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
319 drug discovery papers about Mucopolysaccharidosis type 3, with 6 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
319 drug discovery papers about Mucopolysaccharidosis type 3, with 6 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-03-31 | 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.
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.
2026-02-02 | 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.
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.
2026-03-31 | 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.
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.
2026-02-02 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
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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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Trehalose | small molecules | EMA | 2020-08-21 | — | FGK Representative Service GmbH |
Trehalose | small molecules | FDA | 2020-04-29 | — | Seelos Therapeutics, Inc. |
Genistein sodium salt dihydrate | small molecules | EMA | 2012-04-02 | — | Axcentua Pharmaceuticals AB |
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