RARE DISEASE
Mucopolysaccharidosis type 3
Mucopolysaccharidosis type 3
Mucopolysaccharidosis type 3
Synonyms: MPS3, MPSIII, Mucopolysaccharidosis type III, Sanfilippo disease
Synonyms: MPS3, MPSIII, Mucopolysaccharidosis type III, Sanfilippo disease
Synonyms: MPS3, MPSIII, Mucopolysaccharidosis type III, Sanfilippo disease
Drug discovery
3
drugs
With orphan designations
Overview
Mucopolysaccharidosis type III (Sanfilippo syndrome) is an autosomal recessive lysosomal storage disorder caused by deficiencies in heparan sulfate-degrading enzymes (SGSH, NAGLU, HGSNAT, or GNS genes). It primarily manifests as progressive neurocognitive decline with behavioral disturbances, sleep disorders, and somatic complications (hepatosplenomegaly, skeletal abnormalities). Neurodegeneration typically begins between ages 2-6, leading to severe dementia, motor decline, and premature death. No disease-modifying therapies are approved [1][2][6].
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
322 drug discovery papers about Mucopolysaccharidosis type 3, with 6 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
322 drug discovery papers about Mucopolysaccharidosis type 3, with 6 first-in-class and 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-02-24 | Synthetic analogue of adrenocorticotropic hormone, ACTH (4-7) PGP delays neurological manifestations in diseases of mucopolysaccharidosis III spectrum by reducing neuroinflammation and rescuing neurotransmission, synaptogenesis, and axonal demyelination
Summary Mucopolysaccharidosis III (MPS III or Sanfilippo disease) is a spectrum of 4 genetic disorders (MPS IIIA-D), caused by defects in the genes SGSH, NAGLU, HGSNAT and GNS encoding enzymes involved in degradation of heparan sulfate (HS). HS accumulates in brain tissues and causes neuronal dysfunction and neurodegeneration leading to neuropsychiatric problems, developmental delays, childhood dementia, blindness and death during the second decade of life. Previously, we demonstrated that pathophysiological mechanisms, underlying MPS IIIC in mouse models, involves functional pathological changes, affecting synaptogenesis and synaptic transmission and leading to learning and memory deficits. These results suggested that a treatment for MPS III could be developed by using compounds inducing synaptogenesis. In the current study, we tested the efficacy of a synthetic peptide ACTH (4-7) PGP, an analog of adrenocorticotropic hormone fragment, previously used as a neuroprotective and anti-inflammatory medication for treatment of acute neurological conditions, including stroke. We show that intranasal administration of ACTH (4-7) PGP restores defective synaptic transmission in CA1 pyramidal neurons of MPS IIIA and MPS IIIC mouse models and rescues the decrease in synaptic proteins in cultured MPS IIIC mouse hippocampal neurons and iPSC-derived neurons of human MPS IIIA, MPS IIIB and MPS IIIC patients. Furthermore, daily intranasal administration of ACTH (4-7) PGP to MPS IIIC and MPS IIIA mice reduces hyperactivity and rescues defects in working and spatial memory, delays progression of CNS pathology including neuroinflammation and axonal demyelination, and increases the lifespan. Together with the absence of any adverse reactions to ACTH (4-7) PGP in the MPS III and WT mice, our results justify testing the drug’s efficacy in clinical settings.
2026-01-01 | Recurrent infections and immunodeficiency in a patientwith Sanfilippo syndrome (MPS type 3)
Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a rare lysosomal storage disorder characterized by progressive neurodegeneration, behavioral abnormalities, and multisystemic involvement, with autosomal recessive inheritance.Recent findings suggest that immune system disorders may play a role in the pathogenesis and clinical complications of the disease, in addition to the classic neurological presentation.In this case, total IgG and subclass deficiencies were detected in an 18-year-old female patient who was being monitored for frequent respiratory tract infections, and intravenous immunoglobulin (IVIG) treatment was initiated with a diagnosis of humoral immunodeficiency.A significant decrease in the incidence of post-treatment infections and hospital admissions has been observed.Immune system involvement in MPS patients may increase the risk of infection.Therefore, immunological evaluation and appropriate treatment approaches are critical for improving quality of life.
2025-12-08 | Available datapackage for study 'An Open-Label Extension of Study HGT-SAN-055 Evaluating Long Term Safety and Clinical Outcomes of Intrathecal Administration of rhHNS in Patients With Sanfilippo Syndrome Type A (MPS IIIA)'
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 9 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, intermediates of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser accumulation outside the brain. MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 4.5 years for the majority of patients. Patients present a wide spectrum and severity of clinical symptoms. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and intellectual development. In addition, there are abnormal behaviors including but not limited to aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan to 15 years of age on average.The purpose of this study is to collect long term safety and tolerability data in patients with MPS IIIA who previously received rhHNS in study HGT-SAN-055 (NCT01155778).
2025-12-08 | Available datapackage for study 'A Phase I/II Safety, Tolerability, Ascending Dose and Dose Frequency Study of Recombinant Human Heparan N-Sulfatase (rhHNS) Intrathecal Administration Via an Intrathecal Drug Delivery Device in Patients With Sanfilippo Syndrome Type A (MPS IIIA)'
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase). MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 4.5 years for the majority of patients. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and intellectual development. In addition, there are abnormal behaviors including but not limited to aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan of 15 years of age on average.The purpose of this study is to determine the safety and tolerability of rhHNS via ascending doses administered via an a surgically implanted intrathecal drug delivery device (IDDD) intrathecal (IT) route once monthly (or every two weeks) for 6 months in patients with MPS IIIA.
2025-12-08 | Available datapackage for study 'A Randomized, Controlled, Open-label, Multicenter, Phase IIb Safety and Efficacy Study of rhHNS (Recombinant Human Heparan N Sulfatase) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Early Stage Mucopolysaccharidosis Type IIIA Disease'
Sanfilippo syndrome Type A, or Mucopolysaccharidosis (MPS) IIIA, is a rare lysosomal storage disease caused by deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, there is an accumulation of the glycosaminoglycan, heparan sulfate, resulting in progressive neurodegeneration. Symptoms are usually first noted in the 1st or 2nd year of life, although definitive diagnosis is often delayed, with an average age of diagnosis of 4.5 years. The disease is characterized by developmental delays initially, followed by neurological developmental arrest, then regression. These developmental deficits are typically associated with severe behavioral disturbances. Patients have a significantly reduced lifespan, with few surviving beyond the 2nd or 3rd decade.The purpose of this study is to evaluate the safety and efficacy of recombinant human heparan-N-sulfatase (rhHNS) in pediatric patients with Early Stage Mucopolysaccharidosis Type III A 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.
2025-03-19 | 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.
2025-01-09 | Extracellular Vesicles as Tools for Crossing the Blood–Brain Barrier to Treat Lysosomal Storage Diseases
Extracellular vesicles (EVs) are nanosized, membrane-bound structures that have emerged as promising tools for drug delivery, especially in the treatment of lysosomal storage disorders (LSDs) with central nervous system (CNS) involvement. This review highlights the unique properties of EVs, such as their biocompatibility, capacity to cross the blood-brain barrier (BBB), and potential for therapeutic cargo loading, including that of enzymes and genetic material. Current therapies for LSDs, like enzyme replacement therapy (ERT), often fail to address neurological symptoms due to their inability to cross the BBB. EVs offer a viable alternative, allowing for targeted delivery to the CNS and improving therapeutic outcomes. We discuss recent advancements in the engineering and modification of EVs to enhance targeting, circulation time and cargo stability, and provide a detailed overview of their application in LSDs, such as Gaucher and Fabry diseases, and Sanfilippo syndrome. Despite their potential, challenges remain in scaling production, ensuring isolation purity, and meeting regulatory requirements. Future developments will focus on overcoming these barriers, paving the way for the clinical translation of EV-based therapies in LSDs and other CNS disorders.
2024-07-27 | Generation of a novel immunodeficient mouse model of Mucopolysaccharidosis type IIIA to test human stem cell-based therapies.
Mucopolysaccharidosis Type IIIA (MPSIIIA) is a rare inherited lysosomal storage disease caused by mutations in the SGSH gene. This genetic variation results in the deficiency of the N-sulfoglucosamine sulfohydrolase enzyme, preventing the breakdown of heparan sulfate within lysosomes. The progressive accumulation of partially degraded substrate ultimately leads to brain pathology, for which there is currently no approved treatment. An established MPSIIIA mouse model has proved to be a vital asset to test several brain-targeting strategies. Nonetheless, the assessment of human stem cell-based products, an emerging research field, necessitates the use of an immunocompromised xenogeneic disease model. In the present study, we addressed this issue by generating a highly immunodeficient mouse model of MPSIIIA (NOD/SCID/GammaC chain null-MPSIIIA) through five generations of crossing an established MPSIIIA mouse model and a NOD/SCID/GammaC chain null (NSG) mouse. The immune system composition, behavioural phenotype and histopathological hallmarks of the NSG-MPSIIIA model were then evaluated. We demonstrated that NSG-MPSIIIA mice display compromised adaptive immunity, ultimately facilitating the successful engraftment of human iPSC-derived neural progenitor cells in the brain up to three months post-delivery. Furthermore, female NSG-MPSIIIA exhibit spatial working memory deficits and hyperactive behaviour, similar to MPSIIIA mice, which usually manifest around 5 months of age. NSG-MPSIIIA mice also developed primary disease-related neuropathological features in common with the MPSIIIA model, including lysosomal enlargement with storage of excess sulphated heparan sulphate and increased gliosis in several areas of the brain. In the future, the NSG-MPSIIIA mouse model holds the potential to serve as a valuable platform for evaluating human stem-cell based therapies for MPSIIIA patients.
gene therapies
2026-09-26 | Clinical and biochemical correction of a patient with neurodegenerative Mucopolysaccharidosis IIIA using hematopoietic stem cell gene therapy.
Autologous haematopoietic stem cell gene therapy (HSC-GT) is an emerging therapy for treatment-refractory neurodegenerative lysosomal storage disorders (LSD). Mucopolysaccharidosis IIIA (MPSIIIA) is a devastating LSD where pathogenic variants in the SGSH gene lead to toxic heparan sulfate accumulation, inflammation and cell death. Children present with developmental delay, neurodegeneration, significant behavioural disturbance, and die in late teens. We report 80-month outcomes for a patient with severe MPSIIIA following treatment with investigational autologous HSC-GT (OTL-201), at 30-months of age. Haematopoietic stem and progenitor cells (HSPC) were collected from peripheral blood following mobilisation with G-CSF and Plerixafor. HSPC were transduced with a lentiviral vector containing the SGSH gene and the CD11b promoter. The product was infused following myeloablative conditioning with busulfan. Product engraftment was rapid, with production of sustained supra-physiological SGSH enzyme measured in leukocytes, plasma and cerebrospinal fluid (CSF), and reductions in substrate heparan sulfate to within the normal range in urine, plasma and CSF. Neurocognitive outcomes on the Bayley Scale of Infant Development (BSID-III) and parental-reported outcomes showed improvements compared to natural history. This demonstrates sustained long-term efficacy and safety of HSC-GT in a patient with severe MPSIIIA, setting the scene for a phase I/II clinical trial in younger patients.
2026-08-11 | Human iPSC-derived neural progenitor gene therapy improves outcomes in a neuropathic lysosomal disease.
Mucopolysaccharidosis type IIIA (MPS IIIA) is a neuropathic lysosomal storage disorder caused by SGSH mutations leading to heparan sulfate accumulation in the brain. This drives progressive cognitive decline, neuroinflammation, and behavioral abnormalities. No effective disease-modifying therapy exists, as current approaches fail to deliver sufficient enzyme to the brain or halt neurodegeneration. Here, we report a neural stem cell gene therapy that achieves high enzyme delivery and restores cognitive function, likely through integration of healthy neural cells across multiple brain regions. Induced pluripotent stem cells were generated from healthy and MPS IIIA patient fibroblasts, differentiated into neural progenitor cells, and transduced with lentiviral vectors encoding codon-optimized SGSH and luciferase. Modified cells were bilaterally transplanted into the striatum of NSG-MPSIIIA mice at 2 months of age. Three months post-injection, behavioral and histological analyses demonstrated full correction of spatial working memory deficits and significant reductions in heparan sulfate storage and astrogliosis. This allogeneic, enzyme-expressing neural cell strategy addresses both enzyme deficiency and neurodegeneration, offering a promising therapeutic avenue for MPS IIIA and broader lysosomal storage disorders.
2026-02-02 | A Rare Compound Heterozygous NAGLU Gene Mutation in Two Siblings with Mucopolysaccharidosis type Iiib.
Mucopolysaccharidosis (MPS) type III, or Sanfilippo syndrome, is an autosomal recessive lysosomal storage disorder caused by mutations in genes encoding enzymes responsible for glycosaminoglycan (GAG) degradation. This case report describes two siblings with MPS type IIIB who exhibit a rare compound heterozygous mutation in the NAGLU gene. A 7-year-old girl and her 4-year-old brother were referred for evaluation due to learning disabilities, aggressiveness, and coarse facial features. Enzyme assay using tandem mass spectrometry on dried blood spots in both siblings revealed absent N-acetyl-α-glucosaminidase activity. Targeted sequencing confirmed the diagnosis, identifying two heterozygous mutations-an in-frame insertion and a missense mutation-in exon 3 of the NAGLU gene: c.214_237dup (p.Ala72_Gly79dup) and c.625A>C (p.Thr209Pro). This rare genetic finding in two siblings with Sanfilippo syndrome type B underscores the importance of precise mutation identification. Accurate characterization of defective gene variants may provide insights into potential targets for gene therapy in monogenic disorders.
2025-10-31 | Rewiring Decline: Targeting Early Neurodegeneration in Sanfilippo Syndrome Through Gene Correction and Molecular Parallels with Alzheimer’s Disease
Specific Aims: This project is built around three aims: figuring out what's happening early in the brain, fixing the genetic glitch that causes it, and learning how to actually get that fix where it will do the most good.Aim 1: Investigate Sanfilippo's early brain alterations and compare them to Alzheimer's.Gene expression and inflammatory profiles in brain samples from both disease conditions will be investigated.If the same signals were found, especially close to synapses or glial activity, it can mean that there's an overlap beneath.That correlation can help in learning more about both diseases and shine a spotlight on Sanfilippo more within the neurodegeneration community.Aim 2: Repair the mutated gene in patient-derived neurons through CRISPR.By producing neurons from patient iPSCs and fixing the gene in situ, it can be seen if this restores enzyme function and reduces cell damage.Lysosomal accumulation and signs of improved neuron function will be watched very closely.If correction works at this level, it's a big step toward therapy.Aim 3: Develop a delivery system that can cross the blood-brain barrier using monoclonal antibodies.Even if the gene is fixed, unless it's able to get to the brain, it won't be of any use.This objective puts labeled nanoparticle carriers to the test to get therapeutic material beyond the barrier.If it does, it's a game changer in the delivery of Sanfilippo treatments but also for other brain disorders.These aims aren't isolated; they build on each other.If successful, this research could offer more than just new data.It could bring us closer to real options for families who've been waiting too long.
2025-10-27 | Natural history, clinical symptoms, and cognitive development of Japanese patients with mucopolysaccharidosis III.
Mucopolysaccharidosis type III (MPS III) is an autosomal recessive lysosomal storage disorder characterized by severe progressive neurocognitive deterioration. Currently, no definitive treatment for MPS III is available, although novel therapies are being developed. This retrospective study characterized the natural history, clinical symptoms, treatment strategies, and cognitive development of MPS III in Japan, which will provide the basis for evaluating the efficacy of new therapies. Twelve patients (three with MPS IIIA, nine with MPS IIIB) registered in the Japan Registration System for Metabolic & Inherited Diseases or their parents completed survey questions on patient background, diagnostic information, treatment history, and developmental age (DA). Mean age at diagnosis was 4 years and 7 months (standard deviation: 1 year and 6 months), with no notable difference between MPS IIIA and IIIB. All 12 patients had substantial developmental delay and progressive decline, as demonstrated by plotting DA against chronological age, as well as bone deformity, dysmorphic facial features (hirsutism), impaired motor and language development (language delay, hyperactivity, gait disorder), and sleep disturbance. Developmental delay had begun by approximately 3 years old when DA was usually first assessed, with regression occurring thereafter; regression was more gradual in MPS IIIB than in MPS IIIA. Most patients received daily care (e.g., tubal feeding) and medications to control symptoms (e.g., anticonvulsants). This was the first study to evaluate changes in DA, clinical symptoms, and treatment of patients with MPS III in Japan. These results can be used as natural history data in the future evaluation of new treatments.
small molecules
2026-09-21 | Drug screen and machine learning predict neuroprotective agents in a preclinical human model of childhood dementia.
Childhood dementias are a group of paediatric neurodegenerative disorders characterised by neurocognitive decline, and in many cases underpinned by pathophysiological mechanisms similar to adult-onset dementias. In this study, we use patient-derived induced pluripotent stem cells (iPSCs) from children with one of the most prevalent childhood dementias, Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome. The derived cortical cultures exhibit lysosomal dysfunction, heparan sulfate accumulation, progressive neurodegeneration and astrocytic reactivity, recapitulating prototypical in-vivo phenotypes. Using a multimodal drug screening platform that integrates machine learning, high-content confocal imaging, single-nuclei transcriptomics and electrophysiology, we identify at least nine repurposed compounds that significantly mitigate these adverse effects within two weeks of treatment in vitro, demonstrating potential for rapid clinical translation. This human preclinical model for MPS IIIA, coupled with a robust multimodal therapeutic interrogation platform, serves as an exemplar for advancing drug discovery for childhood dementias and the broader neurodegenerative disease spectrum.
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.
2026-04-08 | Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks.
Alterations in synaptic homeostasis are linked to cognitive and behavioural impairments in brain disorders. However, synaptic dysfunction in childhood dementia is poorly understood. Here, we generate human cortical circuits from induced pluripotent stem cells (iPSCs) derived from donors with Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome, a common form of childhood-onset dementia. Action potential firing capacity and morphology of MPS IIIA patient neurons in culture are similar to those of neurons from neurotypical donors. However, long-term neural maturation reveals excitation/inhibition imbalances caused by hyperactive excitatory synapses, disrupted network dynamics, and dysregulated gene expression linked to synaptic homeostasis. This study validates in vitro human neural models to detect neurophysiological phenotypes in childhood dementias and supports drug discovery strategies that target synaptic dysfunction to improve cognition in MPS IIIA and related brain disorders.
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.
other
2026-03-31 | RNA-seq dataset of brain tissue from MPSIIIA (Sgsh D31N) mouse model following antisense oligonucleotide treatment
This dataset contains RNA sequencing (RNA-seq) data generated from brain tissue of a murine model of mucopolysaccharidosis type IIIA (MPSIIIA). The model used was B6.Cg-Sgsh^MPSIIIA/PstJ mice (Jackson Laboratories), which harbor a missense mutation in the murine Sgsh gene (c.91G>A, p.D31N). Homozygous mice exhibit approximately 3–4% of normal SGSH enzymatic activity, resulting in extensive lysosomal accumulation of heparan sulfate (HS) and progressive neurodegeneration. RNA was extracted from brain tissue of wild-type, disease-model (Sgsh homozygous), and antisense oligonucleotide (ASO)-treated mice. RNA-seq libraries were prepared using the MARS-seq protocol and sequenced on an Illumina NovaSeq platform, generating single-end reads (~26 million reads per sample). Raw sequencing data are provided as FASTQ files, along with accompanying sample metadata. This dataset enables analysis of differential gene expression and transcriptional signatures associated with MPSIIIA pathology, as well as transcriptional changes following ASO-mediated reduction of EXT1 expression. The dataset is associated with the study:“Antisense oligonucleotides mediated substrate reduction therapy ameliorates heparan sulfate accumulation in MPSIIIA models. All animal procedures were approved by the Sheba Medical Center IACUC.
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.
2023-12-16 | Glycosaminoglycan-induced proinflammatory cytokine levels as disease marker in mucopolysaccharidosis.
Recently, it has been shown disturbances in oxidant/antioxidant system and increases in some inflammatory markers in animal studies and in some Mucopolysaccharidoses (MPSs) patients. In this study, we aimed to determine the oxidative stress/antioxidant parameters and pro-inflammatory cytokine levels in the serum of MPS patients, in order to evaluate the possible role of inflammation in these patient groups regarding to accumulated metabolites. MPS I (n = 3), MPS II (n = 8), MPS III (n = 4), MPS IVA (n = 3), MPS VI (n = 3), and VII (n = 1) patients and 20 age-matched healthy subjects were included into the study. There was no statistically significant change in activities of SOD, Catalase, GSH-Px and lipid peroxidation levels in erythrocytes between the MPS patients and healthy controls. While IL-1alpha (p = 0.054), IL-6 (p = 0.008) levels, and chitotriosidase activity (p = 0.003) elevated in MPS3 patients, IL1α (p = 0.006), IL-1β (p = 0.006), IL-6 (p = 0.006), IFNγ (p = 0.006), and NFκB (p = 0.006) levels increased in MPS-6 patients. Elevated levels of IL-6, IL1α and chitotriosidase activity demonstrated macrophage activation in MPSIII untreated with enzyme replacement. Our study showed for the first time that high levels of IL1α, IL-6, IL1β and NFκB were present in MPSVI patients, demonstrating the induction of inflammation by dermatan sulphate. The low level of paraoxonase in MPSVI patients may be a good marker for cardiac involvement. Overall, this study provides important insights into the relationship between lysosomal storage of glycosaminoglycan and inflammation in MPS patients. It highlights possible pathways for the increased release of inflammatory molecules and suggests new targets for the development of treatments.
proteins
2026-02-24 | Synthetic analogue of adrenocorticotropic hormone, ACTH (4-7) PGP delays neurological manifestations in diseases of mucopolysaccharidosis III spectrum by reducing neuroinflammation and rescuing neurotransmission, synaptogenesis, and axonal demyelination
Summary Mucopolysaccharidosis III (MPS III or Sanfilippo disease) is a spectrum of 4 genetic disorders (MPS IIIA-D), caused by defects in the genes SGSH, NAGLU, HGSNAT and GNS encoding enzymes involved in degradation of heparan sulfate (HS). HS accumulates in brain tissues and causes neuronal dysfunction and neurodegeneration leading to neuropsychiatric problems, developmental delays, childhood dementia, blindness and death during the second decade of life. Previously, we demonstrated that pathophysiological mechanisms, underlying MPS IIIC in mouse models, involves functional pathological changes, affecting synaptogenesis and synaptic transmission and leading to learning and memory deficits. These results suggested that a treatment for MPS III could be developed by using compounds inducing synaptogenesis. In the current study, we tested the efficacy of a synthetic peptide ACTH (4-7) PGP, an analog of adrenocorticotropic hormone fragment, previously used as a neuroprotective and anti-inflammatory medication for treatment of acute neurological conditions, including stroke. We show that intranasal administration of ACTH (4-7) PGP restores defective synaptic transmission in CA1 pyramidal neurons of MPS IIIA and MPS IIIC mouse models and rescues the decrease in synaptic proteins in cultured MPS IIIC mouse hippocampal neurons and iPSC-derived neurons of human MPS IIIA, MPS IIIB and MPS IIIC patients. Furthermore, daily intranasal administration of ACTH (4-7) PGP to MPS IIIC and MPS IIIA mice reduces hyperactivity and rescues defects in working and spatial memory, delays progression of CNS pathology including neuroinflammation and axonal demyelination, and increases the lifespan. Together with the absence of any adverse reactions to ACTH (4-7) PGP in the MPS III and WT mice, our results justify testing the drug’s efficacy in clinical settings.
2026-01-01 | Recurrent infections and immunodeficiency in a patientwith Sanfilippo syndrome (MPS type 3)
Sanfilippo syndrome (mucopolysaccharidosis type III, MPS III) is a rare lysosomal storage disorder characterized by progressive neurodegeneration, behavioral abnormalities, and multisystemic involvement, with autosomal recessive inheritance.Recent findings suggest that immune system disorders may play a role in the pathogenesis and clinical complications of the disease, in addition to the classic neurological presentation.In this case, total IgG and subclass deficiencies were detected in an 18-year-old female patient who was being monitored for frequent respiratory tract infections, and intravenous immunoglobulin (IVIG) treatment was initiated with a diagnosis of humoral immunodeficiency.A significant decrease in the incidence of post-treatment infections and hospital admissions has been observed.Immune system involvement in MPS patients may increase the risk of infection.Therefore, immunological evaluation and appropriate treatment approaches are critical for improving quality of life.
2025-12-08 | Available datapackage for study 'An Open-Label Extension of Study HGT-SAN-055 Evaluating Long Term Safety and Clinical Outcomes of Intrathecal Administration of rhHNS in Patients With Sanfilippo Syndrome Type A (MPS IIIA)'
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 9 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, intermediates of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser accumulation outside the brain. MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 4.5 years for the majority of patients. Patients present a wide spectrum and severity of clinical symptoms. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and intellectual development. In addition, there are abnormal behaviors including but not limited to aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan to 15 years of age on average.The purpose of this study is to collect long term safety and tolerability data in patients with MPS IIIA who previously received rhHNS in study HGT-SAN-055 (NCT01155778).
2025-12-08 | Available datapackage for study 'A Phase I/II Safety, Tolerability, Ascending Dose and Dose Frequency Study of Recombinant Human Heparan N-Sulfatase (rhHNS) Intrathecal Administration Via an Intrathecal Drug Delivery Device in Patients With Sanfilippo Syndrome Type A (MPS IIIA)'
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase). MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 4.5 years for the majority of patients. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and intellectual development. In addition, there are abnormal behaviors including but not limited to aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan of 15 years of age on average.The purpose of this study is to determine the safety and tolerability of rhHNS via ascending doses administered via an a surgically implanted intrathecal drug delivery device (IDDD) intrathecal (IT) route once monthly (or every two weeks) for 6 months in patients with MPS IIIA.
2025-12-08 | Available datapackage for study 'A Randomized, Controlled, Open-label, Multicenter, Phase IIb Safety and Efficacy Study of rhHNS (Recombinant Human Heparan N Sulfatase) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Early Stage Mucopolysaccharidosis Type IIIA Disease'
Sanfilippo syndrome Type A, or Mucopolysaccharidosis (MPS) IIIA, is a rare lysosomal storage disease caused by deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, there is an accumulation of the glycosaminoglycan, heparan sulfate, resulting in progressive neurodegeneration. Symptoms are usually first noted in the 1st or 2nd year of life, although definitive diagnosis is often delayed, with an average age of diagnosis of 4.5 years. The disease is characterized by developmental delays initially, followed by neurological developmental arrest, then regression. These developmental deficits are typically associated with severe behavioral disturbances. Patients have a significantly reduced lifespan, with few surviving beyond the 2nd or 3rd decade.The purpose of this study is to evaluate the safety and efficacy of recombinant human heparan-N-sulfatase (rhHNS) in pediatric patients with Early Stage Mucopolysaccharidosis Type III A 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.
2025-03-19 | 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.
2025-01-09 | Extracellular Vesicles as Tools for Crossing the Blood–Brain Barrier to Treat Lysosomal Storage Diseases
Extracellular vesicles (EVs) are nanosized, membrane-bound structures that have emerged as promising tools for drug delivery, especially in the treatment of lysosomal storage disorders (LSDs) with central nervous system (CNS) involvement. This review highlights the unique properties of EVs, such as their biocompatibility, capacity to cross the blood-brain barrier (BBB), and potential for therapeutic cargo loading, including that of enzymes and genetic material. Current therapies for LSDs, like enzyme replacement therapy (ERT), often fail to address neurological symptoms due to their inability to cross the BBB. EVs offer a viable alternative, allowing for targeted delivery to the CNS and improving therapeutic outcomes. We discuss recent advancements in the engineering and modification of EVs to enhance targeting, circulation time and cargo stability, and provide a detailed overview of their application in LSDs, such as Gaucher and Fabry diseases, and Sanfilippo syndrome. Despite their potential, challenges remain in scaling production, ensuring isolation purity, and meeting regulatory requirements. Future developments will focus on overcoming these barriers, paving the way for the clinical translation of EV-based therapies in LSDs and other CNS disorders.
2024-07-27 | Generation of a novel immunodeficient mouse model of Mucopolysaccharidosis type IIIA to test human stem cell-based therapies.
Mucopolysaccharidosis Type IIIA (MPSIIIA) is a rare inherited lysosomal storage disease caused by mutations in the SGSH gene. This genetic variation results in the deficiency of the N-sulfoglucosamine sulfohydrolase enzyme, preventing the breakdown of heparan sulfate within lysosomes. The progressive accumulation of partially degraded substrate ultimately leads to brain pathology, for which there is currently no approved treatment. An established MPSIIIA mouse model has proved to be a vital asset to test several brain-targeting strategies. Nonetheless, the assessment of human stem cell-based products, an emerging research field, necessitates the use of an immunocompromised xenogeneic disease model. In the present study, we addressed this issue by generating a highly immunodeficient mouse model of MPSIIIA (NOD/SCID/GammaC chain null-MPSIIIA) through five generations of crossing an established MPSIIIA mouse model and a NOD/SCID/GammaC chain null (NSG) mouse. The immune system composition, behavioural phenotype and histopathological hallmarks of the NSG-MPSIIIA model were then evaluated. We demonstrated that NSG-MPSIIIA mice display compromised adaptive immunity, ultimately facilitating the successful engraftment of human iPSC-derived neural progenitor cells in the brain up to three months post-delivery. Furthermore, female NSG-MPSIIIA exhibit spatial working memory deficits and hyperactive behaviour, similar to MPSIIIA mice, which usually manifest around 5 months of age. NSG-MPSIIIA mice also developed primary disease-related neuropathological features in common with the MPSIIIA model, including lysosomal enlargement with storage of excess sulphated heparan sulphate and increased gliosis in several areas of the brain. In the future, the NSG-MPSIIIA mouse model holds the potential to serve as a valuable platform for evaluating human stem-cell based therapies for MPSIIIA patients.
gene therapies
2026-09-26 | Clinical and biochemical correction of a patient with neurodegenerative Mucopolysaccharidosis IIIA using hematopoietic stem cell gene therapy.
Autologous haematopoietic stem cell gene therapy (HSC-GT) is an emerging therapy for treatment-refractory neurodegenerative lysosomal storage disorders (LSD). Mucopolysaccharidosis IIIA (MPSIIIA) is a devastating LSD where pathogenic variants in the SGSH gene lead to toxic heparan sulfate accumulation, inflammation and cell death. Children present with developmental delay, neurodegeneration, significant behavioural disturbance, and die in late teens. We report 80-month outcomes for a patient with severe MPSIIIA following treatment with investigational autologous HSC-GT (OTL-201), at 30-months of age. Haematopoietic stem and progenitor cells (HSPC) were collected from peripheral blood following mobilisation with G-CSF and Plerixafor. HSPC were transduced with a lentiviral vector containing the SGSH gene and the CD11b promoter. The product was infused following myeloablative conditioning with busulfan. Product engraftment was rapid, with production of sustained supra-physiological SGSH enzyme measured in leukocytes, plasma and cerebrospinal fluid (CSF), and reductions in substrate heparan sulfate to within the normal range in urine, plasma and CSF. Neurocognitive outcomes on the Bayley Scale of Infant Development (BSID-III) and parental-reported outcomes showed improvements compared to natural history. This demonstrates sustained long-term efficacy and safety of HSC-GT in a patient with severe MPSIIIA, setting the scene for a phase I/II clinical trial in younger patients.
2026-08-11 | Human iPSC-derived neural progenitor gene therapy improves outcomes in a neuropathic lysosomal disease.
Mucopolysaccharidosis type IIIA (MPS IIIA) is a neuropathic lysosomal storage disorder caused by SGSH mutations leading to heparan sulfate accumulation in the brain. This drives progressive cognitive decline, neuroinflammation, and behavioral abnormalities. No effective disease-modifying therapy exists, as current approaches fail to deliver sufficient enzyme to the brain or halt neurodegeneration. Here, we report a neural stem cell gene therapy that achieves high enzyme delivery and restores cognitive function, likely through integration of healthy neural cells across multiple brain regions. Induced pluripotent stem cells were generated from healthy and MPS IIIA patient fibroblasts, differentiated into neural progenitor cells, and transduced with lentiviral vectors encoding codon-optimized SGSH and luciferase. Modified cells were bilaterally transplanted into the striatum of NSG-MPSIIIA mice at 2 months of age. Three months post-injection, behavioral and histological analyses demonstrated full correction of spatial working memory deficits and significant reductions in heparan sulfate storage and astrogliosis. This allogeneic, enzyme-expressing neural cell strategy addresses both enzyme deficiency and neurodegeneration, offering a promising therapeutic avenue for MPS IIIA and broader lysosomal storage disorders.
2026-02-02 | A Rare Compound Heterozygous NAGLU Gene Mutation in Two Siblings with Mucopolysaccharidosis type Iiib.
Mucopolysaccharidosis (MPS) type III, or Sanfilippo syndrome, is an autosomal recessive lysosomal storage disorder caused by mutations in genes encoding enzymes responsible for glycosaminoglycan (GAG) degradation. This case report describes two siblings with MPS type IIIB who exhibit a rare compound heterozygous mutation in the NAGLU gene. A 7-year-old girl and her 4-year-old brother were referred for evaluation due to learning disabilities, aggressiveness, and coarse facial features. Enzyme assay using tandem mass spectrometry on dried blood spots in both siblings revealed absent N-acetyl-α-glucosaminidase activity. Targeted sequencing confirmed the diagnosis, identifying two heterozygous mutations-an in-frame insertion and a missense mutation-in exon 3 of the NAGLU gene: c.214_237dup (p.Ala72_Gly79dup) and c.625A>C (p.Thr209Pro). This rare genetic finding in two siblings with Sanfilippo syndrome type B underscores the importance of precise mutation identification. Accurate characterization of defective gene variants may provide insights into potential targets for gene therapy in monogenic disorders.
2025-10-31 | Rewiring Decline: Targeting Early Neurodegeneration in Sanfilippo Syndrome Through Gene Correction and Molecular Parallels with Alzheimer’s Disease
Specific Aims: This project is built around three aims: figuring out what's happening early in the brain, fixing the genetic glitch that causes it, and learning how to actually get that fix where it will do the most good.Aim 1: Investigate Sanfilippo's early brain alterations and compare them to Alzheimer's.Gene expression and inflammatory profiles in brain samples from both disease conditions will be investigated.If the same signals were found, especially close to synapses or glial activity, it can mean that there's an overlap beneath.That correlation can help in learning more about both diseases and shine a spotlight on Sanfilippo more within the neurodegeneration community.Aim 2: Repair the mutated gene in patient-derived neurons through CRISPR.By producing neurons from patient iPSCs and fixing the gene in situ, it can be seen if this restores enzyme function and reduces cell damage.Lysosomal accumulation and signs of improved neuron function will be watched very closely.If correction works at this level, it's a big step toward therapy.Aim 3: Develop a delivery system that can cross the blood-brain barrier using monoclonal antibodies.Even if the gene is fixed, unless it's able to get to the brain, it won't be of any use.This objective puts labeled nanoparticle carriers to the test to get therapeutic material beyond the barrier.If it does, it's a game changer in the delivery of Sanfilippo treatments but also for other brain disorders.These aims aren't isolated; they build on each other.If successful, this research could offer more than just new data.It could bring us closer to real options for families who've been waiting too long.
2025-10-27 | Natural history, clinical symptoms, and cognitive development of Japanese patients with mucopolysaccharidosis III.
Mucopolysaccharidosis type III (MPS III) is an autosomal recessive lysosomal storage disorder characterized by severe progressive neurocognitive deterioration. Currently, no definitive treatment for MPS III is available, although novel therapies are being developed. This retrospective study characterized the natural history, clinical symptoms, treatment strategies, and cognitive development of MPS III in Japan, which will provide the basis for evaluating the efficacy of new therapies. Twelve patients (three with MPS IIIA, nine with MPS IIIB) registered in the Japan Registration System for Metabolic & Inherited Diseases or their parents completed survey questions on patient background, diagnostic information, treatment history, and developmental age (DA). Mean age at diagnosis was 4 years and 7 months (standard deviation: 1 year and 6 months), with no notable difference between MPS IIIA and IIIB. All 12 patients had substantial developmental delay and progressive decline, as demonstrated by plotting DA against chronological age, as well as bone deformity, dysmorphic facial features (hirsutism), impaired motor and language development (language delay, hyperactivity, gait disorder), and sleep disturbance. Developmental delay had begun by approximately 3 years old when DA was usually first assessed, with regression occurring thereafter; regression was more gradual in MPS IIIB than in MPS IIIA. Most patients received daily care (e.g., tubal feeding) and medications to control symptoms (e.g., anticonvulsants). This was the first study to evaluate changes in DA, clinical symptoms, and treatment of patients with MPS III in Japan. These results can be used as natural history data in the future evaluation of new treatments.
small molecules
2026-09-21 | Drug screen and machine learning predict neuroprotective agents in a preclinical human model of childhood dementia.
Childhood dementias are a group of paediatric neurodegenerative disorders characterised by neurocognitive decline, and in many cases underpinned by pathophysiological mechanisms similar to adult-onset dementias. In this study, we use patient-derived induced pluripotent stem cells (iPSCs) from children with one of the most prevalent childhood dementias, Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome. The derived cortical cultures exhibit lysosomal dysfunction, heparan sulfate accumulation, progressive neurodegeneration and astrocytic reactivity, recapitulating prototypical in-vivo phenotypes. Using a multimodal drug screening platform that integrates machine learning, high-content confocal imaging, single-nuclei transcriptomics and electrophysiology, we identify at least nine repurposed compounds that significantly mitigate these adverse effects within two weeks of treatment in vitro, demonstrating potential for rapid clinical translation. This human preclinical model for MPS IIIA, coupled with a robust multimodal therapeutic interrogation platform, serves as an exemplar for advancing drug discovery for childhood dementias and the broader neurodegenerative disease spectrum.
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.
2026-04-08 | Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks.
Alterations in synaptic homeostasis are linked to cognitive and behavioural impairments in brain disorders. However, synaptic dysfunction in childhood dementia is poorly understood. Here, we generate human cortical circuits from induced pluripotent stem cells (iPSCs) derived from donors with Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome, a common form of childhood-onset dementia. Action potential firing capacity and morphology of MPS IIIA patient neurons in culture are similar to those of neurons from neurotypical donors. However, long-term neural maturation reveals excitation/inhibition imbalances caused by hyperactive excitatory synapses, disrupted network dynamics, and dysregulated gene expression linked to synaptic homeostasis. This study validates in vitro human neural models to detect neurophysiological phenotypes in childhood dementias and supports drug discovery strategies that target synaptic dysfunction to improve cognition in MPS IIIA and related brain disorders.
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.
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2026-03-31 | RNA-seq dataset of brain tissue from MPSIIIA (Sgsh D31N) mouse model following antisense oligonucleotide treatment
This dataset contains RNA sequencing (RNA-seq) data generated from brain tissue of a murine model of mucopolysaccharidosis type IIIA (MPSIIIA). The model used was B6.Cg-Sgsh^MPSIIIA/PstJ mice (Jackson Laboratories), which harbor a missense mutation in the murine Sgsh gene (c.91G>A, p.D31N). Homozygous mice exhibit approximately 3–4% of normal SGSH enzymatic activity, resulting in extensive lysosomal accumulation of heparan sulfate (HS) and progressive neurodegeneration. RNA was extracted from brain tissue of wild-type, disease-model (Sgsh homozygous), and antisense oligonucleotide (ASO)-treated mice. RNA-seq libraries were prepared using the MARS-seq protocol and sequenced on an Illumina NovaSeq platform, generating single-end reads (~26 million reads per sample). Raw sequencing data are provided as FASTQ files, along with accompanying sample metadata. This dataset enables analysis of differential gene expression and transcriptional signatures associated with MPSIIIA pathology, as well as transcriptional changes following ASO-mediated reduction of EXT1 expression. The dataset is associated with the study:“Antisense oligonucleotides mediated substrate reduction therapy ameliorates heparan sulfate accumulation in MPSIIIA models. All animal procedures were approved by the Sheba Medical Center IACUC.
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.
2023-12-16 | Glycosaminoglycan-induced proinflammatory cytokine levels as disease marker in mucopolysaccharidosis.
Recently, it has been shown disturbances in oxidant/antioxidant system and increases in some inflammatory markers in animal studies and in some Mucopolysaccharidoses (MPSs) patients. In this study, we aimed to determine the oxidative stress/antioxidant parameters and pro-inflammatory cytokine levels in the serum of MPS patients, in order to evaluate the possible role of inflammation in these patient groups regarding to accumulated metabolites. MPS I (n = 3), MPS II (n = 8), MPS III (n = 4), MPS IVA (n = 3), MPS VI (n = 3), and VII (n = 1) patients and 20 age-matched healthy subjects were included into the study. There was no statistically significant change in activities of SOD, Catalase, GSH-Px and lipid peroxidation levels in erythrocytes between the MPS patients and healthy controls. While IL-1alpha (p = 0.054), IL-6 (p = 0.008) levels, and chitotriosidase activity (p = 0.003) elevated in MPS3 patients, IL1α (p = 0.006), IL-1β (p = 0.006), IL-6 (p = 0.006), IFNγ (p = 0.006), and NFκB (p = 0.006) levels increased in MPS-6 patients. Elevated levels of IL-6, IL1α and chitotriosidase activity demonstrated macrophage activation in MPSIII untreated with enzyme replacement. Our study showed for the first time that high levels of IL1α, IL-6, IL1β and NFκB were present in MPSVI patients, demonstrating the induction of inflammation by dermatan sulphate. The low level of paraoxonase in MPSVI patients may be a good marker for cardiac involvement. Overall, this study provides important insights into the relationship between lysosomal storage of glycosaminoglycan and inflammation in MPS patients. It highlights possible pathways for the increased release of inflammatory molecules and suggests new targets for the development of treatments.
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Drug Discovery Landscape
3 orphan drug designations for Mucopolysaccharidosis type 3.
3 orphan drug designations for Mucopolysaccharidosis type 3.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Trehalose | small molecules | EMA | — | FGK Representative Service GmbH |
Trehalose | small molecules | FDA | — | Seelos Therapeutics, Inc. |
Genistein sodium salt dihydrate | small molecules | EMA | Axcentua Pharmaceuticals AB |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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