RARE DISEASE
Mucopolysaccharidosis type 6
Mucopolysaccharidosis type 6
Mucopolysaccharidosis type 6
Synonyms: ARSB deficiency, ASB deficiency, Arylsulfatase B deficiency, MPS6, MPSVI, Maroteaux-Lamy disease, Mucopolysaccharidosis type VI, N-acetylgalactosamine 4-sulfatase deficiency
Synonyms: ARSB deficiency, ASB deficiency, Arylsulfatase B deficiency, MPS6, MPSVI, Maroteaux-Lamy disease, Mucopolysaccharidosis type VI, N-acetylgalactosamine 4-sulfatase deficiency
Synonyms: ARSB deficiency, ASB deficiency, Arylsulfatase B deficiency, MPS6, MPSVI, Maroteaux-Lamy disease, Mucopolysaccharidosis type VI, N-acetylgalactosamine 4-sulfatase deficiency
Drug discovery
8
drugs
With orphan designations
Overview
Mucopolysaccharidosis type VI (MPS VI/Maroteaux-Lamy syndrome) is an autosomal recessive lysosomal storage disorder caused by deficient arylsulfatase B activity, leading to dermatan sulfate accumulation. It manifests with progressive skeletal dysplasia (dysostosis multiplex), organomegaly, cardiac valve disease, corneal clouding, and respiratory complications, while typically sparing cognitive function. Diagnosis combines clinical evaluation, enzyme activity assays <10% normal [1][2][8], and genetic confirmation of ARSB mutations. Enzyme replacement therapy with galsulfase forms the cornerstone of disease-modifying treatment [1][3][16].
Burden
Functional: 55% school/work absenteeism [4], 78% need assistive mobility devices by adolescence [6][12]
Systemic: Spinal cord compression (34%), progressive valvulopathy (91%), corneal opacity (75%) [6][8][12]
Economic: Mean 3.9-year diagnostic delay [4][9], ERT interruptions in 44-48% due to access barriers [4]
Key monitoring includes annual cervical spine MRI, pulmonary function tests, and echocardiography [3][10]. Early ERT initiation correlates with improved growth velocity (Δ height Z-score +0.8) [13].
Therapies
ERT: Weekly IV galsulfase improves endurance (6MWT↑ 92m over 24 weeks [3]), reduces urinary GAGs [13], with long-term stabilization [16]
Adjuvant care: Orthopedic/cardiac surgeries (68% require ≥1 procedure [4]), CPAP for sleep apnea [3], corneal transplants [10]
Emerging approaches: HSCT preserves visceral/organ function but limited skeletal impact [16]
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
297 drug discovery papers about Mucopolysaccharidosis type 6, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
297 drug discovery papers about Mucopolysaccharidosis type 6, with 2 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-06-13 | Long-Term Outcomes of Hematopoietic Stem Cell Transplantation in Mucopolysaccharidoses Patients Without Radiation.
Mucopolysaccharidosis (MPS) is an inherited lysosomal storage disorder (LSD) subcategory caused by the glycosaminoglycans (GAG) endo- and exo-glycosidases malfunction or dysfunction, leading to GAG accumulation. Due to the enzyme replacement therapy's (ERT's) limitations and challenges, HSCT is considered the only standard curative option in some MPS subtypes. The cross-sectional study was conducted on MPS subtypes I, II, and VI patients with an indication for HSCT between September 2016 and December 2023. A myeloablative conditioning (MAC) regimen without radiation was administered to all patients. In this study, the OS was 75.3% for all patients. Considering different MPS subtypes, the OS rate was 71.6%, 62.5%, and 81.3% for MPS-I, II, and VI patients, respectively. There was no graft failure using PB donor cells, and all alive patients reached normal enzyme activity 1 year post-HSCT. Considering growth parameters, we showed that MPS I patients could benefit from HSCT more than MPS VI patients. However, MPS VI patients showed better OS. Data regarding the comparison of HSCT outcomes in different MPS subtypes are limited, and HSCT outcomes in MPS VI patients are mostly limited to case reports. A conditioning regimen without radiation should be considered in all patients to reduce post-HSCT complications.
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.
2025-03-14 | Hematopoietic stem cell transplantation in pediatric patients with type VI mucopolysaccharidosis.
It is uncertain whether hematopoietic stem cell transplantation (HSCT), versus standard enzyme replacement therapy (ERT), is effective for type VI mucopolysaccharidosis (MPS VI). New related advances in HSCT prompted an examination of the transplant procedures performed in a recent cohort. This single-center retrospective study reviewed the medical records of 17 pediatric patients with MPS VI who underwent allogeneic HSCT in 2021-2023. All conditioning regimens were myeloablative. Engraftment days, complications, and survival data were recorded. As follow-up was short, we recorded only 6-minute walk test distance before versus after HSCT. The patients underwent transplantation at a median of 6-year postdiagnosis. All were engrafted and had a full or mixed chimerism. Enzyme levels were within normal ranges. Walking tests of all evaluable patients improved at a median 9-month follow-up. HSCT aims to improve the disease and provides a permanent solution at the enzyme level, eliminating ERT. Our study showed that HSCT, a less expensive and permanent treatment option, should be offered to patients with MPS VI.
2023-12-16 | Generation of induced pluripotent stem cell line (RCMGi012-A) from fibroblasts of patient with mucopolysaccharidosis type VI.
Skin fibroblasts obtained from a 5-year-old girl with genetically proven (two heterozygous mutations in ARSB gene) and clinically manifested mucopolysaccharidosis type VI were successfully transformed into induced pluripotent stem cells by using Sendai virus-based reprogramming vectors including the four Yamanaka factors namely SOX2, OCT3/4, KLF4, and c-MYC. These iPSCs expressed pluripotency markers, had a normal karyotype and the potential to differentiate into three germ layers in spontaneous differentiation assay. The line may be used for cell differentiation and pharmacological investigations, and also may provide a model for development of a personalized treatment including drug screening and genome editing.
2023-11-24 | [Long-term outcome of hematopoietic stem cell transplantation in two children with Mucopolysaccharidosis].
To explore the long-term efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with Mucopolysaccharidosis (MPS), which has rarely been reported in China. A 18-month-old boy and a 23-month-old girl undergoing alloHSCT for MPS VI and MPS IH Shanghai Children's Medical Center on March 30, 2006 and September 6, 2006 were selected as the study subjects. A busulfan-based myeloablative regimen was used as the conditioning regimen. Peripheral stem cells were respectively collected from a human leucocyte antigen (HLA) matched sibling carrier donor and a HLA 9/10 matched unrelated donor. Both patients were followed up for more than 15 years. The functions of internal organs before and after the transplantation were compared, and child 1 was also compared with his untreated brother and healthy brother. Both children have achieved full donor chimerism after the transplantation, and their enzymatic activities have remained stable. The enzymatic activity of the child 1 was slightly lower than normal but similar to that of his carrier donor, whilst that of the child 2 was normal. Both children have attended schools with good academic performance. Compared with his untreated brother, the respiratory function and hearing of child 1 have significantly improved. However, his orthopedic and cardiac disorders have still remained and required medical intervention. For child 2, her obstructive pulmonary disease was resolved and cognitive development was well preserved after the HSCT. Her heart disease has become stabilized and even improved with time, though her corneal clouding and skeletal malformation still required surgery. MPS patients can sustain long-term and stable enzymatic activities after successful alloHSCT. Compared with untreated patients, their health can be significantly improved, along with considerably prolonged survival, though the long-term efficacy of HSCT for different organs may vary to a certain extent.
proteins
2026-06-16 | A Rare Case of Mucopolysaccharidosis Presenting With Dysostosis Multiplex and Preserved Intelligence in a Seven-Year-Old Girl From Northeast India.
Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by a deficiency of enzymes required for the degradation of glycosaminoglycans (GAGs). These disorders are characterized by progressive multisystem involvement, including skeletal deformities, organomegaly, and variable neurocognitive impairment. We report a case of a seven-year-old girl presenting with recurrent respiratory complaints. Clinical examination revealed coarse facial features, short stature, short neck, hepatomegaly, joint stiffness, corneal clouding, and hearing impairment. Radiological findings showed features of dysostosis multiplex, including J-shaped sella turcica and oar-shaped ribs. Urinary GAG was positive. Cognitive function was normal. Based on clinical and investigative findings, a diagnosis of MPS type I-S (Scheie syndrome) or mild MPS type VI (Maroteaux-Lamy syndrome) was considered. This case highlights the importance of early clinical suspicion of MPS in children presenting with multisystem involvement and skeletal abnormalities, even in the presence of preserved intelligence. Early diagnosis is crucial for timely management and genetic counseling.
2026-05-18 | RPE Abnormality Is a Potential Primary Cause for Retinal Degeneration in Mucopolysaccharidosis Type VI Patients and a Rat Model.
Mucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in ARSB, leading to deficiency of N-acetylgalactosamine 4-sulfatase and accumulation of glycosaminoglycans. Although enzyme replacement therapy (ERT) alleviates systemic symptoms, its efficacy for ocular complications is limited. Because ocular manifestations may require distinct therapeutic approaches, a precise understanding of the underlying retinal pathology is essential. This study aimed to characterize ocular and retinal involvement in MPS VI through clinical and experimental analyses. Comprehensive ophthalmic examinations were performed in siblings with MPS VI, and histological and electrophysiological assessments were conducted in an MPS VI rat model. Retinal morphology, retinal pigment epithelium (RPE) integrity, and electroretinographic responses were evaluated. In patients, no apparent photoreceptor degeneration was detected, although subtle functional impairment could not be excluded. Consistently, MPS VI rats exhibited preserved photoreceptor structures but reduced electroretinogram amplitudes. Although RPE abnormalities were not evident in patients, rats showed pronounced RPE alterations, suggesting RPE involvement as a potential origin of retinal dysfunction. Our findings suggest that retinal dysfunction in MPS VI may primarily arise from RPE pathology rather than photoreceptor loss. Detailed retinal evaluations in aging patients are warranted, and therapeutic approaches targeting the RPE, such as localized ERT or RPE cell transplantation may provide future benefits.
2025-10-22 | Abstract C005: Arylsulfatase B inhibits progression of malignant melanoma by COP1-mediated apoptosis in syngeneic and humanized mouse models
Abstract The enzyme Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) removes the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate (C4S) and is required for C4S degradation in mammalian cells. Congenital, inactivating mutations of ARSB are the cause of Mucopolysaccharidosis (MPS) VI, and replacement therapy with rhARSB is routinely used with benefit for MPS VI patients. In several malignancies, including malignant melanoma, prostate, mammary, and colon, ARSB expression and activity are reduced, leading to increased C4S. Recently, we have reported that treatment of syngeneic B16F10 melanomas by recombinant human ARSB reduces the volume of subcutaneous and metastatic pulmonary melanomas and improves survival (PMID:37813168; PMID:40562100). Similar effects of rhARSB are evident following treatment of A375 melanomas in the humanized PBMC NSG mouse model. ARSB enhances apoptosis in melanomas by increasing expression of the E3 ubiquitin ligase constitutive photomorphogenic (COP)1, a known inhibitor of responses to ultraviolet B. In melanomas, COP1 reduces ETS1 and expression of BCL2, leading to increase in cleaved caspase-3. The increase in COP1 follows rhARSB-induced declines in Ras GTPase activity and phospho(Ser473)-AKT1, leading to increase in nuclear FOXO3 and COP1 promoter activation. The cellular signaling and transcriptional effects of rhARSB are mediated by changes in chondroitin 4-sulfation, which affect C4S binding with critical molecules, including galectin-3, SHP2 (PTPN11), and IL-8. Galectin-3 binds less when ARSB is reduced, leading to increased availability to act as a co-transcriptional activator with Sp1 or AP1. In contrast, SHP2, the ubiquitous non-receptor tyrosine phosphatase, binds more with C4S when ARSB is reduced, leading to sustained phosphorylation of SHP2 targets, including phospho-ERK1/2 and phospho-p38 MAPK. These effects on critical signaling molecules lead to changes in expression of chondroitin sulfate proteoglycan 4 (CSPG4), matrix metalloproteinase (MMP)2, and MMP9 and contribute to the malignant melanoma phenotype. Inverse effects of rhARSB and ARSB siRNA are evident, with rhARSB acting as a tumor suppressor and ARSB siRNA as a tumor promoter. Citation Format: Joanne K. Tobacman, Insug O-Sullivan, Sumit Bhattacharyya. Arylsulfatase B inhibits progression of malignant melanoma by COP1-mediated apoptosis in syngeneic and humanized mouse models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C005.
2025-10-01 | Sanfilippo Syndrome: Brain Clinical Picture
This case involves a 20-year-old female patient who experienced three episodes of tonic–clonic seizures after becoming agitated upon waking up at home. The patient has exhibited behavioral abnormalities and speech impairment since childhood and was diagnosed with mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome) at the age of 14 years. The diagnosis was confirmed through chromatography of glycosaminoglycans, revealing the presence of heparan sulfate with greater mobility in urine and a concentration of 25 mg/mmol creatinine in urine. The patient has been under the care of a multidisciplinary team. Computed tomography revealed typical findings of Sanfilippo syndrome, including diffuse cortical thickening of the bone structures evaluated, volumetric reduction of brain parenchyma, accentuation of furrows between cortical gyri and Sylvian fissures, and compensatory dilation of the ventricular system [Figure 1].Figure 1: (a) A computed tomography (CT) scan of the bone window demonstrates diffuse bone thickening. (b) CT in the soft-tissue window shows the widening of the sulci between the cortical gyri and Sylvian fissures and compensatory dilation of the ventricular system. (c) CT in the soft-tissue window reveals volumetric reduction of the brain parenchyma.Sanfilippo syndrome is an autosomal recessive disease characterized by an enzymatic disorder affecting the degradation of heparan sulfate, an intra- and extracellular proteoglycan found in various cells.[1,2] In the United States, its incidence is approximately 1 in 70,000 live births.[3] The syndrome is categorized into four subtypes based on the specific enzymatic deficiency, with MPS IIIA and IIB being the most prevalent.[1] This condition is a progressive neurodegenerative disorder, and its symptoms arise from the accumulation of heparan sulfate in the central nervous system, leading to cognitive decline, motor dysfunction, and behavioral abnormalities.[4,5] The most significant neuroradiological features include abnormal white matter signal intensity, dilation of periventricular spaces, widening of cortical sulci, cerebral atrophy, enlargement of extraventricular spaces, and spinal cord compression,[6] as evidenced in this case. Concerning the skeletal system, key radiological findings consist of dysostosis multiplex, which encompasses various bone malformations found in the skull, hands, legs, arms, and spine.[7] Abnormal storage of glycosaminoglycans leads to hepatomegaly and splenomegaly while also causing damage to cartilage and synovial recesses in joints.[7] As of now, there is no approved treatment for MPS III. However, various treatments are under investigation, including enzyme replacement therapies, substrate reduction therapies, and gene and cell therapies. According to Kong et al., it is anticipated that an approved treatment will become available in the near future.[8] Ethics statement This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its amendments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and that due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2024-03-22 | Abstract 5979: Recombinant N-acetylgalactosamine-4-sulfatase (arylsulfatase B; ARSB) inhibits lung metastases in murine B16F10 syngeneic tumor model
Abstract Activity of the enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B: ARSB), which removes the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate (C4S) and dermatan sulfate, is reduced in several malignant cell lines and human tissues, including melanomas, mammary, prostate, and colon. Following tail vein injection of B16F10 melanoma cells in 12-week-old female C57BL/6J mice (n=11) and subsequent treatment by tail vein injection of bioactive, recombinant human ARSB (0.2 mg/kg), on days 2 and 7, development of metastatic lung lesions was markedly reduced. The average number of lesions declined from mean value of 114 (range: 10-278; n=5) to mean value of 2.5 (range: 0-9; n=6). These findings are consistent with our previous report of significant increase in survival and decrease in size of B16F10 subcutaneous melanomas in C57BL/6J mice treated with exogenous ARSB. The underlying mechanisms leading to inhibition of melanoma proliferation have profound impact on vital signaling pathways and transcriptional events. These pathways involve more or less binding with C4S when ARSB activity is modified. Notably, galectin-3 binding with C4S increases following exogenous ARSB, leading to decline in free nuclear galectin-3. This leads to reduced expression of the melanoma biomarker chondroitin sulfate proteoglycan CSPG)-4; also known as melanoma-associated chondroitin sulfate proteoglycan (MCSP). Expression of Programmed Death-Ligand 1 (PD-L1) is also reduced, declining from 1.34 ± 0.23 ng/mg protein (n=5) to 0.50 ± 0.05 ng/mg protein (n=6) following ARSB treatment. Inverse to the effect on galectin-3, SHP2, the ubiquitous non-receptor tyrosine phosphatase (PTPN11), binds less to C4S following treatment with exogenous ARSB. The resulting activation of SHP2 impacts on MAPK signaling, reducing phospho-ERK1/2 and phospho(T180/Y182)-p38-MAPK. These effects contribute to decline in matrix metalloproteinases MMP2 and MMP9 and thereby restrain invasiveness and metastasis. Following treatment with exogenous ARSB, the serum MMP2 declined from 267 ± 38 (ng/ml; n=5) to 121 ± 16 ng/ml (n=6), consistent with the observed decline in melanoma lesions. The impact of ARSB on signaling pathways and transcriptional events demonstrates how modification of a critical sulfation and the resulting impact on binding with C4S influences vital cell processes and can suppress tumor development. Recombinant human ARSB is an approved agent for the treatment of Mucopolysaccharidosis VI and is used safely and effectively for this congenital deficiency of ARSB. Exogenous ARSB may become an effective treatment for acquired deficiency of ARSB in melanoma. Citation Format: Joanne Kramer Tobacman, Sumit Bhattacharyya, Insug O-Sullivan. Recombinant N-acetylgalactosamine-4-sulfatase (arylsulfatase B; ARSB) inhibits lung metastases in murine B16F10 syngeneic tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5979.
small molecules
2026-06-19 | Anesthetic Management of Cesarean Section in a Patient With Mucopolysaccharidosis VI (MPS VI): A Case Report.
Mucopolysaccharidosis VI (MPS VI), a rare lysosomal storage disorder, leads to multisystem involvement (airway, skeletal, cardiac, and spinal pathologies) that significantly elevates anesthetic risks during cesarean delivery. A 29-year-old primigravida with MPS VI underwent clinically indicated elective cesarean section at 26 weeks' gestation due to progressive lower limb weakness that made her unable to tolerate continued pregnancy, following multidisciplinary obstetric and anesthesiology evaluation. Critical clinical features included extreme short stature, wheelchair dependence, macroglossia, severely restricted mouth opening (Mallampati class IV), and concomitant aortic valve disease. Ultrasound-guided continuous epidural anesthesia was administered through incremental injection of lidocaine carbonate, achieving adequate surgical anesthesia (T6 sensory level). The procedure was completed uneventfully, with hemodynamic stability and successful delivery of a viable neonate. This case demonstrates that continuous epidural anesthesia, when supported by comprehensive preoperative evaluation, ultrasound guidance, and contingency general anesthesia preparedness, represents a viable option for cesarean delivery in MPS VI patients.
2026-05-08 | Assessment of bone health and bone mineral density in patients with mucopolysaccharidosis receiving enzyme replacement therapy.
Most patients with mucopolysaccharidosis (MPS) experience skeletal involvement due to impaired bone remodeling, glycosaminoglycan (GAG) accumulation, reduced mobility, and nutritional deficiencies. These factors may predispose to low bone mass and increased fracture risk. This study assessed bone mineral density (BMD) using height-adjusted dual-energy X-ray absorptiometry (DXA) in pediatric MPS patients receiving enzyme replacement therapy (ERT) and examined its associations with clinical, functional, and biochemical parameters. This cross-sectional study included 29 children with biochemically and/or genetically confirmed MPS receiving ERT at Tanta University Hospital. Children under 5 years and ERT-naïve patients were excluded. BMD was measured at the lumbar spine (L1-L4) and femoral neck using DXA and adjusted for height-for-age z-score (HAZ). Clinical data, Katz Activities of Daily Living (ADL) score, anthropometry, and biochemical markers of bone metabolism were recorded. Statistical analyses included the Shapiro-Wilk test, Pearson correlation, and two-tailed t-test (p < 0.05). The cohort included 29 patients (19 males, 10 females; mean age 9.79 ± 3.85 years): 13 with MPS IVA, 11 with MPS I, 3 with MPS II, and 2 with MPS VI. Mean HAZ-adjusted BMD z-scores were - 1.84 ± 1.38 (right femur), - 2.07 ± 1.22 (left femur), and - 3.00 ± 1.49 (lumbar spine). Low bone mass for age (HAZ-adjusted z ≤ - 2) was present in 20/29 (68.9%) patients, predominantly affecting the spine. Vitamin D insufficiency/deficiency was observed in 75.9% of patients. Katz ADL score correlated strongly with BMD at all sites, particularly the lumbar spine (r = 0.88, p < 0.001). Total calcium and vitamin D levels showed positive correlations with BMD. Patients with cardiac involvement had significantly lower BMI than those without cardiac disease (p < 0.001). Pediatric patients with MPS receiving ERT show a high prevalence of low bone mass for age, driven by a multifactorial interaction between impaired mobility, nutritional deficiencies, and intrinsic skeletal pathology. Routine height-adjusted DXA monitoring, early physiotherapy, and proactive vitamin D and calcium supplementation should be integrated into comprehensive MPS care.
2026-04-13 | Microwave-Assisted Synthesis and Enzyme Stabilization Study of N‑Alkyl Praziquantel Analogs for Arylsulfatase B: Possible Leads for Mucopolysaccharidosis VI Therapy.
Mutations in the lysosomal enzyme arylsulfatase B result in the genetic disorder mucopolysaccharidosis VI. Current treatment for mucopolysaccharidosis VI requires intravenous enzyme replacement therapy which suffers from incomplete biodistribution. Alternative therapeutic approaches based on small molecules acting as enzyme stabilizers or pharmacological chaperones facilitate the transport of mutant enzymes to the lysosome and may offer improved biodistribution. Herein we describe the development of a facile microwave-assisted reductive amination to synthesize N-alkyl substituted analogs of praziquantel. The analogs were then tested for their ability to stabilize wild-type arylsulfatase B against thermal denaturation. We identify one analog that does not inhibit recombinant arylsulfatase B but can stabilize it against thermal denaturation as a potential lead compound in the treatment of mucopolysaccharidosis VI.
2026-03-12 | Ultrasound-guided one-point puncture lumbosacral plexus block combined with laryngeal mask airway general anesthesia for thigh amputation in a patient with mucopolysaccharidosis: a case report
Mucopolysaccharidosis (MPS) is a group of rare inherited lysosomal storage disorders caused by deficiencies of specific enzymes, leading to abnormal accumulation of glycosaminoglycans in tissues throughout the body. It is often associated with a difficult airway, cervical spine instability, restrictive pulmonary dysfunction, and cardiovascular pathologies, which significantly increase perioperative risks. This manuscript reports a case of a 36-year-old male MPS patient (clinical phenotype highly suggestive of type IV) who underwent right mid-to-upper thigh amputation for a pathological fracture of the right femur. Given his potential difficult airway (Mallampati class III, thyromental distance <6 cm), mild kyphosis, and restrictive pulmonary dysfunction, the anesthetic plan consisted of an ultrasound-guided one-point puncture, dual-target lumbosacral plexus block (35 mL of 0.15% ropivacaine) combined with supraglottic airway (laryngeal mask airway, LMA) under general anesthesia. The block successfully provided an L2-S3 sensory level and served as the basis for postoperative multimodal analgesia. The surgery lasted 2 h with 500 mL blood loss, requiring 2 units of red blood cells. Hemodynamics remained stable, and no additional muscle relaxants were administered. The patient regained consciousness and the LMA was removed 10 min postoperatively. The Numerical Rating Scale (NRS) pain scores at 2, 6, 12, and 24 h postoperatively were 2, 3, 2, and 1, respectively. Functional exercise began on postoperative day 1 without major complications. The patient was discharged 15 days after surgery and was hospitalized for a total of 18 days. With strict patient selection and thorough preparation of emergency airway protocols, combining an LMA with an ultrasound-guided one-point puncture lumbosacral plexus block can be a safe and feasible individualized anesthetic strategy for lower limb proximal surgery in MPS patients. This approach helps avoid intubation risks, reduces opioid consumption, and promotes early recovery. However, due to the considerable difficulty of airway management in patients with MPS, elective surgery requires multidisciplinary consultation and comprehensive airway assessment to ensure perioperative safety.
2026-02-26 | Chronic myeloid leukaemia in a child with mucopolysaccharidosis type VI: diagnostic and management challenges.
A child presented with progressive abdominal swelling, pallor and longstanding skeletal and facial abnormalities. Examination revealed hepatosplenomegaly, coarse facies, joint stiffness and cardiac murmurs. Investigations showed hyperleucocytosis with BCR-ABL1 positivity confirming chronic myeloid leukaemia, while radiological and echocardiographic findings supported a clinical diagnosis of mucopolysaccharidosis type VI (MPS VI). The coexistence of these two rare disorders created diagnostic and management challenges, particularly as urinary glycosaminoglycan testing was inconclusive and enzyme assays were unavailable. The patient was stabilised with hydroxyurea and subsequently commenced on imatinib, achieving haematological remission, while supportive measures addressed the multisystem complications of MPS VI. This case highlights the need for vigilance in recognising malignancy in children with rare genetic disorders, the limitations of confirmatory testing in low-resource settings and the importance of multidisciplinary, individualised care when treatments for one condition may complicate the other.
gene therapies
2026-07-01 | Rare and rarer: percutaneous transcatheter mitral commissurotomy using over-the-wire technique in a patient with mucopolysaccharidosis—a case report
Abstract Background Percutaneous transcatheter mitral commissurotomy (PTMC) by the Inoue technique is the traditional technique to relieve rheumatic mitral stenosis. Mucopolysaccharidoses, a group of rare lysosomal storage disorders, result in skeletal and vertebral anomalies and cardiac valvular abnormalities. The coexistence of both pathologies is rare, and mitral stenosis in such a scenario may pose significant technical challenges. Case summary We present the case of a short statured 15-year-old girl with mucopolysaccharidosis Type VI with severe mitral stenosis and moderate aortic stenosis. Echocardiography revealed features suggestive of rheumatic involvement rather than due to the syndrome. Due to high surgical risk and unique anatomical characteristics, percutaneous approach was more amenable than surgery. The patient underwent successful PTMC using an unconventional over-the-wire technique instead of the traditional Inoue technique. Discussion This case highlights the importance of a case-based approach in unique anatomic and high-risk situations for better outcomes, which may need out-of-the-box thinking.
2025-12-05 | Histology scores.
Mucopolysaccharidosis VI (MPS VI) is a rare, autosomal recessive lysosomal storage disease caused by mutations in the arylsulfatase B gene (ARSB). Ocular manifestations of MPS VI include progressive corneal clouding, leading to vision loss. Herein, an adeno-associated virus (AAV) ARSB corneal gene addition strategy was evaluated in a naturally occurring MPS VI feline model. The AAV serotype 8 capsid was packaged with a single-strand optimized human ARSB expression cassette (optARSB) and administered to MPS VI feline corneas at a dose of 1e9 vector genomes via intrastromal injection. All AAV8-optARSB injections were well tolerated, resulting in a complete reversal of pre-existing corneal clouding within 2–3 weeks, which was maintained throughout the study. Sequential dosing of the contralateral cornea 7 weeks after the first dose also cleared the storage disease with similar kinetics despite more advanced disease. Confocal microscopy, histological analyses, and electron microscopy revealed disorganization in the posterior corneal stroma in untreated animals with AAV8-optARSB-treated corneas demonstrating improved morphology and tissue organization. Human arylsulfatase B was observed throughout the corneal stroma with decreased smooth muscle actin staining following AAV8-optARSB treatment. The collective results demonstrate that reversing feline MPS VI corneal clouding using intrastromal low-dose AAV8-optARSB is safe and effective. Furthermore, as this strategy relied on the same AAV capsid, vector dose, genetic cassette context, injection type, and volume deemed safe and effective for the treatment of MPS I, the data derived herein support a standardized pipeline for AAV corneal gene therapy.
2025-12-05 | Adeno-associated vector corneal gene therapy reverses corneal clouding in a feline model of mucopolysaccharidosis VI.
Mucopolysaccharidosis VI (MPS VI) is a rare, autosomal recessive lysosomal storage disease caused by mutations in the arylsulfatase B gene (ARSB). Ocular manifestations of MPS VI include progressive corneal clouding, leading to vision loss. Herein, an adeno-associated virus (AAV) ARSB corneal gene addition strategy was evaluated in a naturally occurring MPS VI feline model. The AAV serotype 8 capsid was packaged with a single-strand optimized human ARSB expression cassette (optARSB) and administered to MPS VI feline corneas at a dose of 1e9 vector genomes via intrastromal injection. All AAV8-optARSB injections were well tolerated, resulting in a complete reversal of pre-existing corneal clouding within 2-3 weeks, which was maintained throughout the study. Sequential dosing of the contralateral cornea 7 weeks after the first dose also cleared the storage disease with similar kinetics despite more advanced disease. Confocal microscopy, histological analyses, and electron microscopy revealed disorganization in the posterior corneal stroma in untreated animals with AAV8-optARSB-treated corneas demonstrating improved morphology and tissue organization. Human arylsulfatase B was observed throughout the corneal stroma with decreased smooth muscle actin staining following AAV8-optARSB treatment. The collective results demonstrate that reversing feline MPS VI corneal clouding using intrastromal low-dose AAV8-optARSB is safe and effective. Furthermore, as this strategy relied on the same AAV capsid, vector dose, genetic cassette context, injection type, and volume deemed safe and effective for the treatment of MPS I, the data derived herein support a standardized pipeline for AAV corneal gene therapy.
2025-10-09 | Mucopolysaccharidosis VI: Therapeutic strategies and perspectives.
Mucopolysaccharidosis VI, also known as Maroteaux-Lamy syndrome, is a lysosomal storage disorder (LSD) caused by pathogenic mutations in the ARSB gene, resulting in arylsulfatase (ARSB) deficiency and the lysosomal accumulation of dermatan sulfate (DS) and chondroitin 4-sulfate (C4S). DS and C4S accumulation leads to multisystemic symptoms in MPS VI patients in cartilage, bone, heart valves, cornea, liver, and respiratory tract. Currently, enzyme replacement therapy (ERT) is the only approved treatment for patients with MPS VI, providing clinical benefits that include increased survival and improved quality of life. However, ERT has a limited impact on bone manifestations. Significant advances have been made in gene therapy (GT) using classical adeno-associated virus and the CRISPR/Cas9 system, providing promising alternatives in MPS VI. Importantly, hematopoietic stem cell transplantation (HSCT) in combination with GT may also offer a novel alternative. Additionally, substrate reduction therapy with odiparcil, immunomodulation, and stop codon read-through therapies have been explored in MPS VI. Future directions in MPS VI should include targeting cellular alterations, such as mitochondrial dysfunction, exploring cartilage-targeting alternatives, and implementing pharmacological chaperones. This manuscript highlights recent progress and emerging strategies for treating MPS VI.
2025-04-13 | AAV gene therapy for mucopolysaccharidoses.
Adeno-associated viral (AAV) vectors emerge as a promising treatment option for genetic diseases. They are recognized as the most effective in vivo gene therapy due to their safety, efficacy, and ability to provide long-term therapeutic transgene expression.1,2,3 Rossi et al.1 have demonstrated that AAV gene therapy is effective and safe for treating patients with mucopolysaccharidosis VI, paving the way for potential treatments for mucopolysaccharidoses.
other
2025-07-18 | Functional Analysis of Complex Structural and Splice-Altering Variants in the ARSB Gene Towards the Personalized Antisense-Based Therapy for Mucopolysaccharidosis Type VI Patients.
Mucopolysaccharidosis Type VI (MPS VI) is a lysosomal storage disorder associated with biallelic pathogenic variants in the ARSB gene. Herein, we present three patients with biochemical and clinical pictures of MPS VI, for whom routine molecular genetic analysis using Sanger sequencing of ARSB failed to identify one or both causative variants. RNA analysis of patients' samples revealed alterations of the wild-type ARSB mRNA isoform in all cases, and one case required further analysis using whole genome sequencing. As a result, we identified one complex structural variant, which is a 52-kb insertion of the LHFPL2 gene fragment in the ARSB Intron 4, derived from nonallelic homologous recombination and leading to premature transcription termination, a recurrent deep intronic variant leading to pseudoexon activation and an intragenic deletion altering the integrity and splicing of the ARSB Exon 2. Using a minigene-based cellular model, we demonstrated that the identified pseudoexon can be efficiently blocked by antisense molecules incorporated into modified U7 small nuclear RNAs and circular RNAs. The same approach was used to block the overlapping polymorphic pseudoexon in the ARSB gene and increase the amount of wild-type mRNA isoform approximately twofold.
2023-06-02 | Increased Cerebral Serum Amyloid A2 and Parameters of Oxidation in Arylsulfatase B (N-Acetylgalactosamine-4-Sulfatase)-Null Mice
Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer's disease (AD), and the impact of modified chondroitin sulfates is being investigated in several animal and cell-based models of AD. Published reports have shown the role of accumulation of chondroitin 4-sulfate and decline in Arylsulfatase B (ARSB; B-acetylgalactosamine-4-sulfatase) in other pathology, including nerve injury, traumatic brain injury, and spinal cord injury. However, the impact of ARSB deficiency on AD pathobiology has not been reported, although changes in ARSB were associated with AD in two prior reports. The enzyme ARSB removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate and is required for their degradation. When ARSB activity declines, these sulfated glycosaminoglycans accumulate, as in the inherited disorder Mucopolysaccharidosis VI.Reports about chondroitin sulfate, chondroitin sulfate proteoglycans, and chondroitin sulfatases in AD were reviewed.Measurements of SAA2, iNOS, lipid peroxidation, chondroitin sulfate proteoglycan 4 (CSPG4), and other parameters were performed in cortex and hippocampus from ARSB-null mice and controls by QRT-PCR, ELISA, and other standard assays.SAA2 mRNA expression and protein, CSPG4 mRNA, chondroitin 4-sulfate, and iNOS were increased significantly in ARSB-null mice. Measures of lipid peroxidation and redox state were significantly modified.Findings indicate that decline in ARSB leads to changes in expression of parameters associated with AD in the hippocampus and cortex of the ARSB-deficient mouse. Further investigation of the impact of decline in ARSB on the development of AD may provide a new approach to prevent and treat AD.
2018-02-01 | Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI: 10-year follow up (case report)
Two of the most prominent challenges that limit the clinical success of siRNA therapies are a lack of control over cargo release from the delivery vehicle and an incomplete understanding of the link between gene silencing dynamics and siRNA dosing. Herein, we address these challenges through the formulation of siRNA polyplexes containing light-responsive polymer mixtures, whose varied compositions and triggered release behavior provide enhanced gene silencing and controlled dose responses that can be predicted by simple kinetic models. Through the straightforward mixing of two block copolymers, the level of gene knockdown was easily optimized to achieve the maximum level of GAPDH protein silencing in NIH/3T3 cells (~70%) using a single siRNA dose. The kinetic model was used to describe the dynamic changes in mRNA and protein concentrations in response to siRNA treatment. These predictions enabled the application of a second dose of siRNA to maximally suppress gene expression over multiple days, leading to a further 50% reduction in protein levels relative to those measured following a single dose. Furthermore, polyplexes remained dormant in cells until exposed to the photo-stimulus, demonstrating the complete control over siRNA activity as well as the stability of the nanocarriers. Thus, this work demonstrates that pairing advances in biomaterials design with simple kinetic modeling provides new insight into gene silencing dynamics and presents a powerful strategy to control gene expression through siRNA delivery.Our manuscript describes two noteworthy impacts: (1) we designed mixed polymer formulations to enhance gene silencing, and (2) we simultaneously developed a simple kinetic model for determining optimal siRNA dose responses to maintain silencing over several days. These advances address critical challenges in siRNA delivery and provide new opportunities in therapeutics development. The structure-function relationships prevalent in these formulations were established to enable tuning and forecasting of nanocarrier efficiency a priori, leading to siRNA dosing regimens able to maximally suppress gene expression. Our advances are significant because the mixed polymer formulations provide a straightforward and scalable approach to tailor siRNA delivery regimens. Moreover, the implementation of accurate dosing frameworks addresses a major knowledge gap that has hindered clinical implementation of siRNA.
cell therapies
2025-06-13 | Long-Term Outcomes of Hematopoietic Stem Cell Transplantation in Mucopolysaccharidoses Patients Without Radiation.
Mucopolysaccharidosis (MPS) is an inherited lysosomal storage disorder (LSD) subcategory caused by the glycosaminoglycans (GAG) endo- and exo-glycosidases malfunction or dysfunction, leading to GAG accumulation. Due to the enzyme replacement therapy's (ERT's) limitations and challenges, HSCT is considered the only standard curative option in some MPS subtypes. The cross-sectional study was conducted on MPS subtypes I, II, and VI patients with an indication for HSCT between September 2016 and December 2023. A myeloablative conditioning (MAC) regimen without radiation was administered to all patients. In this study, the OS was 75.3% for all patients. Considering different MPS subtypes, the OS rate was 71.6%, 62.5%, and 81.3% for MPS-I, II, and VI patients, respectively. There was no graft failure using PB donor cells, and all alive patients reached normal enzyme activity 1 year post-HSCT. Considering growth parameters, we showed that MPS I patients could benefit from HSCT more than MPS VI patients. However, MPS VI patients showed better OS. Data regarding the comparison of HSCT outcomes in different MPS subtypes are limited, and HSCT outcomes in MPS VI patients are mostly limited to case reports. A conditioning regimen without radiation should be considered in all patients to reduce post-HSCT complications.
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.
2025-03-14 | Hematopoietic stem cell transplantation in pediatric patients with type VI mucopolysaccharidosis.
It is uncertain whether hematopoietic stem cell transplantation (HSCT), versus standard enzyme replacement therapy (ERT), is effective for type VI mucopolysaccharidosis (MPS VI). New related advances in HSCT prompted an examination of the transplant procedures performed in a recent cohort. This single-center retrospective study reviewed the medical records of 17 pediatric patients with MPS VI who underwent allogeneic HSCT in 2021-2023. All conditioning regimens were myeloablative. Engraftment days, complications, and survival data were recorded. As follow-up was short, we recorded only 6-minute walk test distance before versus after HSCT. The patients underwent transplantation at a median of 6-year postdiagnosis. All were engrafted and had a full or mixed chimerism. Enzyme levels were within normal ranges. Walking tests of all evaluable patients improved at a median 9-month follow-up. HSCT aims to improve the disease and provides a permanent solution at the enzyme level, eliminating ERT. Our study showed that HSCT, a less expensive and permanent treatment option, should be offered to patients with MPS VI.
2023-12-16 | Generation of induced pluripotent stem cell line (RCMGi012-A) from fibroblasts of patient with mucopolysaccharidosis type VI.
Skin fibroblasts obtained from a 5-year-old girl with genetically proven (two heterozygous mutations in ARSB gene) and clinically manifested mucopolysaccharidosis type VI were successfully transformed into induced pluripotent stem cells by using Sendai virus-based reprogramming vectors including the four Yamanaka factors namely SOX2, OCT3/4, KLF4, and c-MYC. These iPSCs expressed pluripotency markers, had a normal karyotype and the potential to differentiate into three germ layers in spontaneous differentiation assay. The line may be used for cell differentiation and pharmacological investigations, and also may provide a model for development of a personalized treatment including drug screening and genome editing.
2023-11-24 | [Long-term outcome of hematopoietic stem cell transplantation in two children with Mucopolysaccharidosis].
To explore the long-term efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with Mucopolysaccharidosis (MPS), which has rarely been reported in China. A 18-month-old boy and a 23-month-old girl undergoing alloHSCT for MPS VI and MPS IH Shanghai Children's Medical Center on March 30, 2006 and September 6, 2006 were selected as the study subjects. A busulfan-based myeloablative regimen was used as the conditioning regimen. Peripheral stem cells were respectively collected from a human leucocyte antigen (HLA) matched sibling carrier donor and a HLA 9/10 matched unrelated donor. Both patients were followed up for more than 15 years. The functions of internal organs before and after the transplantation were compared, and child 1 was also compared with his untreated brother and healthy brother. Both children have achieved full donor chimerism after the transplantation, and their enzymatic activities have remained stable. The enzymatic activity of the child 1 was slightly lower than normal but similar to that of his carrier donor, whilst that of the child 2 was normal. Both children have attended schools with good academic performance. Compared with his untreated brother, the respiratory function and hearing of child 1 have significantly improved. However, his orthopedic and cardiac disorders have still remained and required medical intervention. For child 2, her obstructive pulmonary disease was resolved and cognitive development was well preserved after the HSCT. Her heart disease has become stabilized and even improved with time, though her corneal clouding and skeletal malformation still required surgery. MPS patients can sustain long-term and stable enzymatic activities after successful alloHSCT. Compared with untreated patients, their health can be significantly improved, along with considerably prolonged survival, though the long-term efficacy of HSCT for different organs may vary to a certain extent.
proteins
2026-06-16 | A Rare Case of Mucopolysaccharidosis Presenting With Dysostosis Multiplex and Preserved Intelligence in a Seven-Year-Old Girl From Northeast India.
Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by a deficiency of enzymes required for the degradation of glycosaminoglycans (GAGs). These disorders are characterized by progressive multisystem involvement, including skeletal deformities, organomegaly, and variable neurocognitive impairment. We report a case of a seven-year-old girl presenting with recurrent respiratory complaints. Clinical examination revealed coarse facial features, short stature, short neck, hepatomegaly, joint stiffness, corneal clouding, and hearing impairment. Radiological findings showed features of dysostosis multiplex, including J-shaped sella turcica and oar-shaped ribs. Urinary GAG was positive. Cognitive function was normal. Based on clinical and investigative findings, a diagnosis of MPS type I-S (Scheie syndrome) or mild MPS type VI (Maroteaux-Lamy syndrome) was considered. This case highlights the importance of early clinical suspicion of MPS in children presenting with multisystem involvement and skeletal abnormalities, even in the presence of preserved intelligence. Early diagnosis is crucial for timely management and genetic counseling.
2026-05-18 | RPE Abnormality Is a Potential Primary Cause for Retinal Degeneration in Mucopolysaccharidosis Type VI Patients and a Rat Model.
Mucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in ARSB, leading to deficiency of N-acetylgalactosamine 4-sulfatase and accumulation of glycosaminoglycans. Although enzyme replacement therapy (ERT) alleviates systemic symptoms, its efficacy for ocular complications is limited. Because ocular manifestations may require distinct therapeutic approaches, a precise understanding of the underlying retinal pathology is essential. This study aimed to characterize ocular and retinal involvement in MPS VI through clinical and experimental analyses. Comprehensive ophthalmic examinations were performed in siblings with MPS VI, and histological and electrophysiological assessments were conducted in an MPS VI rat model. Retinal morphology, retinal pigment epithelium (RPE) integrity, and electroretinographic responses were evaluated. In patients, no apparent photoreceptor degeneration was detected, although subtle functional impairment could not be excluded. Consistently, MPS VI rats exhibited preserved photoreceptor structures but reduced electroretinogram amplitudes. Although RPE abnormalities were not evident in patients, rats showed pronounced RPE alterations, suggesting RPE involvement as a potential origin of retinal dysfunction. Our findings suggest that retinal dysfunction in MPS VI may primarily arise from RPE pathology rather than photoreceptor loss. Detailed retinal evaluations in aging patients are warranted, and therapeutic approaches targeting the RPE, such as localized ERT or RPE cell transplantation may provide future benefits.
2025-10-22 | Abstract C005: Arylsulfatase B inhibits progression of malignant melanoma by COP1-mediated apoptosis in syngeneic and humanized mouse models
Abstract The enzyme Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) removes the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate (C4S) and is required for C4S degradation in mammalian cells. Congenital, inactivating mutations of ARSB are the cause of Mucopolysaccharidosis (MPS) VI, and replacement therapy with rhARSB is routinely used with benefit for MPS VI patients. In several malignancies, including malignant melanoma, prostate, mammary, and colon, ARSB expression and activity are reduced, leading to increased C4S. Recently, we have reported that treatment of syngeneic B16F10 melanomas by recombinant human ARSB reduces the volume of subcutaneous and metastatic pulmonary melanomas and improves survival (PMID:37813168; PMID:40562100). Similar effects of rhARSB are evident following treatment of A375 melanomas in the humanized PBMC NSG mouse model. ARSB enhances apoptosis in melanomas by increasing expression of the E3 ubiquitin ligase constitutive photomorphogenic (COP)1, a known inhibitor of responses to ultraviolet B. In melanomas, COP1 reduces ETS1 and expression of BCL2, leading to increase in cleaved caspase-3. The increase in COP1 follows rhARSB-induced declines in Ras GTPase activity and phospho(Ser473)-AKT1, leading to increase in nuclear FOXO3 and COP1 promoter activation. The cellular signaling and transcriptional effects of rhARSB are mediated by changes in chondroitin 4-sulfation, which affect C4S binding with critical molecules, including galectin-3, SHP2 (PTPN11), and IL-8. Galectin-3 binds less when ARSB is reduced, leading to increased availability to act as a co-transcriptional activator with Sp1 or AP1. In contrast, SHP2, the ubiquitous non-receptor tyrosine phosphatase, binds more with C4S when ARSB is reduced, leading to sustained phosphorylation of SHP2 targets, including phospho-ERK1/2 and phospho-p38 MAPK. These effects on critical signaling molecules lead to changes in expression of chondroitin sulfate proteoglycan 4 (CSPG4), matrix metalloproteinase (MMP)2, and MMP9 and contribute to the malignant melanoma phenotype. Inverse effects of rhARSB and ARSB siRNA are evident, with rhARSB acting as a tumor suppressor and ARSB siRNA as a tumor promoter. Citation Format: Joanne K. Tobacman, Insug O-Sullivan, Sumit Bhattacharyya. Arylsulfatase B inhibits progression of malignant melanoma by COP1-mediated apoptosis in syngeneic and humanized mouse models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C005.
2025-10-01 | Sanfilippo Syndrome: Brain Clinical Picture
This case involves a 20-year-old female patient who experienced three episodes of tonic–clonic seizures after becoming agitated upon waking up at home. The patient has exhibited behavioral abnormalities and speech impairment since childhood and was diagnosed with mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome) at the age of 14 years. The diagnosis was confirmed through chromatography of glycosaminoglycans, revealing the presence of heparan sulfate with greater mobility in urine and a concentration of 25 mg/mmol creatinine in urine. The patient has been under the care of a multidisciplinary team. Computed tomography revealed typical findings of Sanfilippo syndrome, including diffuse cortical thickening of the bone structures evaluated, volumetric reduction of brain parenchyma, accentuation of furrows between cortical gyri and Sylvian fissures, and compensatory dilation of the ventricular system [Figure 1].Figure 1: (a) A computed tomography (CT) scan of the bone window demonstrates diffuse bone thickening. (b) CT in the soft-tissue window shows the widening of the sulci between the cortical gyri and Sylvian fissures and compensatory dilation of the ventricular system. (c) CT in the soft-tissue window reveals volumetric reduction of the brain parenchyma.Sanfilippo syndrome is an autosomal recessive disease characterized by an enzymatic disorder affecting the degradation of heparan sulfate, an intra- and extracellular proteoglycan found in various cells.[1,2] In the United States, its incidence is approximately 1 in 70,000 live births.[3] The syndrome is categorized into four subtypes based on the specific enzymatic deficiency, with MPS IIIA and IIB being the most prevalent.[1] This condition is a progressive neurodegenerative disorder, and its symptoms arise from the accumulation of heparan sulfate in the central nervous system, leading to cognitive decline, motor dysfunction, and behavioral abnormalities.[4,5] The most significant neuroradiological features include abnormal white matter signal intensity, dilation of periventricular spaces, widening of cortical sulci, cerebral atrophy, enlargement of extraventricular spaces, and spinal cord compression,[6] as evidenced in this case. Concerning the skeletal system, key radiological findings consist of dysostosis multiplex, which encompasses various bone malformations found in the skull, hands, legs, arms, and spine.[7] Abnormal storage of glycosaminoglycans leads to hepatomegaly and splenomegaly while also causing damage to cartilage and synovial recesses in joints.[7] As of now, there is no approved treatment for MPS III. However, various treatments are under investigation, including enzyme replacement therapies, substrate reduction therapies, and gene and cell therapies. According to Kong et al., it is anticipated that an approved treatment will become available in the near future.[8] Ethics statement This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and its amendments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and that due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2024-03-22 | Abstract 5979: Recombinant N-acetylgalactosamine-4-sulfatase (arylsulfatase B; ARSB) inhibits lung metastases in murine B16F10 syngeneic tumor model
Abstract Activity of the enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B: ARSB), which removes the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate (C4S) and dermatan sulfate, is reduced in several malignant cell lines and human tissues, including melanomas, mammary, prostate, and colon. Following tail vein injection of B16F10 melanoma cells in 12-week-old female C57BL/6J mice (n=11) and subsequent treatment by tail vein injection of bioactive, recombinant human ARSB (0.2 mg/kg), on days 2 and 7, development of metastatic lung lesions was markedly reduced. The average number of lesions declined from mean value of 114 (range: 10-278; n=5) to mean value of 2.5 (range: 0-9; n=6). These findings are consistent with our previous report of significant increase in survival and decrease in size of B16F10 subcutaneous melanomas in C57BL/6J mice treated with exogenous ARSB. The underlying mechanisms leading to inhibition of melanoma proliferation have profound impact on vital signaling pathways and transcriptional events. These pathways involve more or less binding with C4S when ARSB activity is modified. Notably, galectin-3 binding with C4S increases following exogenous ARSB, leading to decline in free nuclear galectin-3. This leads to reduced expression of the melanoma biomarker chondroitin sulfate proteoglycan CSPG)-4; also known as melanoma-associated chondroitin sulfate proteoglycan (MCSP). Expression of Programmed Death-Ligand 1 (PD-L1) is also reduced, declining from 1.34 ± 0.23 ng/mg protein (n=5) to 0.50 ± 0.05 ng/mg protein (n=6) following ARSB treatment. Inverse to the effect on galectin-3, SHP2, the ubiquitous non-receptor tyrosine phosphatase (PTPN11), binds less to C4S following treatment with exogenous ARSB. The resulting activation of SHP2 impacts on MAPK signaling, reducing phospho-ERK1/2 and phospho(T180/Y182)-p38-MAPK. These effects contribute to decline in matrix metalloproteinases MMP2 and MMP9 and thereby restrain invasiveness and metastasis. Following treatment with exogenous ARSB, the serum MMP2 declined from 267 ± 38 (ng/ml; n=5) to 121 ± 16 ng/ml (n=6), consistent with the observed decline in melanoma lesions. The impact of ARSB on signaling pathways and transcriptional events demonstrates how modification of a critical sulfation and the resulting impact on binding with C4S influences vital cell processes and can suppress tumor development. Recombinant human ARSB is an approved agent for the treatment of Mucopolysaccharidosis VI and is used safely and effectively for this congenital deficiency of ARSB. Exogenous ARSB may become an effective treatment for acquired deficiency of ARSB in melanoma. Citation Format: Joanne Kramer Tobacman, Sumit Bhattacharyya, Insug O-Sullivan. Recombinant N-acetylgalactosamine-4-sulfatase (arylsulfatase B; ARSB) inhibits lung metastases in murine B16F10 syngeneic tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5979.
small molecules
2026-06-19 | Anesthetic Management of Cesarean Section in a Patient With Mucopolysaccharidosis VI (MPS VI): A Case Report.
Mucopolysaccharidosis VI (MPS VI), a rare lysosomal storage disorder, leads to multisystem involvement (airway, skeletal, cardiac, and spinal pathologies) that significantly elevates anesthetic risks during cesarean delivery. A 29-year-old primigravida with MPS VI underwent clinically indicated elective cesarean section at 26 weeks' gestation due to progressive lower limb weakness that made her unable to tolerate continued pregnancy, following multidisciplinary obstetric and anesthesiology evaluation. Critical clinical features included extreme short stature, wheelchair dependence, macroglossia, severely restricted mouth opening (Mallampati class IV), and concomitant aortic valve disease. Ultrasound-guided continuous epidural anesthesia was administered through incremental injection of lidocaine carbonate, achieving adequate surgical anesthesia (T6 sensory level). The procedure was completed uneventfully, with hemodynamic stability and successful delivery of a viable neonate. This case demonstrates that continuous epidural anesthesia, when supported by comprehensive preoperative evaluation, ultrasound guidance, and contingency general anesthesia preparedness, represents a viable option for cesarean delivery in MPS VI patients.
2026-05-08 | Assessment of bone health and bone mineral density in patients with mucopolysaccharidosis receiving enzyme replacement therapy.
Most patients with mucopolysaccharidosis (MPS) experience skeletal involvement due to impaired bone remodeling, glycosaminoglycan (GAG) accumulation, reduced mobility, and nutritional deficiencies. These factors may predispose to low bone mass and increased fracture risk. This study assessed bone mineral density (BMD) using height-adjusted dual-energy X-ray absorptiometry (DXA) in pediatric MPS patients receiving enzyme replacement therapy (ERT) and examined its associations with clinical, functional, and biochemical parameters. This cross-sectional study included 29 children with biochemically and/or genetically confirmed MPS receiving ERT at Tanta University Hospital. Children under 5 years and ERT-naïve patients were excluded. BMD was measured at the lumbar spine (L1-L4) and femoral neck using DXA and adjusted for height-for-age z-score (HAZ). Clinical data, Katz Activities of Daily Living (ADL) score, anthropometry, and biochemical markers of bone metabolism were recorded. Statistical analyses included the Shapiro-Wilk test, Pearson correlation, and two-tailed t-test (p < 0.05). The cohort included 29 patients (19 males, 10 females; mean age 9.79 ± 3.85 years): 13 with MPS IVA, 11 with MPS I, 3 with MPS II, and 2 with MPS VI. Mean HAZ-adjusted BMD z-scores were - 1.84 ± 1.38 (right femur), - 2.07 ± 1.22 (left femur), and - 3.00 ± 1.49 (lumbar spine). Low bone mass for age (HAZ-adjusted z ≤ - 2) was present in 20/29 (68.9%) patients, predominantly affecting the spine. Vitamin D insufficiency/deficiency was observed in 75.9% of patients. Katz ADL score correlated strongly with BMD at all sites, particularly the lumbar spine (r = 0.88, p < 0.001). Total calcium and vitamin D levels showed positive correlations with BMD. Patients with cardiac involvement had significantly lower BMI than those without cardiac disease (p < 0.001). Pediatric patients with MPS receiving ERT show a high prevalence of low bone mass for age, driven by a multifactorial interaction between impaired mobility, nutritional deficiencies, and intrinsic skeletal pathology. Routine height-adjusted DXA monitoring, early physiotherapy, and proactive vitamin D and calcium supplementation should be integrated into comprehensive MPS care.
2026-04-13 | Microwave-Assisted Synthesis and Enzyme Stabilization Study of N‑Alkyl Praziquantel Analogs for Arylsulfatase B: Possible Leads for Mucopolysaccharidosis VI Therapy.
Mutations in the lysosomal enzyme arylsulfatase B result in the genetic disorder mucopolysaccharidosis VI. Current treatment for mucopolysaccharidosis VI requires intravenous enzyme replacement therapy which suffers from incomplete biodistribution. Alternative therapeutic approaches based on small molecules acting as enzyme stabilizers or pharmacological chaperones facilitate the transport of mutant enzymes to the lysosome and may offer improved biodistribution. Herein we describe the development of a facile microwave-assisted reductive amination to synthesize N-alkyl substituted analogs of praziquantel. The analogs were then tested for their ability to stabilize wild-type arylsulfatase B against thermal denaturation. We identify one analog that does not inhibit recombinant arylsulfatase B but can stabilize it against thermal denaturation as a potential lead compound in the treatment of mucopolysaccharidosis VI.
2026-03-12 | Ultrasound-guided one-point puncture lumbosacral plexus block combined with laryngeal mask airway general anesthesia for thigh amputation in a patient with mucopolysaccharidosis: a case report
Mucopolysaccharidosis (MPS) is a group of rare inherited lysosomal storage disorders caused by deficiencies of specific enzymes, leading to abnormal accumulation of glycosaminoglycans in tissues throughout the body. It is often associated with a difficult airway, cervical spine instability, restrictive pulmonary dysfunction, and cardiovascular pathologies, which significantly increase perioperative risks. This manuscript reports a case of a 36-year-old male MPS patient (clinical phenotype highly suggestive of type IV) who underwent right mid-to-upper thigh amputation for a pathological fracture of the right femur. Given his potential difficult airway (Mallampati class III, thyromental distance <6 cm), mild kyphosis, and restrictive pulmonary dysfunction, the anesthetic plan consisted of an ultrasound-guided one-point puncture, dual-target lumbosacral plexus block (35 mL of 0.15% ropivacaine) combined with supraglottic airway (laryngeal mask airway, LMA) under general anesthesia. The block successfully provided an L2-S3 sensory level and served as the basis for postoperative multimodal analgesia. The surgery lasted 2 h with 500 mL blood loss, requiring 2 units of red blood cells. Hemodynamics remained stable, and no additional muscle relaxants were administered. The patient regained consciousness and the LMA was removed 10 min postoperatively. The Numerical Rating Scale (NRS) pain scores at 2, 6, 12, and 24 h postoperatively were 2, 3, 2, and 1, respectively. Functional exercise began on postoperative day 1 without major complications. The patient was discharged 15 days after surgery and was hospitalized for a total of 18 days. With strict patient selection and thorough preparation of emergency airway protocols, combining an LMA with an ultrasound-guided one-point puncture lumbosacral plexus block can be a safe and feasible individualized anesthetic strategy for lower limb proximal surgery in MPS patients. This approach helps avoid intubation risks, reduces opioid consumption, and promotes early recovery. However, due to the considerable difficulty of airway management in patients with MPS, elective surgery requires multidisciplinary consultation and comprehensive airway assessment to ensure perioperative safety.
2026-02-26 | Chronic myeloid leukaemia in a child with mucopolysaccharidosis type VI: diagnostic and management challenges.
A child presented with progressive abdominal swelling, pallor and longstanding skeletal and facial abnormalities. Examination revealed hepatosplenomegaly, coarse facies, joint stiffness and cardiac murmurs. Investigations showed hyperleucocytosis with BCR-ABL1 positivity confirming chronic myeloid leukaemia, while radiological and echocardiographic findings supported a clinical diagnosis of mucopolysaccharidosis type VI (MPS VI). The coexistence of these two rare disorders created diagnostic and management challenges, particularly as urinary glycosaminoglycan testing was inconclusive and enzyme assays were unavailable. The patient was stabilised with hydroxyurea and subsequently commenced on imatinib, achieving haematological remission, while supportive measures addressed the multisystem complications of MPS VI. This case highlights the need for vigilance in recognising malignancy in children with rare genetic disorders, the limitations of confirmatory testing in low-resource settings and the importance of multidisciplinary, individualised care when treatments for one condition may complicate the other.
gene therapies
2026-07-01 | Rare and rarer: percutaneous transcatheter mitral commissurotomy using over-the-wire technique in a patient with mucopolysaccharidosis—a case report
Abstract Background Percutaneous transcatheter mitral commissurotomy (PTMC) by the Inoue technique is the traditional technique to relieve rheumatic mitral stenosis. Mucopolysaccharidoses, a group of rare lysosomal storage disorders, result in skeletal and vertebral anomalies and cardiac valvular abnormalities. The coexistence of both pathologies is rare, and mitral stenosis in such a scenario may pose significant technical challenges. Case summary We present the case of a short statured 15-year-old girl with mucopolysaccharidosis Type VI with severe mitral stenosis and moderate aortic stenosis. Echocardiography revealed features suggestive of rheumatic involvement rather than due to the syndrome. Due to high surgical risk and unique anatomical characteristics, percutaneous approach was more amenable than surgery. The patient underwent successful PTMC using an unconventional over-the-wire technique instead of the traditional Inoue technique. Discussion This case highlights the importance of a case-based approach in unique anatomic and high-risk situations for better outcomes, which may need out-of-the-box thinking.
2025-12-05 | Histology scores.
Mucopolysaccharidosis VI (MPS VI) is a rare, autosomal recessive lysosomal storage disease caused by mutations in the arylsulfatase B gene (ARSB). Ocular manifestations of MPS VI include progressive corneal clouding, leading to vision loss. Herein, an adeno-associated virus (AAV) ARSB corneal gene addition strategy was evaluated in a naturally occurring MPS VI feline model. The AAV serotype 8 capsid was packaged with a single-strand optimized human ARSB expression cassette (optARSB) and administered to MPS VI feline corneas at a dose of 1e9 vector genomes via intrastromal injection. All AAV8-optARSB injections were well tolerated, resulting in a complete reversal of pre-existing corneal clouding within 2–3 weeks, which was maintained throughout the study. Sequential dosing of the contralateral cornea 7 weeks after the first dose also cleared the storage disease with similar kinetics despite more advanced disease. Confocal microscopy, histological analyses, and electron microscopy revealed disorganization in the posterior corneal stroma in untreated animals with AAV8-optARSB-treated corneas demonstrating improved morphology and tissue organization. Human arylsulfatase B was observed throughout the corneal stroma with decreased smooth muscle actin staining following AAV8-optARSB treatment. The collective results demonstrate that reversing feline MPS VI corneal clouding using intrastromal low-dose AAV8-optARSB is safe and effective. Furthermore, as this strategy relied on the same AAV capsid, vector dose, genetic cassette context, injection type, and volume deemed safe and effective for the treatment of MPS I, the data derived herein support a standardized pipeline for AAV corneal gene therapy.
2025-12-05 | Adeno-associated vector corneal gene therapy reverses corneal clouding in a feline model of mucopolysaccharidosis VI.
Mucopolysaccharidosis VI (MPS VI) is a rare, autosomal recessive lysosomal storage disease caused by mutations in the arylsulfatase B gene (ARSB). Ocular manifestations of MPS VI include progressive corneal clouding, leading to vision loss. Herein, an adeno-associated virus (AAV) ARSB corneal gene addition strategy was evaluated in a naturally occurring MPS VI feline model. The AAV serotype 8 capsid was packaged with a single-strand optimized human ARSB expression cassette (optARSB) and administered to MPS VI feline corneas at a dose of 1e9 vector genomes via intrastromal injection. All AAV8-optARSB injections were well tolerated, resulting in a complete reversal of pre-existing corneal clouding within 2-3 weeks, which was maintained throughout the study. Sequential dosing of the contralateral cornea 7 weeks after the first dose also cleared the storage disease with similar kinetics despite more advanced disease. Confocal microscopy, histological analyses, and electron microscopy revealed disorganization in the posterior corneal stroma in untreated animals with AAV8-optARSB-treated corneas demonstrating improved morphology and tissue organization. Human arylsulfatase B was observed throughout the corneal stroma with decreased smooth muscle actin staining following AAV8-optARSB treatment. The collective results demonstrate that reversing feline MPS VI corneal clouding using intrastromal low-dose AAV8-optARSB is safe and effective. Furthermore, as this strategy relied on the same AAV capsid, vector dose, genetic cassette context, injection type, and volume deemed safe and effective for the treatment of MPS I, the data derived herein support a standardized pipeline for AAV corneal gene therapy.
2025-10-09 | Mucopolysaccharidosis VI: Therapeutic strategies and perspectives.
Mucopolysaccharidosis VI, also known as Maroteaux-Lamy syndrome, is a lysosomal storage disorder (LSD) caused by pathogenic mutations in the ARSB gene, resulting in arylsulfatase (ARSB) deficiency and the lysosomal accumulation of dermatan sulfate (DS) and chondroitin 4-sulfate (C4S). DS and C4S accumulation leads to multisystemic symptoms in MPS VI patients in cartilage, bone, heart valves, cornea, liver, and respiratory tract. Currently, enzyme replacement therapy (ERT) is the only approved treatment for patients with MPS VI, providing clinical benefits that include increased survival and improved quality of life. However, ERT has a limited impact on bone manifestations. Significant advances have been made in gene therapy (GT) using classical adeno-associated virus and the CRISPR/Cas9 system, providing promising alternatives in MPS VI. Importantly, hematopoietic stem cell transplantation (HSCT) in combination with GT may also offer a novel alternative. Additionally, substrate reduction therapy with odiparcil, immunomodulation, and stop codon read-through therapies have been explored in MPS VI. Future directions in MPS VI should include targeting cellular alterations, such as mitochondrial dysfunction, exploring cartilage-targeting alternatives, and implementing pharmacological chaperones. This manuscript highlights recent progress and emerging strategies for treating MPS VI.
2025-04-13 | AAV gene therapy for mucopolysaccharidoses.
Adeno-associated viral (AAV) vectors emerge as a promising treatment option for genetic diseases. They are recognized as the most effective in vivo gene therapy due to their safety, efficacy, and ability to provide long-term therapeutic transgene expression.1,2,3 Rossi et al.1 have demonstrated that AAV gene therapy is effective and safe for treating patients with mucopolysaccharidosis VI, paving the way for potential treatments for mucopolysaccharidoses.
other
2025-07-18 | Functional Analysis of Complex Structural and Splice-Altering Variants in the ARSB Gene Towards the Personalized Antisense-Based Therapy for Mucopolysaccharidosis Type VI Patients.
Mucopolysaccharidosis Type VI (MPS VI) is a lysosomal storage disorder associated with biallelic pathogenic variants in the ARSB gene. Herein, we present three patients with biochemical and clinical pictures of MPS VI, for whom routine molecular genetic analysis using Sanger sequencing of ARSB failed to identify one or both causative variants. RNA analysis of patients' samples revealed alterations of the wild-type ARSB mRNA isoform in all cases, and one case required further analysis using whole genome sequencing. As a result, we identified one complex structural variant, which is a 52-kb insertion of the LHFPL2 gene fragment in the ARSB Intron 4, derived from nonallelic homologous recombination and leading to premature transcription termination, a recurrent deep intronic variant leading to pseudoexon activation and an intragenic deletion altering the integrity and splicing of the ARSB Exon 2. Using a minigene-based cellular model, we demonstrated that the identified pseudoexon can be efficiently blocked by antisense molecules incorporated into modified U7 small nuclear RNAs and circular RNAs. The same approach was used to block the overlapping polymorphic pseudoexon in the ARSB gene and increase the amount of wild-type mRNA isoform approximately twofold.
2023-06-02 | Increased Cerebral Serum Amyloid A2 and Parameters of Oxidation in Arylsulfatase B (N-Acetylgalactosamine-4-Sulfatase)-Null Mice
Chondroitin sulfate and chondroitin sulfate proteoglycans have been associated with Alzheimer's disease (AD), and the impact of modified chondroitin sulfates is being investigated in several animal and cell-based models of AD. Published reports have shown the role of accumulation of chondroitin 4-sulfate and decline in Arylsulfatase B (ARSB; B-acetylgalactosamine-4-sulfatase) in other pathology, including nerve injury, traumatic brain injury, and spinal cord injury. However, the impact of ARSB deficiency on AD pathobiology has not been reported, although changes in ARSB were associated with AD in two prior reports. The enzyme ARSB removes 4-sulfate groups from the non-reducing end of chondroitin 4-sulfate and dermatan sulfate and is required for their degradation. When ARSB activity declines, these sulfated glycosaminoglycans accumulate, as in the inherited disorder Mucopolysaccharidosis VI.Reports about chondroitin sulfate, chondroitin sulfate proteoglycans, and chondroitin sulfatases in AD were reviewed.Measurements of SAA2, iNOS, lipid peroxidation, chondroitin sulfate proteoglycan 4 (CSPG4), and other parameters were performed in cortex and hippocampus from ARSB-null mice and controls by QRT-PCR, ELISA, and other standard assays.SAA2 mRNA expression and protein, CSPG4 mRNA, chondroitin 4-sulfate, and iNOS were increased significantly in ARSB-null mice. Measures of lipid peroxidation and redox state were significantly modified.Findings indicate that decline in ARSB leads to changes in expression of parameters associated with AD in the hippocampus and cortex of the ARSB-deficient mouse. Further investigation of the impact of decline in ARSB on the development of AD may provide a new approach to prevent and treat AD.
2018-02-01 | Enzyme replacement therapy attenuates disease progression in two Japanese siblings with mucopolysaccharidosis type VI: 10-year follow up (case report)
Two of the most prominent challenges that limit the clinical success of siRNA therapies are a lack of control over cargo release from the delivery vehicle and an incomplete understanding of the link between gene silencing dynamics and siRNA dosing. Herein, we address these challenges through the formulation of siRNA polyplexes containing light-responsive polymer mixtures, whose varied compositions and triggered release behavior provide enhanced gene silencing and controlled dose responses that can be predicted by simple kinetic models. Through the straightforward mixing of two block copolymers, the level of gene knockdown was easily optimized to achieve the maximum level of GAPDH protein silencing in NIH/3T3 cells (~70%) using a single siRNA dose. The kinetic model was used to describe the dynamic changes in mRNA and protein concentrations in response to siRNA treatment. These predictions enabled the application of a second dose of siRNA to maximally suppress gene expression over multiple days, leading to a further 50% reduction in protein levels relative to those measured following a single dose. Furthermore, polyplexes remained dormant in cells until exposed to the photo-stimulus, demonstrating the complete control over siRNA activity as well as the stability of the nanocarriers. Thus, this work demonstrates that pairing advances in biomaterials design with simple kinetic modeling provides new insight into gene silencing dynamics and presents a powerful strategy to control gene expression through siRNA delivery.Our manuscript describes two noteworthy impacts: (1) we designed mixed polymer formulations to enhance gene silencing, and (2) we simultaneously developed a simple kinetic model for determining optimal siRNA dose responses to maintain silencing over several days. These advances address critical challenges in siRNA delivery and provide new opportunities in therapeutics development. The structure-function relationships prevalent in these formulations were established to enable tuning and forecasting of nanocarrier efficiency a priori, leading to siRNA dosing regimens able to maximally suppress gene expression. Our advances are significant because the mixed polymer formulations provide a straightforward and scalable approach to tailor siRNA delivery regimens. Moreover, the implementation of accurate dosing frameworks addresses a major knowledge gap that has hindered clinical implementation of siRNA.
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Drug Discovery Landscape
8 orphan drug designations for Mucopolysaccharidosis type 6, including 1 approved therapy.
8 orphan drug designations for Mucopolysaccharidosis type 6, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Pentosan polysulfate sodium | small molecules | EMA | 2020-08-21 | — | Paradigm Biopharmaceuticals (Ireland) Limited |
Odiparcil | small molecules | EMA | 2017-08-23 | — | Inventiva |
odiparcil | small molecules | FDA | 2017-08-03 | — | Inventiva SA |
pentosan polysulfate sodium | small molecules | FDA | 2015-01-05 | — | Paradigm Biopharmaceuticals Ltd. |
Adeno-associated viral vector containing the human ARSB gene | gene therapies | EMA | 2011-05-13 | — | Fondazione Telethon Ets |
adeno associated viral vector containing human ARSB gene | gene therapies | FDA | 2011-03-17 | — | Fondazione Telethon |
Galsulfase [Naglazyme] | proteins | EMA | 2001-02-14 | — | [INACTIVE] Biomarin Europe Limited |
N-acetylgalactosamine-4-sulfatase, recombinant human [Naglazyme] | proteins | FDA | 1999-02-17 | 2005-05-31 | BioMarin Pharmaceutical, Inc. |
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