RARE DISEASE
Multiple sulfatase deficiency
Multiple sulfatase deficiency
Multiple sulfatase deficiency
Synonyms: Austin disease, MSD, Mucosulfatidosis
Synonyms: Austin disease, MSD, Mucosulfatidosis
Synonyms: Austin disease, MSD, Mucosulfatidosis
Drug discovery
1
drug
With orphan designation
Overview
Multiple sulfatase deficiency (MSD) is an ultra-rare autosomal recessive lysosomal storage disorder caused by SUMF1 gene mutations, impairing post-translational activation of sulfatase enzymes [1][2][4]. This results in widespread accumulation of sulfated substrates (e.g., glycosaminoglycans, sulfatides), causing multi-system manifestations: neurodevelopmental regression, leukodystrophy, ichthyosis, skeletal anomalies (dysostosis multiplex), and organomegaly [1][9][12]. Classified into neonatal (most severe), late-infantile (most common), and juvenile forms, prognosis is poor with progressive neurodegeneration and reduced life expectancy [2][6][7].
Burden
High morbidity: Progressive neurologic deterioration (motor/cognitive regression, seizures), multisystem complications (hepatosplenomegaly, skeletal deformities) [1][12][19]
Mortality: Median survival ~13 years; neonatal forms often fatal within 1–2 years [2][7][19]
Caregiver burden: Intensive daily care needs due to rapid functional decline and complex medical requirements [12][19]
Therapies
Supportive care: Multidisciplinary management (physiotherapy, skin care, seizure control, and organ-specific monitoring) [2][12]
Experimental therapies: Ex vivo hematopoietic stem cell gene therapy (lentiviral SUMF1 delivery) shows biochemical and functional improvements in preclinical models [3][13][18]
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare skin diseases, rare transplant-related disorders
Research Papers
50 drug discovery papers about Multiple sulfatase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
50 drug discovery papers about Multiple sulfatase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-01-10 | Bone marrow transplantation reverses metabolic alterations in multiple sulfatase deficiency: a case series.
Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome. Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells. There is evidence of correction of currently available biomarkers within 3 months post-HCT. Untargeted metabolomics also shows continued correction of multiple biochemical abnormalities in the post-HCT period. Furthermore, this article also presents the neuropsychological outcomes of these children as well as the results of untargeted metabolomics analysis in this condition. These data suggest biochemical benefits post-transplant along with slowing of disease progression. Long-term follow-up is necessary to fully evaluate the therapeutic benefit of HCT in MSD.
2024-10-25 | Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model.
Multiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD. To test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive). After 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain. Our results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.
2022-06-30 | The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Different Donors in Recipients With Mucopolysaccharidosis
There is limited information regarding hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis (MPS) IV and VI. This study examined the full donor chimerism, specific lysosomal enzyme levels, and the survival of different MPS children after HSCT from various donor sources and compared the prognosis. A total of 42 children with MPS underwent HSCT, 9 cases were type I, 14 were type II, 15 were type IV, and 4 were type VI. A total of 24 patients received peripheral blood stem cells (PBSC) and 18 patients received umbilical cord blood (UCB). Patients who received PBSC were conditioned with intravenous (IV) busulfan every 6 h for a total of 16 doses, IV cyclophosphamide (CY, 200 mg/kg), and antihuman thymocyte globulin (ATG, 10 mg/kg). While conditioning regimen of patients who received UCB was adjusted to ATG (preposed, pre-) + busulfan + fludarabine + Cy, which includes IV ATG (pre-, 6 mg/kg), IV busulfan every 6 h for a total of 16 doses, IV fludarabine (200 mg/m 2 ) and CY (200 mg/kg). Also, 95.2% (40 of 42) of patients achieved full donor chimerism, and all patients’ specific lysosomal enzyme levels reached normal. The estimated overall survival (OS) at 1 year was 92.9%. There was no significant difference in 1-year OS between patients who received PBSC transplantation and those who received UCB grafts (87.5% vs. 100%, p = 0.0247). The incidence of acute and chronic GVHD did not differ between them. The incidences of pneumonia in PBSC recipients and UCB recipients were 45.8 and 33.3%, respectively, but there few patients suffering from respiratory failure (4.2 and 5.6%, respectively) due to pneumonia. The incidence of cytomegaloviremia was also high in both groups, 58.3 and 44.4% respectively, However, no patient developed CMV disease. All deaths (3 of 42) occurred in patients receiving PBSC grafts, and there was no death in patients receiving UCB grafts. There was no death after transplantation in patients with MPS IV and VI. In addition, respiratory and nervous system functions were improved, whereas valvular heart disease was improved in some patients but progressed in more patients after transplantation. In summary, HSCT is a good therapeutic option for MPS, not only for patients with MPS I or II but also for those with MPS IV or VI. The specific lysosomal enzyme levels can be completely restored to normal, which is the basis for patients to resolve a broad range of clinical outcomes. Moreover, UCB with suitable HLA (HLA-match above 7/10 and 4/6) is a suitable donor source for MPS. Patients who underwent UCB transplantation using the conditioning regimen ATG (pre-) + busulfan + fludarabine + Cy can achieve a higher proportion of full donor chimerism and survival with less severe complications. HSCT can improve organs function in patients with MPS, but it is still worth exploring.
1981-02-26 | Complementation of arylsulfatase A in somatic hybrids of metachromatic leukodystrophy and multiple sulfatase deficiency disorder fibroblasts.
Metachromatic leukodystrophy and multiple sulfatase deficiency disorder are severe neurodegenerative diseases inherited as separate autosomal recessive traits. Arylsulfatase A (aryl-sulfate sulfohydrolase, EC 3.1.6.1) activity is deficient in both diseases but in multiple sulfatase deficiency disorder, activities of arylsulfatases B and C and other sulfatases are also reported to be reduced. Somatic hybrid cell clones produced by fusing cultured fibroblasts from patients with these diseases were isolated by a nonselective technique based on unit-gravity sedimentation. Arylsulfatase A activity was restored in these hybrids. The complemented enzyme resembled the normal arylsulfatase A in heat stability, pH optimum, Km, electrophoretic mobility, and immunologic reactivity. Because a structurally normal enzyme can be restored in a hybrid only though intergenic complementation, these results indicate that the mutations responsible for the deficiency of arylsulfatase A activity in metachromatic leukodystrophy and multiple sulfatase deficiency disorder are nonallelic and that at least two genetic loci control the expression of arylsulfatase A activity in the human genome. Furthermore, arylsulfatase C activity was also restored to normal in the hybrids, indicating that a common sulfatase inhibitor is not the cause of the multiple sulfatse deficiency.
1979-12-01 | Genetic complementation studies of multiple sulfatase deficiency.
Cultured fibroblasts from two individuals with multiple sulfatase deficiency (MSD) were found to have decreased activities of arylsulfatases (aryl-sulfate sulfohydrolase, EC 3.1.6.1) A, B, and C as well as iduronate-sulfate sulfatase, sulfamidase, and N-acetylglucosamine-6-sulfate sulfatase. The activity of N-acetylgalactosamine-6-sulfate sulfatase was decreased in one line but not in the other. Mixtures of MSD cell extracts with extracts from normal cells did not result in inhibition of normal sulfatase activities. Mixtures of MSD cell extracts with extracts of fibroblasts from patients with Hunter or Sanfilippo A syndrome did not activate iduronate-sulfate sulfatase or sulfamidase activity. Heterokaryons formed by fusion of MSD cells with Sanfilippo A fibroblasts demonstrated a partial correction of the enzyme deficiency. In similar manner, MSD-Hunter heterokaryons showed a significant increase in iduronate-sulfate-sulfatase activity. Genetic complementation in heterokaryons of MSD fibroblasts and cells of either Sanfilippo A or Hunter syndrome implies a genetic defect in MSD different from that causing specific sulfatase deficiencies.
small molecules
2026-08-11 | New structures of human formylglycine-generating enzyme reveal features important for catalysis, disease and structure-based drug design.
The formylglycine-generating enzyme (FGE) post-translationally modifies the active site of all human sulfatases. Mutations in the SUMF1 gene encoding FGE may lead to catalytically inactive FGE or destabilize the protein. The resulting lack of sulfatase modification causes the rare disease multiple sulfatase deficiency (MSD). Previously, FGE required elastase treatment for crystallization and the structures lacked copper, although FGE is a copper-dependent enzyme. Here, we show that highly active human FGE purified from insect cells natively contains one copper ion and we report six new crystal structures revealing previously unobserved features. Several structures contain the catalytic copper ion coordinated almost linearly by the two catalytic cysteines. A structure of the MSD-causing E130D variant shows distortions in coordination of a structural Ca2+ explaining its lower stability. As part of exploratory ligand-soaking experiments, a structure of FGE soaked with N-acetyl cysteine methyl ester shows the binding of a small molecule to a site other than the active site highlighting a potential binding site to be explored in the development of pharmacological chaperones for FGE. Crystallization of FGE without elastase treatment resulted in a structure in which the previously missing loop is well defined in the electron density and partly covers the active site, indicating that it needs to adopt a different conformation for substrate binding. This assumption is supported by a second structure in which the loop faces away from the active site and leaves the substrate binding groove open and by the occasional occurrence of crystals in which the loop becomes disordered.
2026-01-01 | N-acetyl-L-leucine in Neurological Disorders: Mechanisms, Evidence, and Therapeutic Perspectives.
N-acetyl-L-leucine (NALL), a stereospecific derivative of the essential amino acid L-leucine, has attracted increasing attention as a candidate therapy for neurological disorders. Preclinical and clinical studies suggest both symptomatic and neuroprotective effects. This review summarizes evidence on the mechanisms of action, preclinical findings, and clinical outcomes of NALL, and discusses its therapeutic prospects in neurological health and disease. A structured literature search of PubMed, Scopus, and Google Scholar was conducted to identify preclinical and clinical studies evaluating N-acetyl-L-leucine (NALL) in neurological disorders. Preclinical studies demonstrated that NALL enhances mitochondrial bioenergetics, reduces oxidative stress, restores lysosomal and autophagic function, and modulates neuroinflammation. In rodent models, NALL improved motor coordination, neuronal survival, and recovery following traumatic brain injury. Clinical trials in Niemann-Pick disease type C and GM2 gangliosidoses showed improvements in motor function, quality of life, and disease progression, with sustained benefit during extension phases. Preliminary evidence also suggests possible roles in multiple sclerosis, ataxia telangiectasia, Parkinson’s disease, and multiple sulfatase deficiency. NALL was consistently well tolerated with a favorable safety profile. NALL shows multimodal mechanisms and promising translational potential for both rare and common neurological disorders. While early evidence is encouraging, larger randomized trials are required to confirm efficacy, define optimal dosing, and determine its place in neurological therapeutics.
2025-04-12 | Repurposing Tazarotene for Multiple Sulfatase Deficiency: A Path TowardClinical Application
Despite increasing research efforts, Multiple Sulfatase Deficiency (MSD, MIM #272200) remains an untreatable disease with a high unmet medical need. Various therapeutic approaches, including gene therapy and hematopoietic stem cell transplantation, have been explored. Among them, small-molecule drug identification has been a key strategy for therapy development. Drug repurposing—repositioning existing medications for new indications— offers a fast-track route to treatment by leveraging existing knowledge on formulation, toxicity, dosage, safety, and side effects. This significantly reduces the time and cost associated with early pharmacological and clinical development. A high-throughput drug screening on MSD patient-derived cells identified tazarotene, a third-generation retinoic acid derivative, as a potential therapeutic candidate capable of reversing disease pathology in vitro. Currently approved for topical treatment of plaque psoriasis and acne, tazarotene was previously evaluated for oral administration in clinical trials (Phase I–III) with approximately 1,500 participants. While proven efficacious for its intended indications, oral tazarotene was not licensed by the FDA due to post-marketing safety monitoring concerns.As part of the REMEDI4ALL initiative, an EU-funded consortium of 24 partners—including academia, industry, patient organizations, and regulatory agencies—tazarotene has been selected as a demonstrator project for drug repurposing. REMEDI4ALL has facilitated a target product profile and gap analysis, leading to reformulation, evaluation, and production of oral tazarotene for clinical development in MSD. Collaboration with the pharmaceutical industry ensures access to existing toxicity, preclinical, and clinical data, aiding regulatory processes. These efforts have culminated in scientific advice meetings with regulators, paving the way for the first clinical trial in MSD patients, scheduled to begin by the end of 2025.
2024-04-29 | Mature neurons from iPSCs unveil neurodegeneration-related pathways in mucopolysaccharidosis type II: GSK-3β inhibition for therapeutic potential
Mucopolysaccharidosis (MPS) type II is caused by a deficiency of iduronate-2-sulfatase and is characterized by the accumulation of glycosaminoglycans (GAGs). Without effective therapy, the severe form of MPS II causes progressive neurodegeneration and death. This study generated multiple clones of induced pluripotent stem cells (iPSCs) and their isogenic controls (ISO) from four patients with MPS II neurodegeneration. MPS II-iPSCs were successfully differentiated into cortical neurons with characteristic biochemical and cellular phenotypes, including axonal beadings positive for phosphorylated tau, and unique electrophysiological abnormalities, which were mostly rescued in ISO-iPSC-derived neurons. RNA sequencing analysis uncovered dysregulation in three major signaling pathways, including Wnt/β-catenin, p38 MAP kinase, and calcium pathways, in mature MPS II neurons. Further mechanistic characterization indicated that the dysregulation in calcium signaling led to an elevated intracellular calcium level, which might be linked to compromised survival of neurons. Based on these dysregulated pathways, several related chemicals and drugs were tested using this mature MPS II neuron-based platform and a small-molecule glycogen synthase kinase-3β inhibitor was found to significantly rescue neuronal survival, neurite morphology, and electrophysiological abnormalities in MPS II neurons. Our results underscore that the MPS II-iPSC-based platform significantly contributes to unraveling the mechanisms underlying the degeneration and death of MPS II neurons and assessing potential drug candidates. Furthermore, the study revealed that targeting the specific dysregulation of signaling pathways downstream of GAG accumulation in MPS II neurons with a well-characterized drug could potentially ameliorate neuronal degeneration.
2023-02-15 | Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency
Abstract Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine‐generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA‐approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose‐ and time‐dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.
gene therapies
2024-03-12 | Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency
ABSTRACT Multiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the gene SUMF1, encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplant with ex vivo SUMF1 lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that our SUMF1 lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation. In vivo , we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest that SUMF1 HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.
cell therapies
2025-01-10 | Bone marrow transplantation reverses metabolic alterations in multiple sulfatase deficiency: a case series.
Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome. Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells. There is evidence of correction of currently available biomarkers within 3 months post-HCT. Untargeted metabolomics also shows continued correction of multiple biochemical abnormalities in the post-HCT period. Furthermore, this article also presents the neuropsychological outcomes of these children as well as the results of untargeted metabolomics analysis in this condition. These data suggest biochemical benefits post-transplant along with slowing of disease progression. Long-term follow-up is necessary to fully evaluate the therapeutic benefit of HCT in MSD.
2024-10-25 | Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model.
Multiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD. To test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive). After 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain. Our results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.
2022-06-30 | The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Different Donors in Recipients With Mucopolysaccharidosis
There is limited information regarding hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis (MPS) IV and VI. This study examined the full donor chimerism, specific lysosomal enzyme levels, and the survival of different MPS children after HSCT from various donor sources and compared the prognosis. A total of 42 children with MPS underwent HSCT, 9 cases were type I, 14 were type II, 15 were type IV, and 4 were type VI. A total of 24 patients received peripheral blood stem cells (PBSC) and 18 patients received umbilical cord blood (UCB). Patients who received PBSC were conditioned with intravenous (IV) busulfan every 6 h for a total of 16 doses, IV cyclophosphamide (CY, 200 mg/kg), and antihuman thymocyte globulin (ATG, 10 mg/kg). While conditioning regimen of patients who received UCB was adjusted to ATG (preposed, pre-) + busulfan + fludarabine + Cy, which includes IV ATG (pre-, 6 mg/kg), IV busulfan every 6 h for a total of 16 doses, IV fludarabine (200 mg/m 2 ) and CY (200 mg/kg). Also, 95.2% (40 of 42) of patients achieved full donor chimerism, and all patients’ specific lysosomal enzyme levels reached normal. The estimated overall survival (OS) at 1 year was 92.9%. There was no significant difference in 1-year OS between patients who received PBSC transplantation and those who received UCB grafts (87.5% vs. 100%, p = 0.0247). The incidence of acute and chronic GVHD did not differ between them. The incidences of pneumonia in PBSC recipients and UCB recipients were 45.8 and 33.3%, respectively, but there few patients suffering from respiratory failure (4.2 and 5.6%, respectively) due to pneumonia. The incidence of cytomegaloviremia was also high in both groups, 58.3 and 44.4% respectively, However, no patient developed CMV disease. All deaths (3 of 42) occurred in patients receiving PBSC grafts, and there was no death in patients receiving UCB grafts. There was no death after transplantation in patients with MPS IV and VI. In addition, respiratory and nervous system functions were improved, whereas valvular heart disease was improved in some patients but progressed in more patients after transplantation. In summary, HSCT is a good therapeutic option for MPS, not only for patients with MPS I or II but also for those with MPS IV or VI. The specific lysosomal enzyme levels can be completely restored to normal, which is the basis for patients to resolve a broad range of clinical outcomes. Moreover, UCB with suitable HLA (HLA-match above 7/10 and 4/6) is a suitable donor source for MPS. Patients who underwent UCB transplantation using the conditioning regimen ATG (pre-) + busulfan + fludarabine + Cy can achieve a higher proportion of full donor chimerism and survival with less severe complications. HSCT can improve organs function in patients with MPS, but it is still worth exploring.
1981-02-26 | Complementation of arylsulfatase A in somatic hybrids of metachromatic leukodystrophy and multiple sulfatase deficiency disorder fibroblasts.
Metachromatic leukodystrophy and multiple sulfatase deficiency disorder are severe neurodegenerative diseases inherited as separate autosomal recessive traits. Arylsulfatase A (aryl-sulfate sulfohydrolase, EC 3.1.6.1) activity is deficient in both diseases but in multiple sulfatase deficiency disorder, activities of arylsulfatases B and C and other sulfatases are also reported to be reduced. Somatic hybrid cell clones produced by fusing cultured fibroblasts from patients with these diseases were isolated by a nonselective technique based on unit-gravity sedimentation. Arylsulfatase A activity was restored in these hybrids. The complemented enzyme resembled the normal arylsulfatase A in heat stability, pH optimum, Km, electrophoretic mobility, and immunologic reactivity. Because a structurally normal enzyme can be restored in a hybrid only though intergenic complementation, these results indicate that the mutations responsible for the deficiency of arylsulfatase A activity in metachromatic leukodystrophy and multiple sulfatase deficiency disorder are nonallelic and that at least two genetic loci control the expression of arylsulfatase A activity in the human genome. Furthermore, arylsulfatase C activity was also restored to normal in the hybrids, indicating that a common sulfatase inhibitor is not the cause of the multiple sulfatse deficiency.
1979-12-01 | Genetic complementation studies of multiple sulfatase deficiency.
Cultured fibroblasts from two individuals with multiple sulfatase deficiency (MSD) were found to have decreased activities of arylsulfatases (aryl-sulfate sulfohydrolase, EC 3.1.6.1) A, B, and C as well as iduronate-sulfate sulfatase, sulfamidase, and N-acetylglucosamine-6-sulfate sulfatase. The activity of N-acetylgalactosamine-6-sulfate sulfatase was decreased in one line but not in the other. Mixtures of MSD cell extracts with extracts from normal cells did not result in inhibition of normal sulfatase activities. Mixtures of MSD cell extracts with extracts of fibroblasts from patients with Hunter or Sanfilippo A syndrome did not activate iduronate-sulfate sulfatase or sulfamidase activity. Heterokaryons formed by fusion of MSD cells with Sanfilippo A fibroblasts demonstrated a partial correction of the enzyme deficiency. In similar manner, MSD-Hunter heterokaryons showed a significant increase in iduronate-sulfate-sulfatase activity. Genetic complementation in heterokaryons of MSD fibroblasts and cells of either Sanfilippo A or Hunter syndrome implies a genetic defect in MSD different from that causing specific sulfatase deficiencies.
small molecules
2026-08-11 | New structures of human formylglycine-generating enzyme reveal features important for catalysis, disease and structure-based drug design.
The formylglycine-generating enzyme (FGE) post-translationally modifies the active site of all human sulfatases. Mutations in the SUMF1 gene encoding FGE may lead to catalytically inactive FGE or destabilize the protein. The resulting lack of sulfatase modification causes the rare disease multiple sulfatase deficiency (MSD). Previously, FGE required elastase treatment for crystallization and the structures lacked copper, although FGE is a copper-dependent enzyme. Here, we show that highly active human FGE purified from insect cells natively contains one copper ion and we report six new crystal structures revealing previously unobserved features. Several structures contain the catalytic copper ion coordinated almost linearly by the two catalytic cysteines. A structure of the MSD-causing E130D variant shows distortions in coordination of a structural Ca2+ explaining its lower stability. As part of exploratory ligand-soaking experiments, a structure of FGE soaked with N-acetyl cysteine methyl ester shows the binding of a small molecule to a site other than the active site highlighting a potential binding site to be explored in the development of pharmacological chaperones for FGE. Crystallization of FGE without elastase treatment resulted in a structure in which the previously missing loop is well defined in the electron density and partly covers the active site, indicating that it needs to adopt a different conformation for substrate binding. This assumption is supported by a second structure in which the loop faces away from the active site and leaves the substrate binding groove open and by the occasional occurrence of crystals in which the loop becomes disordered.
2026-01-01 | N-acetyl-L-leucine in Neurological Disorders: Mechanisms, Evidence, and Therapeutic Perspectives.
N-acetyl-L-leucine (NALL), a stereospecific derivative of the essential amino acid L-leucine, has attracted increasing attention as a candidate therapy for neurological disorders. Preclinical and clinical studies suggest both symptomatic and neuroprotective effects. This review summarizes evidence on the mechanisms of action, preclinical findings, and clinical outcomes of NALL, and discusses its therapeutic prospects in neurological health and disease. A structured literature search of PubMed, Scopus, and Google Scholar was conducted to identify preclinical and clinical studies evaluating N-acetyl-L-leucine (NALL) in neurological disorders. Preclinical studies demonstrated that NALL enhances mitochondrial bioenergetics, reduces oxidative stress, restores lysosomal and autophagic function, and modulates neuroinflammation. In rodent models, NALL improved motor coordination, neuronal survival, and recovery following traumatic brain injury. Clinical trials in Niemann-Pick disease type C and GM2 gangliosidoses showed improvements in motor function, quality of life, and disease progression, with sustained benefit during extension phases. Preliminary evidence also suggests possible roles in multiple sclerosis, ataxia telangiectasia, Parkinson’s disease, and multiple sulfatase deficiency. NALL was consistently well tolerated with a favorable safety profile. NALL shows multimodal mechanisms and promising translational potential for both rare and common neurological disorders. While early evidence is encouraging, larger randomized trials are required to confirm efficacy, define optimal dosing, and determine its place in neurological therapeutics.
2025-04-12 | Repurposing Tazarotene for Multiple Sulfatase Deficiency: A Path TowardClinical Application
Despite increasing research efforts, Multiple Sulfatase Deficiency (MSD, MIM #272200) remains an untreatable disease with a high unmet medical need. Various therapeutic approaches, including gene therapy and hematopoietic stem cell transplantation, have been explored. Among them, small-molecule drug identification has been a key strategy for therapy development. Drug repurposing—repositioning existing medications for new indications— offers a fast-track route to treatment by leveraging existing knowledge on formulation, toxicity, dosage, safety, and side effects. This significantly reduces the time and cost associated with early pharmacological and clinical development. A high-throughput drug screening on MSD patient-derived cells identified tazarotene, a third-generation retinoic acid derivative, as a potential therapeutic candidate capable of reversing disease pathology in vitro. Currently approved for topical treatment of plaque psoriasis and acne, tazarotene was previously evaluated for oral administration in clinical trials (Phase I–III) with approximately 1,500 participants. While proven efficacious for its intended indications, oral tazarotene was not licensed by the FDA due to post-marketing safety monitoring concerns.As part of the REMEDI4ALL initiative, an EU-funded consortium of 24 partners—including academia, industry, patient organizations, and regulatory agencies—tazarotene has been selected as a demonstrator project for drug repurposing. REMEDI4ALL has facilitated a target product profile and gap analysis, leading to reformulation, evaluation, and production of oral tazarotene for clinical development in MSD. Collaboration with the pharmaceutical industry ensures access to existing toxicity, preclinical, and clinical data, aiding regulatory processes. These efforts have culminated in scientific advice meetings with regulators, paving the way for the first clinical trial in MSD patients, scheduled to begin by the end of 2025.
2024-04-29 | Mature neurons from iPSCs unveil neurodegeneration-related pathways in mucopolysaccharidosis type II: GSK-3β inhibition for therapeutic potential
Mucopolysaccharidosis (MPS) type II is caused by a deficiency of iduronate-2-sulfatase and is characterized by the accumulation of glycosaminoglycans (GAGs). Without effective therapy, the severe form of MPS II causes progressive neurodegeneration and death. This study generated multiple clones of induced pluripotent stem cells (iPSCs) and their isogenic controls (ISO) from four patients with MPS II neurodegeneration. MPS II-iPSCs were successfully differentiated into cortical neurons with characteristic biochemical and cellular phenotypes, including axonal beadings positive for phosphorylated tau, and unique electrophysiological abnormalities, which were mostly rescued in ISO-iPSC-derived neurons. RNA sequencing analysis uncovered dysregulation in three major signaling pathways, including Wnt/β-catenin, p38 MAP kinase, and calcium pathways, in mature MPS II neurons. Further mechanistic characterization indicated that the dysregulation in calcium signaling led to an elevated intracellular calcium level, which might be linked to compromised survival of neurons. Based on these dysregulated pathways, several related chemicals and drugs were tested using this mature MPS II neuron-based platform and a small-molecule glycogen synthase kinase-3β inhibitor was found to significantly rescue neuronal survival, neurite morphology, and electrophysiological abnormalities in MPS II neurons. Our results underscore that the MPS II-iPSC-based platform significantly contributes to unraveling the mechanisms underlying the degeneration and death of MPS II neurons and assessing potential drug candidates. Furthermore, the study revealed that targeting the specific dysregulation of signaling pathways downstream of GAG accumulation in MPS II neurons with a well-characterized drug could potentially ameliorate neuronal degeneration.
2023-02-15 | Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency
Abstract Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine‐generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA‐approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose‐ and time‐dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.
gene therapies
2024-03-12 | Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of Multiple Sulfatase Deficiency
ABSTRACT Multiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the gene SUMF1, encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplant with ex vivo SUMF1 lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that our SUMF1 lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation. In vivo , we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest that SUMF1 HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.
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Drug Discovery Landscape
1 orphan drug designation for Multiple sulfatase deficiency.
1 orphan drug designation for Multiple sulfatase deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant serotype 9 adeno-associated virus encoding codon optimized human sulfatase modifying factor 1 | gene therapies | FDA | 2024-09-20 | — | National Center for Advancing Translational Sciences, National Institutes of Health |
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