RARE DISEASE
Sanfilippo syndrome type B
Sanfilippo syndrome type B
Sanfilippo syndrome type B
Synonyms: MPS3B, MPSIIIB, Mucopolysaccharidosis type 3B, Mucopolysaccharidosis type IIIB, N-acetyl-alpha-glucosaminidase deficiency
Synonyms: MPS3B, MPSIIIB, Mucopolysaccharidosis type 3B, Mucopolysaccharidosis type IIIB, N-acetyl-alpha-glucosaminidase deficiency
Synonyms: MPS3B, MPSIIIB, Mucopolysaccharidosis type 3B, Mucopolysaccharidosis type IIIB, N-acetyl-alpha-glucosaminidase deficiency
Drug discovery
13
drugs
With orphan designations
Overview
Sanfilippo syndrome type B (MPS IIIB) is a rare autosomal recessive lysosomal storage disorder caused by NAGLU gene mutations, leading to deficient α-N-acetylglucosaminidase activity. This results in heparan sulfate accumulation, triggering progressive neurodegeneration, developmental regression, behavioral disturbances, and multisystem complications. Symptoms typically emerge between ages 1–4, with life expectancy ranging into the late teens/early twenties due to respiratory failure or neurological decline [1][6][16].
Population
Incidence: ~1 in 150,000–200,000 births, with higher prevalence in Southern Europe [7][14][19].
Accounts for ~30% of Sanfilippo cases globally, though represents 81% of MPS III cases in Greece [12][17].
Diagnosis delays common due to nonspecific early symptoms (e.g., speech delays, recurrent infections) [6][14].
Burden
Economic: Lifetime family burden exceeds $8M/child; US cumulative burden (2023–2043) estimated at $2.04B [4][9].
Clinical: Progressive intellectual disability, loss of motor function, and 55–58 disability-adjusted life years (DALYs) per patient [9][16].
Caregiver impact: Parental productivity loss ($0.89–1.32M/child) and mental health challenges [4][9].
Therapies
Supportive care: Multispecialty management of seizures, sleep disorders, and mobility/communication aids [5][16].
Investigational therapies: Intracerebroventricular enzyme replacement (e.g., tralesinidase alfa [3]), AAV-mediated gene therapy [8][13], and substrate reduction therapy [18].
No disease-modifying therapies approved; clinical trials focus on heparan sulfate reduction and CNS delivery [3][18].
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
236 drug discovery papers about Sanfilippo syndrome type B, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
236 drug discovery papers about Sanfilippo syndrome type B, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
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.
2025-03-19 | 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.
2021-04-21 | Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches.
Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.
2018-01-26 | Allogeneic Hematopoietic Stem Cell Transplantation in Thirty-Four Pediatric Cases of Mucopolysaccharidosis-A Ten-Year Report from the China Children Transplant Group.
We investigated the efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in pediatric patients with mucopolysaccharidosis (MPS). A retrospective analysis of transplantation data from 34 cases of MPS from the China Children Transplant Group, treated between December 2004 and September 2015, was conducted. Among the 34 cases, 12 cases were type I, 12 were type II, 4 were type IV, 4 were type VI, and 2 were of an unknown type. The median age at transplantation was 3.75 years (range, 1 to 7 years); the median follow-up time was 14 months (range, 2 to 119 months). Eleven patients underwent unrelated cord blood transplantation and 23 underwent peripheral blood stem cell transplantation (4 cases with an HLA-matched sibling donor, 2 cases with an HLA-mismatched related donor, and 17 cases with an unrelated donor). A busulfan-based myeloablative regimen was used as a conditioning regimen. The estimated overall survival at 3 years was 84.8% ± 6.3% and 91.2% of the patients (31 of 34) achieved full donor chimerism. Twenty-seven children were evaluable and all but 1 (carrier sibling donor; enzyme level improved but failed to reach normal) achieved normal enzyme level after transplantation. The incidence of grades II to IV acute graft-versus-host disease (aGVHD) was 41.1% (14 of 34), wherein the incidence of grades III and IV aGVHD was 11.8% (4 of 34). The incidence of moderate-to-severe chronic graft-versus-host disease was 5.9% (2 of 34). There was a significant difference in the survival rate between children who received transplantation before 2009 and those after 2009 (55.6% versus 95.7%, P = .002); the survival rate was lower in patients with pneumonia before transplantation than in those with no active infection before transplantation (66.7% versus 95.5%, P = .019), and no significant differences in survival rates were observed among children with different disease types, ages at transplantation, donor/graft source, and conditioning regimens. After transplantation, upper-airway obstruction, hepatosplenomegaly, and corneal clouding were significantly improved; hearing and motor function were improved to a certain extent; valvular heart disease was improved in some patients but progressed in others; and short stature and speech skills showed little improvement. AlloHSCT may save the lives of patients with MPS I, II, IV or VI and could improve quality of life. Pretransplantation pneumonia affects transplantation outcomes. Advances in transplantation protocols and techniques help to improve patient prognosis. Well-matched unrelated donors can also be an ideal donor source. Standardized follow-up and a multidisciplinary team contribute to accurate evaluation of long-term post-transplantation outcome and further improve the quality of life of MPS patients.
small molecules
2026-07-08 | Personalized Drug Repurposing Screen Identifies Patient-Specific Therapeutic Candidates for Mucopolysaccharidosis Type IIIB
Background: Mucopolysaccharidosis type IIIB (MPSIIIB, Sanfilippo syndrome type B) is a rare lysosomal storage disease caused by deficiency of alpha-N-acetylglucosaminidase (NAGLU) enzyme, leading to progressive accumulation of heparan sulfate and severe neurological decline. MPSIIIB’s significant genetic heterogeneity presents a major barrier to developing broadly effective treatments and suggests a need for personalized therapeutic strategies. Methods: We established a personalized drug repurposing platform using high-content imaging with lysotracker dye as an indirect functional readout of lysosomal dysfunction to screen compounds that correct lysosomal defects in patient-derived fibroblasts. We screened 2807 compounds on cells from an MPSIIIB patient with a homozygous NAGLU p.Arg297Ter mutation. Hits that reduced lysosomal accumulation by at least 25% with minimal cytotoxicity were validated and subsequently tested for efficacy in fibroblasts from a second patient with a different, compound heterozygous NAGLU genotype. Results: The primary screen yielded 72 hits (2.6% hit rate), with 10 confirmed in dose–response assays. Notably, four clinically approved drugs—baclofen, dextrose, epalrestat and moxifloxacin—reduced lysosomal accumulation in the index patient’s cells. However, none of these four drugs were effective in the second patient’s cells, demonstrating a profound patient-specific effect. Only one non-clinical compound, 6-chlorothymol, showed a trend toward activity in both cell lines. Conclusions: Our study demonstrates a feasible framework for conducting rapid, N-of-1 drug repurposing screens for rare diseases. While we identified four promising candidates for the index patient, the lack of efficacy in a second patient cell line underscores that genetic heterogeneity may preclude a “one-size-fits-all” approach for MPSIIIB. These findings support the integration of individualized drug screening as a potential precision-medicine strategy, offering a potential path toward patient-specific therapies for rare diseases rather than traditional drug development.
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.
2026-02-27 | Evaluation of GlcNAc-Configured Glycomimetics as Pharmacological Chaperones of NAGLU for the Treatment of Mucopolysaccharidosis IIIB.
The interaction of a set of four N-acetyl-glucosamine (GlcNAc) glycomimetics with human N-acetyl-glucosaminidase (NAGLU), the genetically defective enzyme in patients suffering from mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo B syndrome, was investigated to identify potential pharmacological chaperones. Glycomimetic-NAGLU binding was initially studied by molecular docking simulations and a thermal shift assay. The effects of the glycomimetics on NAGLU activity enhancement were studied in fibroblast cells from seven MPS IIIB patients. A significant increase in NAGLU activity in four cell lines in the presence of glycomimetic MK 8719, a molecule tested in a Phase 1 study in healthy volunteers to treat Alzheimer's disease, was demonstrated. Furthermore, MK 8719 prevented the increase in glycosaminoglycan (GAG) levels in four MPS IIIB fibroblast cells, suggesting that this molecule may be worth investigating further as a pharmacological chaperone for MPS IIIB. These results represent an important contribution towards the development of a specific therapy for MPS IIIB.
2026-02-05 | TFEB, FOXO3 and TLR4 in resveratrol-induced autophagy in a mucopolysaccharidosis IIIB mouse model.
Mucopolysaccharidosis (MPS) type IIIB is the progressive degeneration of the central nervous system. Resveratrol is proposed as a potential therapeutic molecule as a drug reducing inflammation and for improving behavior of MPS mice. Here we investigated autophagy in correlation with immune response in an MPS IIIB mouse model. The effects of resveratrol on mouse behavior and the levels of selected cytokines that influence the inflammation were assessed. The study was performed on both male and female mice treated or not with resveratrol. The results of behavioral, molecular and biochemical experiments confirmed that autophagy and immune response are disturbed in MPS IIIB mice. A correlation between behavioral disturbances and levels of heparan sulfate and TLR4 could be observed. The FOXO3 transcription factor was identified as one of the key factors in the resveratrol-mediated stimulation of the autophagy process in the MPS IIIB mouse model, though it was not the sole pathway induced by this compound. We conclude that resveratrol can modulate the degradation of glycosaminoglycans and also may contribute to the reduction of inflammation and the normalization of animal behavior in the MPS IIIB model.
2025-09-11 | Identification of a neuron-specific ferroptosis in the neurodegenerative mucopolysaccharidosis IIIB model
Mucopolysaccharidosis type IIIB (MPSIIIB or Sanfilippo B) is a lysosomal storage disorder marked by progressive neurodegeneration resulting from the accumulation of abnormal heparan sulfate oligosaccharides (HSOs) in the brain.Although neuroinflammation and brain iron accumulation have been reported in both patients and animal models, the mechanisms underlying selective neuronal vulnerability remain largely unresolved.Our recent findings using an MPS IIIB mouse model reveal compelling evidence suggesting that ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death, may contribute to the neurodegenerative process of MPSIII.We identified marked brain iron accumulation, disrupted iron transport and storage mechanisms, and a collapse of antioxidant defense systems, notably through impaired activity of the xCT/GPX4 axis.Additionally, we observed neuron-specific mislocalization of ferroportin (the major iron exporter) and elevated neuronal lipid peroxidation, both hallmarks of ferroptosis.These results indicate a cell-autonomous iron dysregulation in neurons, likely exacerbated by pathological lysosomal expansion due to HSOs accumulation.Importantly, emerging studies have demonstrated that lysosomes can facilitate toxic iron release and promote ferroptosis, especially in cancer cells.In MPS IIIB, we propose that lysosomes may act as active contributors to ferroptotic neuronal death.This lysosome-ferroptosis axis represents a novel and underexplored mechanism of neurodegeneration in MPS IIIB.Investigating the role of lysosomal iron handling in neuronal vulnerability is a priority for our team and collaborators, with the aim of identifying new therapeutic targets to slow neurodegeneration in affected individuals.
gene therapies
2026-06-09 | Three-Month Observational Data for the MPS IIIB Sentinel Subject Following AAV9 Mediated Gene Therapy
Abstract Background Mucopolysaccharidosis type IIIB (MPS IIIB) is a devastating neurodegenerative lysosomal storage disorder caused by alpha-N-acetylglucosaminidase (NAGLU) deficiency. There is currently no approved therapy. We report the 3-month outcomes of a novel intracerebroventricular (ICV) gene therapy in a child with MPS IIIB. Methods In an open-label, single-center, investigator-initiated trial (ChiCTR2600121466), a single dose of RDGT-101 (2.0E14vg of an AAV9 vector encoding human NAGLU ) was administered via ICV infusion. Primary outcomes were safety and tolerability. Secondary outcomes included serum NAGLU activity, urinary heparan sulfate (HS) excretion, and neurocognitive function. Exploratory analyses included hematological parameters. Results The patient achieved serum NAGLU activity (17.06 nmol/mL/hour) approaching that of healthy controls (17.75 ± 1.37 nmol/mL/hour) by Month 3, accompanied by a 58.4% reduction in urinary HS. Clinically, previously severe hand and toe contractures resolved, allowing for full extension. Neurocognitive improvements were observed, including clear articulation, logical conversation, and sustained eye contact. Hematological analyses revealed normalized red blood cell indices and improved iron utilization. No dose-limiting toxicities, serious adverse events, or clinically significant laboratory abnormalities were observed. Conclusions A single ICV infusion of RDGT-101 was safe and well-tolerated in this patient with MPS IIIB. Early biochemical correction was accompanied by marked improvements in somatic, neurocognitive, and hematological parameters. These findings support further investigation of ICV AAV9 gene therapy for MPS IIIB.
2026-05-27 | Mapping Sanfilippo Syndrome: A Multisystem Clinicopathological Autopsy.
Background/Objectives: Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is an autosomal recessive lysosomal storage disorder caused by deficiencies in enzymes required for heparan sulfate degradation. While primarily recognized for its devastating neurodegenerative course, the systemic extent of glycosaminoglycan (GAG) accumulation remains under-characterized. This study aims to provide a detailed multisystemic pathological mapping of MPS III to challenge the traditional "brain-only" disease paradigm and highlight the clinical relevance of extracerebral involvement. Methods: We present a comprehensive clinicopathological analysis of a 15-year-old female patient with a history of profound neuropsychomotor delay, refractory epilepsy, and spastic tetraplegia. Following her death due to terminal bronchopneumonia during palliative care, a complete forensic and pathological autopsy was conducted. Tissue samples from all major organ systems were processed using routine Hematoxylin-Eosin (HE) staining, immunohistochemical staining for CD68, and specialized histochemical stains to identify intracellular storage products. Results: Macroscopic evaluation revealed significant diffuse cerebral atrophy, meningoencephalic edema, cardiac valvulopathy with compensatory myocardial remodeling, and hepatosplenomegaly. Furthermore, erosive gastrointestinal lesions and degenerative renal changes were identified. Histopathological examination confirmed widespread cytoplasmic vacuolization across diverse cell populations, including neurons, hepatocytes, renal tubular cells, and the reticuloendothelial system. These findings demonstrate that GAG deposition is a generalized process affecting nearly every parenchymal structure. Conclusions: Although neurological decline dominates the clinical phenotype, our findings underscore that MPS III is a true systemic storage disorder. Significant involvement of the cardiovascular and visceral systems contributes to the disease's complexity and mortality. This case reinforces the critical diagnostic value of a comprehensive autopsy in delineating the full morphological spectrum of Sanfilippo syndrome, providing essential insights for multidisciplinary management.
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.
2025-01-15 | Pediatric Interventions in a Sanfilippo Syndrome Patient Under General Anesthesia: A Case Report.
Background: Mucopolysaccharidosis (MPS) Type III (MPS III) or Sanfilippo syndrome is a rare autosomal recessive inherited metabolic disorder. This disorder is responsible for lysosomal storage disorder at the cellular aspect. Due to lysosomal enzyme perturbance leading to the alteration of macromolecule metabolisms, this cellular perturbance causes multiple severe systemic and mental outcomes. Sanfilippo syndrome is the most frequent lysosomal disorder among the different types of MPS. Case Presentation: A 9-year-9-month-old female was presented at our private clinic accompanied with her parents and referred from a general practitioner, and the preclinical examination revealed atypical craniofacial structure and skeletal features such as abnormal posture and movements adding on atypical behavioral manifestations such as temper tantrums, speech difficulties, dementia, and destructive behavior.
2025-01-12 | Multi-omics analyses of early-onset familial Alzheimer's disease and Sanfilippo syndrome zebrafish models reveal commonalities in disease mechanisms.
Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII) causes childhood dementia, while Alzheimer's disease is the most common type of adult-onset dementia. There is no cure for either of these diseases, and therapeutic options are extremely limited. Increasing evidence suggests commonalities in the pathogenesis of these diseases. However, a direct molecular-level comparison of these diseases has never been performed. Here, we exploited the power of zebrafish reproduction (large families of siblings from single mating events raised together in consistent environments) to conduct sensitive, internally controlled, comparative transcriptome and proteome analyses of zebrafish models of early-onset familial Alzheimer's disease (EOfAD, psen1Q96_K97del/+) and MPSIIIB (nagluA603fs/A603fs) within single families. We examined larval zebrafish (7 days post fertilisation), representing early disease stages. We also examined the brains of 6-month-old zebrafish, which are approximately equivalent to young adults in humans. We identified substantially more differentially expressed genes and pathways in MPS III zebrafish than in EOfAD-like zebrafish. This is consistent with MPS III being a rapidly progressing and earlier onset form of dementia. Similar changes in expression were detected between the two disease models in gene sets representing extracellular matrix receptor interactions in larvae, and the ribosome and lysosome pathways in 6-month-old adult brains. Cell type-specific changes were detected in MPSIIIB brains at 6 months of age, likely reflecting significant disturbances of oligodendrocyte, neural stem cell, and inflammatory cell functions and/or numbers. Our 'omics analyses have illuminated similar disease pathways between EOfAD and MPS III indicating where efforts to find mutually effective therapeutic strategies can be targeted.
proteins
2024-12-30 | Shared Gene Expression Dysregulation Across Subtypes of Sanfilippo and Morquio Diseases: The Role of PFN1 in Regulating Glycosaminoglycan Levels.
Mucopolysaccharidosis (MPS) is a class of hereditary metabolic diseases that demonstrate itself by accumulating incompletely degraded glycosaminoglycans (GAGs). MPS are classified according to the kind(s) of stored GAG(s) and specific genetic/enzymatic defects. Despite the accumulation of the same type of GAG, two MPS diseases, Sanfilippo (MPS III) and Morquio (MPS IV), are further distinguished into subclasses based on different enzymes that are deficient. Although genetic defects in MPS are known, molecular mechanisms of particular MPS types are still incomplete. This work aimed to investigate gene expression patterns in MPS III and MPS IV subtypes to identify dysregulated genes that could indicate unidentified molecular mechanisms of the diseases. Transcriptomic analyses were conducted to assess gene expression patterns in MPS and control cells. Western blotting and immunohistochemistry determined selected protein levels (products of the most significantly dysregulated genes). Effects of decreased levels of gene expression were investigated using small interferring RNA (siRNA)-mediated gene silencing. Transcriptomic analyses indicated 45 commonly dysregulated genes among all MPS III subtypes and as many as 150 commonly dysregulated genes among both MPS IV subtypes. A few genes revealed particularly high levels of dysregulation, including PFN1, MFAP5, and MMP12. Intriguingly, elevated levels of profilin-1 (product of the PFN1 gene) could be reduced by decreasing GAG levels in genistein-treated MPS III and MPS IV cells, while silencing of PFN1 caused a significant decrease in GAG accumulation in these cells, indicating an interdependent correlation between profilin-1 and GAG levels. A plethora of commonly dysregulated genes were identified in MPS subtypes III and IV. Some of these genes, like PFN1, MFAP5, and MMP12, revealed highly pronounced changes in expression relative to control cells. An interdependent correlation between GAG levels and the expression of the PFN1 gene was identified. Thus, PFN1 could be suggested as a potential new therapeutic target for MPS III and IV.
2022-03-11 | Improving yield of a recombinant biologic in a Brassica hairy root manufacturing process
Hairy root systems have proven to be a viable alternative for recombinant protein production. For recalcitrant proteins, maximizing the productivity of hairy root cultures is essential. The aim of this study was to optimize a Brassica rapa rapa hairy root process for secretion of α-L-iduronidase (IDUA), a biologic of medical value. The process was first optimized with hairy roots expressing eGFP. For the biomass optimization, the highest biomass yields were achieved in modified Gamborg B5 culture medium. For the secretion induction, the optimized secretion media was obtained with additives (1.5g/l PVP + 1mg/l 2,4-D + 20.5g/l KNO ) resulting in 3.4 fold eGFP secretion when compared to the non-induced control. These optimized conditions were applied to the IDUA-expressing hairy root clone, confirming that the highest yields of secreted IDUA occurred when using the already defined additive combination. The functionality of the IDUA protein, secreted and intracellular, was confirmed with an enzymatic activity assay. A >150-fold increase of the IDUA activity was observed using an optimized secretion medium, compared with a non-induced medium. We have proven that our B. rapa rapa hairy root system can be harnessed to secrete recalcitrant proteins, illustrating the high potential of hairy roots in plant molecular farming.
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.
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.
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.
2025-03-19 | 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.
2021-04-21 | Sanfilippo Syndrome: Molecular Basis, Disease Models and Therapeutic Approaches.
Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.
2018-01-26 | Allogeneic Hematopoietic Stem Cell Transplantation in Thirty-Four Pediatric Cases of Mucopolysaccharidosis-A Ten-Year Report from the China Children Transplant Group.
We investigated the efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in pediatric patients with mucopolysaccharidosis (MPS). A retrospective analysis of transplantation data from 34 cases of MPS from the China Children Transplant Group, treated between December 2004 and September 2015, was conducted. Among the 34 cases, 12 cases were type I, 12 were type II, 4 were type IV, 4 were type VI, and 2 were of an unknown type. The median age at transplantation was 3.75 years (range, 1 to 7 years); the median follow-up time was 14 months (range, 2 to 119 months). Eleven patients underwent unrelated cord blood transplantation and 23 underwent peripheral blood stem cell transplantation (4 cases with an HLA-matched sibling donor, 2 cases with an HLA-mismatched related donor, and 17 cases with an unrelated donor). A busulfan-based myeloablative regimen was used as a conditioning regimen. The estimated overall survival at 3 years was 84.8% ± 6.3% and 91.2% of the patients (31 of 34) achieved full donor chimerism. Twenty-seven children were evaluable and all but 1 (carrier sibling donor; enzyme level improved but failed to reach normal) achieved normal enzyme level after transplantation. The incidence of grades II to IV acute graft-versus-host disease (aGVHD) was 41.1% (14 of 34), wherein the incidence of grades III and IV aGVHD was 11.8% (4 of 34). The incidence of moderate-to-severe chronic graft-versus-host disease was 5.9% (2 of 34). There was a significant difference in the survival rate between children who received transplantation before 2009 and those after 2009 (55.6% versus 95.7%, P = .002); the survival rate was lower in patients with pneumonia before transplantation than in those with no active infection before transplantation (66.7% versus 95.5%, P = .019), and no significant differences in survival rates were observed among children with different disease types, ages at transplantation, donor/graft source, and conditioning regimens. After transplantation, upper-airway obstruction, hepatosplenomegaly, and corneal clouding were significantly improved; hearing and motor function were improved to a certain extent; valvular heart disease was improved in some patients but progressed in others; and short stature and speech skills showed little improvement. AlloHSCT may save the lives of patients with MPS I, II, IV or VI and could improve quality of life. Pretransplantation pneumonia affects transplantation outcomes. Advances in transplantation protocols and techniques help to improve patient prognosis. Well-matched unrelated donors can also be an ideal donor source. Standardized follow-up and a multidisciplinary team contribute to accurate evaluation of long-term post-transplantation outcome and further improve the quality of life of MPS patients.
small molecules
2026-07-08 | Personalized Drug Repurposing Screen Identifies Patient-Specific Therapeutic Candidates for Mucopolysaccharidosis Type IIIB
Background: Mucopolysaccharidosis type IIIB (MPSIIIB, Sanfilippo syndrome type B) is a rare lysosomal storage disease caused by deficiency of alpha-N-acetylglucosaminidase (NAGLU) enzyme, leading to progressive accumulation of heparan sulfate and severe neurological decline. MPSIIIB’s significant genetic heterogeneity presents a major barrier to developing broadly effective treatments and suggests a need for personalized therapeutic strategies. Methods: We established a personalized drug repurposing platform using high-content imaging with lysotracker dye as an indirect functional readout of lysosomal dysfunction to screen compounds that correct lysosomal defects in patient-derived fibroblasts. We screened 2807 compounds on cells from an MPSIIIB patient with a homozygous NAGLU p.Arg297Ter mutation. Hits that reduced lysosomal accumulation by at least 25% with minimal cytotoxicity were validated and subsequently tested for efficacy in fibroblasts from a second patient with a different, compound heterozygous NAGLU genotype. Results: The primary screen yielded 72 hits (2.6% hit rate), with 10 confirmed in dose–response assays. Notably, four clinically approved drugs—baclofen, dextrose, epalrestat and moxifloxacin—reduced lysosomal accumulation in the index patient’s cells. However, none of these four drugs were effective in the second patient’s cells, demonstrating a profound patient-specific effect. Only one non-clinical compound, 6-chlorothymol, showed a trend toward activity in both cell lines. Conclusions: Our study demonstrates a feasible framework for conducting rapid, N-of-1 drug repurposing screens for rare diseases. While we identified four promising candidates for the index patient, the lack of efficacy in a second patient cell line underscores that genetic heterogeneity may preclude a “one-size-fits-all” approach for MPSIIIB. These findings support the integration of individualized drug screening as a potential precision-medicine strategy, offering a potential path toward patient-specific therapies for rare diseases rather than traditional drug development.
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.
2026-02-27 | Evaluation of GlcNAc-Configured Glycomimetics as Pharmacological Chaperones of NAGLU for the Treatment of Mucopolysaccharidosis IIIB.
The interaction of a set of four N-acetyl-glucosamine (GlcNAc) glycomimetics with human N-acetyl-glucosaminidase (NAGLU), the genetically defective enzyme in patients suffering from mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo B syndrome, was investigated to identify potential pharmacological chaperones. Glycomimetic-NAGLU binding was initially studied by molecular docking simulations and a thermal shift assay. The effects of the glycomimetics on NAGLU activity enhancement were studied in fibroblast cells from seven MPS IIIB patients. A significant increase in NAGLU activity in four cell lines in the presence of glycomimetic MK 8719, a molecule tested in a Phase 1 study in healthy volunteers to treat Alzheimer's disease, was demonstrated. Furthermore, MK 8719 prevented the increase in glycosaminoglycan (GAG) levels in four MPS IIIB fibroblast cells, suggesting that this molecule may be worth investigating further as a pharmacological chaperone for MPS IIIB. These results represent an important contribution towards the development of a specific therapy for MPS IIIB.
2026-02-05 | TFEB, FOXO3 and TLR4 in resveratrol-induced autophagy in a mucopolysaccharidosis IIIB mouse model.
Mucopolysaccharidosis (MPS) type IIIB is the progressive degeneration of the central nervous system. Resveratrol is proposed as a potential therapeutic molecule as a drug reducing inflammation and for improving behavior of MPS mice. Here we investigated autophagy in correlation with immune response in an MPS IIIB mouse model. The effects of resveratrol on mouse behavior and the levels of selected cytokines that influence the inflammation were assessed. The study was performed on both male and female mice treated or not with resveratrol. The results of behavioral, molecular and biochemical experiments confirmed that autophagy and immune response are disturbed in MPS IIIB mice. A correlation between behavioral disturbances and levels of heparan sulfate and TLR4 could be observed. The FOXO3 transcription factor was identified as one of the key factors in the resveratrol-mediated stimulation of the autophagy process in the MPS IIIB mouse model, though it was not the sole pathway induced by this compound. We conclude that resveratrol can modulate the degradation of glycosaminoglycans and also may contribute to the reduction of inflammation and the normalization of animal behavior in the MPS IIIB model.
2025-09-11 | Identification of a neuron-specific ferroptosis in the neurodegenerative mucopolysaccharidosis IIIB model
Mucopolysaccharidosis type IIIB (MPSIIIB or Sanfilippo B) is a lysosomal storage disorder marked by progressive neurodegeneration resulting from the accumulation of abnormal heparan sulfate oligosaccharides (HSOs) in the brain.Although neuroinflammation and brain iron accumulation have been reported in both patients and animal models, the mechanisms underlying selective neuronal vulnerability remain largely unresolved.Our recent findings using an MPS IIIB mouse model reveal compelling evidence suggesting that ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulated cell death, may contribute to the neurodegenerative process of MPSIII.We identified marked brain iron accumulation, disrupted iron transport and storage mechanisms, and a collapse of antioxidant defense systems, notably through impaired activity of the xCT/GPX4 axis.Additionally, we observed neuron-specific mislocalization of ferroportin (the major iron exporter) and elevated neuronal lipid peroxidation, both hallmarks of ferroptosis.These results indicate a cell-autonomous iron dysregulation in neurons, likely exacerbated by pathological lysosomal expansion due to HSOs accumulation.Importantly, emerging studies have demonstrated that lysosomes can facilitate toxic iron release and promote ferroptosis, especially in cancer cells.In MPS IIIB, we propose that lysosomes may act as active contributors to ferroptotic neuronal death.This lysosome-ferroptosis axis represents a novel and underexplored mechanism of neurodegeneration in MPS IIIB.Investigating the role of lysosomal iron handling in neuronal vulnerability is a priority for our team and collaborators, with the aim of identifying new therapeutic targets to slow neurodegeneration in affected individuals.
gene therapies
2026-06-09 | Three-Month Observational Data for the MPS IIIB Sentinel Subject Following AAV9 Mediated Gene Therapy
Abstract Background Mucopolysaccharidosis type IIIB (MPS IIIB) is a devastating neurodegenerative lysosomal storage disorder caused by alpha-N-acetylglucosaminidase (NAGLU) deficiency. There is currently no approved therapy. We report the 3-month outcomes of a novel intracerebroventricular (ICV) gene therapy in a child with MPS IIIB. Methods In an open-label, single-center, investigator-initiated trial (ChiCTR2600121466), a single dose of RDGT-101 (2.0E14vg of an AAV9 vector encoding human NAGLU ) was administered via ICV infusion. Primary outcomes were safety and tolerability. Secondary outcomes included serum NAGLU activity, urinary heparan sulfate (HS) excretion, and neurocognitive function. Exploratory analyses included hematological parameters. Results The patient achieved serum NAGLU activity (17.06 nmol/mL/hour) approaching that of healthy controls (17.75 ± 1.37 nmol/mL/hour) by Month 3, accompanied by a 58.4% reduction in urinary HS. Clinically, previously severe hand and toe contractures resolved, allowing for full extension. Neurocognitive improvements were observed, including clear articulation, logical conversation, and sustained eye contact. Hematological analyses revealed normalized red blood cell indices and improved iron utilization. No dose-limiting toxicities, serious adverse events, or clinically significant laboratory abnormalities were observed. Conclusions A single ICV infusion of RDGT-101 was safe and well-tolerated in this patient with MPS IIIB. Early biochemical correction was accompanied by marked improvements in somatic, neurocognitive, and hematological parameters. These findings support further investigation of ICV AAV9 gene therapy for MPS IIIB.
2026-05-27 | Mapping Sanfilippo Syndrome: A Multisystem Clinicopathological Autopsy.
Background/Objectives: Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is an autosomal recessive lysosomal storage disorder caused by deficiencies in enzymes required for heparan sulfate degradation. While primarily recognized for its devastating neurodegenerative course, the systemic extent of glycosaminoglycan (GAG) accumulation remains under-characterized. This study aims to provide a detailed multisystemic pathological mapping of MPS III to challenge the traditional "brain-only" disease paradigm and highlight the clinical relevance of extracerebral involvement. Methods: We present a comprehensive clinicopathological analysis of a 15-year-old female patient with a history of profound neuropsychomotor delay, refractory epilepsy, and spastic tetraplegia. Following her death due to terminal bronchopneumonia during palliative care, a complete forensic and pathological autopsy was conducted. Tissue samples from all major organ systems were processed using routine Hematoxylin-Eosin (HE) staining, immunohistochemical staining for CD68, and specialized histochemical stains to identify intracellular storage products. Results: Macroscopic evaluation revealed significant diffuse cerebral atrophy, meningoencephalic edema, cardiac valvulopathy with compensatory myocardial remodeling, and hepatosplenomegaly. Furthermore, erosive gastrointestinal lesions and degenerative renal changes were identified. Histopathological examination confirmed widespread cytoplasmic vacuolization across diverse cell populations, including neurons, hepatocytes, renal tubular cells, and the reticuloendothelial system. These findings demonstrate that GAG deposition is a generalized process affecting nearly every parenchymal structure. Conclusions: Although neurological decline dominates the clinical phenotype, our findings underscore that MPS III is a true systemic storage disorder. Significant involvement of the cardiovascular and visceral systems contributes to the disease's complexity and mortality. This case reinforces the critical diagnostic value of a comprehensive autopsy in delineating the full morphological spectrum of Sanfilippo syndrome, providing essential insights for multidisciplinary management.
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.
2025-01-15 | Pediatric Interventions in a Sanfilippo Syndrome Patient Under General Anesthesia: A Case Report.
Background: Mucopolysaccharidosis (MPS) Type III (MPS III) or Sanfilippo syndrome is a rare autosomal recessive inherited metabolic disorder. This disorder is responsible for lysosomal storage disorder at the cellular aspect. Due to lysosomal enzyme perturbance leading to the alteration of macromolecule metabolisms, this cellular perturbance causes multiple severe systemic and mental outcomes. Sanfilippo syndrome is the most frequent lysosomal disorder among the different types of MPS. Case Presentation: A 9-year-9-month-old female was presented at our private clinic accompanied with her parents and referred from a general practitioner, and the preclinical examination revealed atypical craniofacial structure and skeletal features such as abnormal posture and movements adding on atypical behavioral manifestations such as temper tantrums, speech difficulties, dementia, and destructive behavior.
2025-01-12 | Multi-omics analyses of early-onset familial Alzheimer's disease and Sanfilippo syndrome zebrafish models reveal commonalities in disease mechanisms.
Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII) causes childhood dementia, while Alzheimer's disease is the most common type of adult-onset dementia. There is no cure for either of these diseases, and therapeutic options are extremely limited. Increasing evidence suggests commonalities in the pathogenesis of these diseases. However, a direct molecular-level comparison of these diseases has never been performed. Here, we exploited the power of zebrafish reproduction (large families of siblings from single mating events raised together in consistent environments) to conduct sensitive, internally controlled, comparative transcriptome and proteome analyses of zebrafish models of early-onset familial Alzheimer's disease (EOfAD, psen1Q96_K97del/+) and MPSIIIB (nagluA603fs/A603fs) within single families. We examined larval zebrafish (7 days post fertilisation), representing early disease stages. We also examined the brains of 6-month-old zebrafish, which are approximately equivalent to young adults in humans. We identified substantially more differentially expressed genes and pathways in MPS III zebrafish than in EOfAD-like zebrafish. This is consistent with MPS III being a rapidly progressing and earlier onset form of dementia. Similar changes in expression were detected between the two disease models in gene sets representing extracellular matrix receptor interactions in larvae, and the ribosome and lysosome pathways in 6-month-old adult brains. Cell type-specific changes were detected in MPSIIIB brains at 6 months of age, likely reflecting significant disturbances of oligodendrocyte, neural stem cell, and inflammatory cell functions and/or numbers. Our 'omics analyses have illuminated similar disease pathways between EOfAD and MPS III indicating where efforts to find mutually effective therapeutic strategies can be targeted.
proteins
2024-12-30 | Shared Gene Expression Dysregulation Across Subtypes of Sanfilippo and Morquio Diseases: The Role of PFN1 in Regulating Glycosaminoglycan Levels.
Mucopolysaccharidosis (MPS) is a class of hereditary metabolic diseases that demonstrate itself by accumulating incompletely degraded glycosaminoglycans (GAGs). MPS are classified according to the kind(s) of stored GAG(s) and specific genetic/enzymatic defects. Despite the accumulation of the same type of GAG, two MPS diseases, Sanfilippo (MPS III) and Morquio (MPS IV), are further distinguished into subclasses based on different enzymes that are deficient. Although genetic defects in MPS are known, molecular mechanisms of particular MPS types are still incomplete. This work aimed to investigate gene expression patterns in MPS III and MPS IV subtypes to identify dysregulated genes that could indicate unidentified molecular mechanisms of the diseases. Transcriptomic analyses were conducted to assess gene expression patterns in MPS and control cells. Western blotting and immunohistochemistry determined selected protein levels (products of the most significantly dysregulated genes). Effects of decreased levels of gene expression were investigated using small interferring RNA (siRNA)-mediated gene silencing. Transcriptomic analyses indicated 45 commonly dysregulated genes among all MPS III subtypes and as many as 150 commonly dysregulated genes among both MPS IV subtypes. A few genes revealed particularly high levels of dysregulation, including PFN1, MFAP5, and MMP12. Intriguingly, elevated levels of profilin-1 (product of the PFN1 gene) could be reduced by decreasing GAG levels in genistein-treated MPS III and MPS IV cells, while silencing of PFN1 caused a significant decrease in GAG accumulation in these cells, indicating an interdependent correlation between profilin-1 and GAG levels. A plethora of commonly dysregulated genes were identified in MPS subtypes III and IV. Some of these genes, like PFN1, MFAP5, and MMP12, revealed highly pronounced changes in expression relative to control cells. An interdependent correlation between GAG levels and the expression of the PFN1 gene was identified. Thus, PFN1 could be suggested as a potential new therapeutic target for MPS III and IV.
2022-03-11 | Improving yield of a recombinant biologic in a Brassica hairy root manufacturing process
Hairy root systems have proven to be a viable alternative for recombinant protein production. For recalcitrant proteins, maximizing the productivity of hairy root cultures is essential. The aim of this study was to optimize a Brassica rapa rapa hairy root process for secretion of α-L-iduronidase (IDUA), a biologic of medical value. The process was first optimized with hairy roots expressing eGFP. For the biomass optimization, the highest biomass yields were achieved in modified Gamborg B5 culture medium. For the secretion induction, the optimized secretion media was obtained with additives (1.5g/l PVP + 1mg/l 2,4-D + 20.5g/l KNO ) resulting in 3.4 fold eGFP secretion when compared to the non-induced control. These optimized conditions were applied to the IDUA-expressing hairy root clone, confirming that the highest yields of secreted IDUA occurred when using the already defined additive combination. The functionality of the IDUA protein, secreted and intracellular, was confirmed with an enzymatic activity assay. A >150-fold increase of the IDUA activity was observed using an optimized secretion medium, compared with a non-induced medium. We have proven that our B. rapa rapa hairy root system can be harnessed to secrete recalcitrant proteins, illustrating the high potential of hairy roots in plant molecular farming.
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.
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.
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Drug Discovery Landscape
13 orphan drug designations for Sanfilippo syndrome type B.
13 orphan drug designations for Sanfilippo syndrome type B.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Alpha-N-acetyl glucosaminidase fused to a humanised monoclonal antibody against transferrin receptor | proteins | EMA | 2025-06-20 | — | JCR Europe B.V. |
a recombinant glycoprotein consisting of modified human alpha-N-acetylglucosaminidase (mhNAGLU) and a humanized antibody that specifically recognizes hTfR | proteins | FDA | 2025-04-25 | — | JCR Pharmaceuticals Co., Ltd. |
recombinant adeno-associated virus serotype 9 vector containing the codon optimized human alpha-N-acetylglucosaminidase (NAGLU) gene | gene therapies | FDA | 2023-08-01 | — | NeuroGT, Inc. |
Recombinant adeno-associated viral vector serotype 9 containing the human N-alpha-acetylglucosaminidase gene | gene therapies | EMA | 2017-01-12 | — | Pharma Gateway AB |
Chimeric fusion protein of recombinant human alpha-N-acetylglucosaminidase and human insulin-like growth factor 2 | proteins | EMA | 2015-01-15 | — | Regintel Limited |
chimeric fusion protein of recombinant human alpha-N-acetylglucosaminidase and human insulin-like growth factor 2 | proteins | FDA | 2014-11-25 | — | Spruce Biosciences |
Recombinant AAV9 expressing human alpha-N-acetylglucosaminidase | gene therapies | FDA | 2014-04-30 | — | Sangrail Biologics |
Lesinidase alfa [SBC-103] | proteins | EMA | 2013-06-19 | — | [INACTIVE] Alexion Europe |
recombinant human alpha-N-acetylglucosaminidase | proteins | FDA | 2013-04-15 | — | Alexion Pharmaceuticals, Inc. |
recombinant human Naglu- insulin-like growth factor II | proteins | FDA | 2013-03-05 | — | Shire Human Genetic Therapies, Inc. |
Adeno-associated viral vector serotype 9 containing the human N-acetyl-alpha-glucosaminidase gene | gene therapies | EMA | 2013-01-24 | — | Esteve Pharmaceuticals S.A. |
adeno-associated viral vector serotype 9 containing human N-acetylglucosaminidase alpha gene | gene therapies | FDA | 2012-12-27 | — | Esteve Pharmaceuticals, S.A. |
Adeno-associated viral vector containing the human alpha-N-acetylglucosaminidase gene | gene therapies | EMA | 2011-10-27 | — | Institut Pasteur |
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