cartilage and synovial recesses in joints.[7] As of now, there is no approved treatment for MPS III. However, various treatments are under investigation, including enzyme replacement therapies, substrate reduction therapies, and gene and cell therapies. According to Kong et al., it is anticipated that an approved treatment will become available in the near future.[8] Ethics statement This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its amendments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and that due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2024-07-26 | Role of Botulinum Toxin in Treatment of Secondary Dystonia: A Case Series and Overview of Literature.
Dystonia can present in primary and secondary forms, depending on co-occurring symptoms and syndromic associations. In contrast to primary dystonia, secondary forms of dystonia are often associated with lesions in the putamen or globus pallidus. Such disorders are commonly neurodegenerative or neurometabolic conditions which produce varied neurologic as well as systemic manifestations other than dystonia. Chemo-denervation with botulinum toxin has been successfully used for focal or segmental dystonia. However, studies evaluating the effect of BoNT therapy on patients with secondary dystonia are sparse, given the heterogeneity in etiology and presentation. We present a series of patients with secondary dystonia who were managed with botulinum toxin therapy. Patients included in this series had a confirmed neurometabolic cause of dystonia. A total of 14 patients, with ages ranging from 17 to 36 years, with disorders including Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN), Niemann-Pick disease type C (NPC), glutaric aciduria type 1, Sanfilippo syndrome (Mucopolysaccharidosis Type IIIb), and GM2 gangliosidosis (Sandhoff disease) are presented. Most patients experienced a mild to moderate improvement in treated dystonia with benefits ranging from 6 to 12 weeks, with the median length of the benefits lasting approximately eight weeks, without any significant adverse effects. Although the secondary causes of dystonia are complex and diverse, our presented data and the available reports of the use of botulinum toxin support the conclusion that chemo-denervation plays an important role in symptom alleviation.
2021-06-23 | Evaluation of artificial signal peptides for secretion of two lysosomal enzymes in CHO cells
Enzyme replacement therapy (ERT) is a scientifically rational and clinically proven treatment for lysosomal storage diseases. Most enzymes used for ERT are purified from the culture supernatant of mammalian cells. However, it is challenging to purify lysosomal enzymes with sufficient quality and quantity for clinical use due to their low secretion levels in mammalian cell systems. To improve the secretion efficiency of recombinant lysosomal enzymes, we evaluated the impact of artificial signal peptides on the production of recombinant lysosomal enzymes in Chinese hamster ovary (CHO) cell lines. We engineered two recombinant human lysosomal enzymes, N-acetyl-α-glucosaminidase (rhNAGLU) and glucosamine (N-acetyl)-6-sulfatase (rhGNS), by replacing their native signal peptides with nine different signal peptides derived from highly secretory proteins and expressed them in CHO K1 cells. When comparing the native signal peptides, we found that rhGNS was secreted into media at higher levels than rhNAGLU. The secretion of rhNAGLU and rhGNS can, however, be carefully controlled by altering signal peptides. The secretion of rhNAGLU was relatively higher with murine Igκ light chain and human chymotrypsinogen B1 signal peptides, whereas Igκ light chain signal peptide 1 and human chymotrypsinogen B1 signal peptides were more effective for rhGNS secretion, suggesting that human chymotrypsinogen B1 signal peptide is the most appropriate for increasing lysosomal enzyme secretion. Collectively, our results indicate that altering signal peptide can modulate the secretion of recombinant lysosome enzymes and will enable lysosomal enzyme production for clinical use.
2021-05-17 | Update of treatment for mucopolysaccharidosis type III (sanfilippo syndrome).
Mucopolysaccharidosis III (Sanfilippo syndrome, MPS III) is caused by lysosomal enzyme deficiency, which is a rare autosomal recessive hereditary disease. For now, there is no approved treatment for MPS III despite lots of efforts providing new vision of its molecular basis, as well as governments providing regulatory and economic incentives to stimulate the development of specific therapies. Those efforts and incentives attract academic institutions and industry to provide potential therapies for MPS III, including enzyme replacement therapies, substrate reduction therapies, gene and cell therapies, and so on, which were discussed in this paper.
2018-06-18 | Targeting Heparan Sulfate Proteoglycans as a Novel Therapeutic Strategy for Mucopolysaccharidoses
Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS). We demonstrate that this protein is able to reduce lysosomal defects in primary fibroblasts from MPS I and MPS IIIB patients. We also show that, by masking the excess of extracellular accumulated HS in MPS fibroblasts, fibroblast growth factor (FGF) signal transduction can be positively modulated. We, therefore, suggest the use of a competitive binding molecule for HS in MPSs as an alternative strategy to prevent the detrimental extracellular substrate storage. Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by the deficiency of lysosomal enzymes needed to catabolize glycosaminoglycans (GAGs). Four therapeutic options are currently considered: enzyme replacement therapy, substrate reduction therapy, gene therapy, and hematopoietic stem cell transplantation. However, while some of them exhibit limited clinical efficacy and require high costs, others are still in development. Therefore, alternative treatments for MPSs need to be explored. Here we describe an innovative therapeutic approach based on the use of a recombinant protein that is able to bind the excess of extracellular accumulated heparan sulfate (HS). We demonstrate that this protein is able to reduce lysosomal defects in primary fibroblasts from MPS I and MPS IIIB patients. We also show that, by masking the excess of extracellular accumulated HS in MPS fibroblasts, fibroblast growth factor (FGF) signal transduction can be positively modulated. We, therefore, suggest the use of a competitive binding molecule for HS in MPSs as an alternative strategy to prevent the detrimental extracellular substrate storage.
gene therapies
2026-08-01 | A Rare Septuagenarian Patient with a Mild Form of Mucopolysaccharidosis Type IIIC with Ocular Manifestations, a Case Report
Purpose: We present an atypical case of mucopolysaccharidosis (MPS) type IIIC to contribute to the growing understanding of its clinical heterogeneity and expand the known phenotypic spectrum of the disorder. This report describes one of the oldest known patients with genetically confirmed MPS IIIC. Case presentation: The patient received genetic testing in her seventies, revealing variations in the HGSNAT and NAGLU genes, two genes associated with MPS III. Her clinical presentation consisted primarily of retinal dystrophy, diagnosed via clinical presentation in addition to OCT and ERG. The patient also showed signs of peripheral neuropathy which were initially presumed to be idiopathic. She did not exhibit the typical behavioral involvement and craniofacial abnormalities expected of MPS type IIIC. Conclusions: This presentation broadens the recognized clinical spectrum of MPS IIIC and may facilitate earlier diagnosis in adults with similar, seemingly idiopathic findings. Improved recognition of such atypical cases may support timely genetic testing and potential therapeutic options.
2026-07-23 | Extracellular vesicles derived from cells overexpressing HGSNAT rescue defects in Mucopolysaccharidosis IIIC neurons
Summary Mucopolysaccharidosis III type C (MPS IIIC) is a rare neurological lysosomal storage disorder caused by genetic deficiency of the lysosomal membrane enzyme, heparan-α-glucosaminide N-acetyltransferase (HGSNAT). To assess the feasibility of therapeutic strategies based on cross-correction of neurons by HGSNAT secreted from transplanted cells overexpressing the enzyme, we generated induced cortical neurons (iCN) from induced pluripotent stem cells (iPSCs) derived from MPS IIIC patients. The neurons were treated with extracellular vesicles (EV) purified from the culture medium conditioned by human endothelial cells transduced with a lentiviral vector encoding EGFP-tagged HGSNAT (LV-HGSNAT-EGFP). The isolated EV showed supraphysiologic HGSNAT activity levels and efficiently delivered the enzyme to the lysosomes of MPS IIIC iCN reducing lysosomal size and restoring normal synaptic protein levels. EV-mediated delivery of HGSNAT to neurons was further confirmed by the analysis of MPS IIIC iCN either co-cultured with iPSC-derived MPS IIIC microglia (iMGL) transduced with LV-HGSNAT-EGFP or treated with the iMGL conditioned medium. MPS IIIC iCN co-cultured with iMGL overexpressing HGSNAT achieved a complete phenotypic rescue, including normalization of lysosomal size, and the levels of heparan sulfate, G M2 -ganglioside, synaptic proteins and brain-derived neurotropic factor. Treatment of MPS IIIC iCNs with conditioned medium led to a partial defects correction. Our findings reveal the translational potential of EV-mediated enzyme delivery in MPS IIIC patients treated with LV-mediated haematopoietic progenitor stem cell gene therapy.
2026-06-26 | Pathogenic Variants in HGSNAT associated with Autosomal Recessive Retinitis Pigmentosa without Overt Sanfilippo Syndrome.
Biallelic variants in the HGSNAT gene are associated with Sanfilippo syndrome, a rare lysosomal storage disorder caused by deficiency of heparan acetyl CoA glucosamine N-Acetyl-transferase enzyme(HGSNAT). The syndrome is characterized by multiple systemic findings, including progressive neurological and retinal degeneration. Retinitis pigmentosa due to HGSNAT gene variants are rarely reported without systemic manifestations. Here we describe two patients with retinitis pigmentosa and reduced enzymatic activity. One of our patients also had hearing loss. We also present a review of the literature for cases of non-syndromic retinal dystrophy associated with HGSNAT variants in the discussion. The first patient with retinitis pigmentosa and hearing loss has two variants of uncertain significance in the HGSNAT gene(p.Thr522Met and p.Cys79Arg). HGSNAT enzyme activity was 0.43nmol/17hr/mg(normal:5.8-45nmol/17hr/mg protein). Our second patient with isolated retinitis pigmentosa has two heterozygous pathogenic variants in HGSNAT (p.Arg124Trp and p.Ala615Thr). HGSNAT enzyme activity was 1.13nmol/17hr/mg(normal:5.8-45nmol/17hr/mg protein). The retinal findings are consistent with HGSNAT-related disease. The first case is the second report of retinitis pigmentosa and hearing loss linked to HGSNAT-related disease. Both cases showed reduced HGSNAT enzyme activity in blood. Although more evidence is needed to definitively link adult-onset hearing loss to HGSNAT variants, it may be due to reduced enzyme activity.
2026-01-27 | Unveiling Mucopolysaccharidosis IIIC in Brazil: Diagnostic Journey and Clinical Features of Brazilian Patients Identified Through the MPS Brazil Network.
Mucopolysaccharidosis type IIIC (MPS IIIC) is a rare lysosomal storage disorder caused by pathogenic variants in the HGSNAT gene. Data from large patient cohorts remain scarce, particularly in Latin America. We retrospectively analyzed clinical, biochemical, and genetic data from patients diagnosed with MPS IIIC through the MPS Brazil Network. Diagnosis was based on reduced activity of acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), elevated urinary glycosaminoglycans (uGAGs), and/or molecular genetics tests. A total of 101 patients were confirmed with MPS IIIC, representing one of the largest cohorts worldwide. Females accounted for 60% of cases. The mean age at symptom onset was 5.4 ± 3.9 years, while the mean age at diagnosis was 11.7 ± 6.9 years, reflecting a 6-year diagnostic delay. Most patients initially presented with developmental delay (82%) and facial dysmorphism (80%), whereas behavioral manifestations were less frequently identified (25%), suggesting a milder phenotype than previously reported. Genetic information was available for 28% of patients, showing recurrent alleles (c.372-2A>G, c.252dupT) and several novel mutations, which expand the mutational spectrum of the disease. Genotype-phenotype similarities with Portuguese, Italian, and Chinese cases suggest shared ancestry contributions. Regional differences included earlier diagnoses in the North of Brazil and high consanguinity rates in the Northeast region. This study describes the largest Brazilian cohort of MPS IIIC, documenting novel variants and regional heterogeneity. Findings highlight diagnostic delays, ancestry influences, and the urgent need for disease-modifying therapies.
2026-01-01 | Mucopolysaccharidosis type IIIC diagnosed at the age of 12 years: Why was the disease diagnosed so late?
Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases associated with impaired lysosomal degradation of glycosaminoglycans.The aim of this manuscript is to report a case of a patient with mucopolysaccharidosis type IIIC (MPS IIIC) diagnosed at 12 years of age -to raise awareness among pediatricians, pediatric neurologists, and endocrinologists about the possible misdiagnosis.The patient was initially diagnosed with autism spectrum disorder and hyperactivity with normal motor development.During follow-up, psychomotor regression with moderate intellectual disability was observed.The patient was referred for further metabolic work-up only after the results of molecular analysis suggesting MPS IIIC.The final diagnosis was established based on clinical, biochemical, and molecular analyses.
other
2025-11-27 | Neuroinflammation as a Novel Therapeutic Frontier for Sanfilippo Syndrome.
Glycosaminoglycans (GAGs), also named 'mucopolysaccharides', are nodal constituents of the connective tissue matrix which go through synthesis, demolition, and reconstruction within several cellular structures: an abnormal GAG catabolism is the basis of progressive intra-lysosomal accumulation of non-metabolized GAGs, defining all mucopolysaccharidoses (MPS), protean disorders characterized by physical abnormalities and multi-organ failure depending on the specific site of non-renewable GAGs stored. A severe cognitive decline is typically observed in the Sanfilippo syndrome, which corresponds to MPS type III, a group of four inherited neurodegenerative diseases resulting from the lack of specific enzymes involved in heparan sulfate (HS) metabolism. As a consequence, the storage of partially degraded HS fragments within lysosomes of the central nervous system elicits chain inflammatory reactions involving the NLRP3-inflammasome in microglia and astrocytes, which cease their homeostatic and immune functions and finally compromise neuron survival. This article provides an overview of the neuroinflammatory picture observed in children with MPS type III, postulating a role of HS accumulation to prime innate immunity responses which culminate with pro-inflammatory cytokine release in the brain and highlighting the relevance of interleukin-1 as a main contributor to neuroinflammation.
2025-10-01 | A case report on the treatment of autoimmune hemolytic anemia after CBT by daratumumab in a mucopolysaccharidosis type III patient.
Mucopolysaccharidosis type III, also referred to as Sanfilippo disease, is a rare hereditary lysosomal storage illness and one of the more common variants. The illness can affect all tissues and organs of the body, with the central nervous system being the most profoundly impacted. Autoimmune hemolytic anemia (AIHA) is a rare, diverse, antibody-mediated disorder characterized by the production of antibodies that target and destroy red blood cells, leading to their rapid destruction. AIHA is a prevalent and notable complication in recipients following umbilical cord blood stem cell transplantation. Immunosuppressive treatments, including intravenous immunoglobulin and rituximab, have been the primary therapeutic modalities. There is no consensus on the appropriate treatment for post-transplant severe AIHA. This article details a 5-year-old male diagnosed with mucopolysaccharidosis type III. He developed AIHA + 144 days after umbilical cord blood stem cell transplantation. Genetic testing, cranial CT, blood cell analysis, direct/indirect antihuman globulin test. Treatment encompasses red blood cell transfusion to rectify anemia, intravenous administration of methylprednisolone, calcium gluconate, alkaline solutions, plasma exchange, rituximab, gamma globulin, and more symptomatic therapies. The symptoms of hemolysis were inadequately managed throughout the disease progression and were alleviated upon therapy with daratumumab. The treatment was conducted without adverse effects, and the problem was well managed. A telephonic follow-up with the patient was conducted by our department 546 days post-discharge. The child's cognitive ability, linguistic skills, and other neurological processes remained stable without further decline. This report discusses a child with MPS III, a rare disorder characterized by complex and varied phenotypes, including distinctive facial features, short stature, cognitive regression, varying degrees of skeletal deformities, and hepatosplenomegaly. The patient has autoimmune hemolysis after umbilical cord blood transplantation. For patients who do not respond to rituximab and gamma globulin, daratumumab may be considered.
2025-02-01 | mRNA Degradation as a Therapeutic Solution for Mucopolysaccharidosis Type IIIC: Use of Antisense Oligonucleotides to Promote Downregulation of Heparan Sulfate Synthesis
Mucopolysaccharidosis type IIIC is a neurodegenerative lysosomal storage disorder (LSD) characterized by the accumulation of undegraded heparan sulfate (HS) due to the lack of an enzyme responsible for its degradation: acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). Classical treatments are ineffective. Here, we attempt a new approach in genetic medicine, genetic substrate reduction therapy (gSRT), to counteract this neurological disorder. Briefly, we used synthetic oligonucleotides, particularly gapmer antisense oligonucleotides (ASOs), to target the synthesis of the accumulated compounds at the molecular level, downregulating a specific gene involved in the first step of HS biosynthesis, XYLT1. Our goal was to reduce HS production and, consequently, its accumulation. Initially, five gapmer ASOs were designed and their potential to decrease XYLT1 mRNA levels were tested in patient-derived fibroblasts. Subsequent analyses focused on the two best performing molecules alone. The results showed a high inhibition of the XYLT1 gene mRNA (around 90%), a decrease in xylosyltransferase I (XT-I) protein levels and a reduction in HS storage 6 and 10 days after transfection (up to 21% and 32%, respectively). Overall, our results are highly promising and may represent the initial step towards the development of a potential therapeutic option not only for MPS IIIC, but virtually for every other MPS III form. Ultimately, the same principle may also apply to other neuropathic MPS.
2024-11-22 | Development of a novel tool for individual treatment trials in mucopolysaccharidosis.
Mucopolysaccharidosis (MPS) encompasses a group of genetic lysosomal storage disorders, linked to reduced life expectancy and a significant lack of effective treatment options. Immunomodulatory drugs could have the potential to be a relevant medical approach, as the accumulation of undegraded substances initiates an innate immune response, which leads to inflammation and clinical deterioration. However, immunomodulators are not licensed for this indication. Consequently, we aim to provide evidence advocating fast access to innovative individual treatment trials (ITTs) with immunomodulatory drugs and high-quality evaluation of drug effects by implementing a risk-benefit model tailored for MPS. The iterative methodology of our novel decision analysis framework (DAF) involves three key steps: (i) literature review on promising treatment targets and immunomodulators in MPS; (ii) quantitative risk-benefit assessment (RBA) of selected molecules; (iii) assigning phenotypic profiles and quantitative evaluations. The results facilitate a personalized application of the model and are based on published evidence as well as interdisciplinary experts' consensus and patient perspectives. Four promising immunomodulators have been identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra is anticipated as a treatment of choice for neuronopathic MPS patients. Nevertheless, a comprehensive RBA should always be completed on an individual basis. Our evidence-based DAF tool for ITTs directly addresses the substantial unmet medical need in MPS and characterizes an initial stride toward precision medicine with immunomodulators.
2024-01-18 | Drosophila melanogaster models of MPS IIIC (Hgsnat‐deficiency) highlight the role of glia in disease presentation
Abstract Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan‐α‐glucosaminide N ‐acetyltransferase ( HGSNAT ; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep–wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As HGSNAT is conserved in Drosophila melanogaster , we now describe the creation and characterisation of the first Drosophila models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi‐mediated knockdown of hgsnat were confirmed to have a reduced level of HGSNAT transcripts and age‐dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre‐synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in hgsnat neuronal knockdown lines. Further, when hgsnat was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that hgsnat function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Sanfilippo syndrome type C.
2 orphan drug designations for Sanfilippo syndrome type C.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
adeno-associated viral vector 9-containing the human heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) gene (AAV9- HGSNAT) | gene therapies | FDA | — | Phoenix Nest, Inc. |
Adeno-associated viral vector serotype 9 containing the human HGSNAT gene | gene therapies | EMA | — | Cochamo Pharma Limited |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.