RARE DISEASE
Mucopolysaccharidosis type 4
Mucopolysaccharidosis type 4
Mucopolysaccharidosis type 4
Synonyms: MPS4, MPSIV, Morquio disease, Mucopolysaccharidosis type IV
Synonyms: MPS4, MPSIV, Morquio disease, Mucopolysaccharidosis type IV
Synonyms: MPS4, MPSIV, Morquio disease, Mucopolysaccharidosis type IV
Drug discovery
1
drug
With orphan designation
Overview
Mucopolysaccharidosis type IV (MPS IV/Morquio syndrome) is an autosomal recessive lysosomal storage disorder caused by deficient GALNS (IVA) or GLB1 (IVB) enzymes, leading to keratan/chondroitin sulfate accumulation. It manifests with severe skeletal dysplasia, short stature, spinal instability, joint hypermobility, cardiopulmonary compromise, and corneal clouding, while preserving cognition. Life-threatening complications include cervical spinal cord compression and tracheal obstruction [1][11][12][15].
Therapies
IVA: Weekly IV elosulfase alfa (ERT) improves endurance/respiratory function [6][8][13]; hematopoietic stem cell transplantation (HSCT) has limited skeletal benefits [8][16]
Surgical: Spinal fusion for cervical instability, tracheal reconstruction, and joint surgeries [8][12][17]
Supportive: Multidisciplinary care for respiratory, cardiac, and pain management [8][12][15]
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
232 drug discovery papers about Mucopolysaccharidosis type 4, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
232 drug discovery papers about Mucopolysaccharidosis type 4, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-09-11 | Haematopoietic stem cell transplant in a case of mucopolysaccharidosis IV with Fanconi anaemia and bone marrow failure.
Mucopolysaccharidosis type IV (MPS IV; Morquio syndrome) is a rare lysosomal storage disorder characterised by skeletal dysplasia and multisystem involvement, while Fanconi anaemia (FA) is an inherited bone marrow failure syndrome associated with chromosomal instability and hypersensitivity to conditioning agents. The coexistence of these two disorders poses a unique therapeutic challenge, particularly when haematopoietic stem cell transplantation (HSCT) is indicated. We report a child with MPS IV and FA who underwent HSCT with a non-myeloablative conditioning regimen. The procedure was carefully individualised to balance engraftment success with minimisation of toxicity. This case highlights the complexities of managing overlapping genetic conditions requiring HSCT and demonstrates the value of multidisciplinary planning and personalised transplant strategies in achieving favourable clinical outcomes.
2026-04-28 | Long-Term Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Mucopolysaccharidosis IVA: A 10-Year Follow-Up from a Single-Center Experience in China.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential approach for pediatric mucopolysaccharidosis IVA (MPS IVA). However, delayed diagnosis and higher transplant-related complications have limited its broader use. This study investigated treatment-related benefit and up to 10-year outcomes following HSCT in children with MPS IVA. Study Design We retrospectively analyzed 19 pediatric patients with a severe phenotype of MPS IVA who underwent HSCT between January 2015 and July 2025. N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity, height growth, and organ dysfunction (cardiac, auditory, and visual) was evaluated to analyze the benefit of HSCT. The donor sources include human leukocyte antigen (HLA)-matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT, n = 5), HLA-matched unrelated donor PBSCT (MUD-PBSCT, n = 7), and single-unit unrelated umbilical cord blood transplantation (UD-UCBT, n = 7). The overall survival rate was 94.7% (18/19), apart from 1 mortality due to pulmonary infection. All surviving patients achieved full donor engraftment and durable restoration of GALNS activity. There is no severe graft-versus-host disease (GVHD) was observed. The majority of patients exhibited no deterioration in auditory, visual, respiratory, or cardiac function. During the long-term follow-up period, our cases showed a continued linear growth post-HSCT. Here we demonstrated the data of our HSCT experience in MPS IVA with the safety and efficacy of HSCT. More data with an expanded patient cohort are imperative to delineate the capacity of HSCT to repair severe skeletal manifestations in MPS IVA.
2026-01-31 | Allogeneic Hematopoietic Cell Transplantation for Morquio A Syndrome: An International Retrospective Study.
Mucopolysaccharidosis IV A (MPS IVA) or Morquio A syndrome is a lysosomal storage disorder that results from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), causing deposition of glycosaminoglycans, keratan sulfate, and chondroitin-6-sulfate in multiple organs. The main clinical manifestations include severe short stature, severe cervical spine stenosis, and progressive skeletal dysplasia, which leads to severe mobility limitation resulting in patients becoming wheelchair-bound in their second decade of life, and overall shortened life span. The current standard of care for Morquio A is weekly enzyme replacement therapy (ERT). However, ERT is expensive, not widely available worldwide, and offers limited long-term benefits. Allogeneic hematopoietic cell transplantation (HCT) is a way to provide a life-long endogenous enzyme and has the potential to improve outcomes. The main objectives of this study were to investigate the safety and assess the benefits of allogeneic HCT in the treatment of patients with Morquio A. We performed a retrospective study of 41 patients who underwent allogeneic HCT at 9 international centers. Forty-one patients with Morquio A received allogeneic HCT. Three patients experienced graft failure and underwent second transplants. Most (77%) of the transplants were performed using either matched or mismatched unrelated donors, and 71% of the transplants utilized peripheral blood stem cells as the graft source. The overall 3-year survival rate was 90.5%. Graft-versus-host disease (GVHD) was a direct or indirect contributor to mortality in 3 out of 4 patients. The median myeloid engraftment was 100% at the last follow-up, with a median follow-up of 3 years; the median times for neutrophil and platelet engraftment were 12 and 13 days, respectively. The incidence of grade II to IV acute GVHD was 35.5%. Interestingly, in patients who had received pretransplant ERT, the incidence of acute grade II to IV GVHD was 14.9%, compared to 45% in those who had not received pretransplant ERT (P = .075). The incidence of grades III to IV acute and chronic GVHD was 14.2% and 12.7%, respectively. When available, disease-specific outcomes showed complete to near normalization of metabolic biomarkers, as well as improvement in movement scores, stability of heart function, eyes, and cervical spine stenosis. Notably, in patients transplanted below the age of 3 years, growth continued in 6 out of 8 patients, while this effect was less notable in the older cohort. Allogeneic HCT for patients with Morquio A is safe and feasible. This treatment can potentially lead to significantly improved biochemical markers of the disease, preservation of organs, and better clinical manifestations. Additionally, when performed at a young age, ideally before the age of 3 years, allogeneic HCT may result in improved growth. The use of bone marrow as a stem cell source whenever possible, combined with effective GVHD prophylaxis, may enhance transplant success and disease-related outcomes. Long-term benefits and risks require further investigation.
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.
2024-10-15 | Hematopoietic stem cell transplantation in children with mucopolysaccharidosis IVA: single center experience.
Mucopolysaccharidosis IVA (MPS IVA; Morquio syndrome) is a lysosomal storage disorder and features systemic skeletal dysplasia that is caused by defective Nacetylgalactosamine-6-sulfate sulfatase (GALNS). Although there are convincing data for hematopoietic stem cell transplantation (HSCT) in certain types of MPS, the studies are limited for MPS IVA and more data is still pending to show the efficacy/safety of HSCT. This study included 3 girls and 7 boys, with a median age of 75,5 months (35-186 months), who underwent allogeneic HSCT for severe MPS IVA between February 12, 2021, and March 10, 2023. Enzyme levels, height growth, the most involved organs (ear, eye, and heart), and the activities of daily living (ADL) scoring system were monitored to assess the benefit of HSCT. In a median follow-up of 20 months (9-34 months), there is no severe transplant-related adverse event was observed. In all cases, normal enzyme levels were reached after HSCT. During the short follow-up period, our cases showed an increase in stature and improvement in daily activity functions. Here we present the data of our HSCT experience in MPS IVA with promising results regarding both safety and efficacy. Although there are signs of amelioration with HSCT, we need more data and long-term follow-up to comment properly on the benefits of HSCT in MPS IVA.
small molecules
2026-05-04 | Development of Small-Molecule Allosteric Modulators of Beta-Galactosidase (β-Gal) for the Treatment of GM1 Gangliosidosis and Morquio B.
GM1 gangliosidosis and Morquio B are rare lysosomal storage disorders (LSDs) with significant unmet medical needs. These disorders result from mutations in the galactosidase beta 1 (GLB1) gene, leading to impaired β-galactosidase (β-Gal) activity and toxic substrate accumulation. The lack of approved disease-modifying therapies for GM1 gangliosidosis and Morquio B, along with the challenges of achieving effective central nervous system delivery, has driven interest in small-molecule pharmacological chaperones (PCs) to restore β-Gal stability and function. Using Gain Therapeutics' Magellan™ platform, a novel allosteric binding site on β-Gal was identified, enabling the discovery of a new class of Structurally Targeted Allosteric Regulators (STARs). Medicinal chemistry optimization produced a structurally unique STAR compound series, demonstrating broad β-Gal stabilizing effects. The therapeutic potential of these compounds was evaluated in vitro using a canine fibroblast model of GM1 gangliosidosis, where they were shown to significantly reduce toxic GM1 ganglioside accumulation. Immunocytochemistry-based assays confirmed substrate clearance and provided reliable structure-activity relationships, guiding further compound development. Notably, STARs achieved greater substrate clearance than the competitive PC N-nonyl-deoxygalactonojirimycin (NN-DGJ) under the conditions tested, as demonstrated by immunocytochemistry-based assays. While these findings are encouraging, further in vivo studies are required to validate the therapeutic efficacy of these few STAR compounds, particularly in addressing the neurodegenerative aspects of GM1 gangliosidosis. This study underscores the potential of the Magellan platform in identifying STAR molecules and provides a strong foundation for further optimization and preclinical validation in GLB1-related disorders, particularly GM1 gangliosidosis.
2026-03-30 | 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.
2025-03-17 | Cathepsin B inhibition blocks amyloidogenesis in the mouse models of neurological lysosomal diseases MPS IIIC and sialidosis.
Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs), including mucopolysaccharidoses (MPS); however, the molecular mechanism underlying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3- to 5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-Geo and Hgsnat P304L ) and sialidosis (Neu1 ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC, and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing thioflavin-S+, β-amyloid+ aggregates consistent with a pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (Hgsnat P304L /Ctsb -/- ) mice as well as Hgsnat P304L and Neu1 ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor E64 showed a drastic reduction in neuronal thioflavin-S+/APP+ deposits. Neurons of Hgsnat P304L /Ctsb -/- mice and E64-treated Hgsnat P304L mice also showed reduced levels of P62+, LC3+ puncta, GM2 ganglioside, and misfolded subunit C of mitochondrial ATP synthase, consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat P304L mice, implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.
2024-09-16 | AYURVEDIC MANAGEMENT OF MORQUIO SYNDROME IN A PEDIATRIC PA-TIENT – A CASE STUDY
Mucopolysaccharidosis type IV, also known as Morquio syndrome, a rare hereditary disease of autosomal recessive storage that is a progressive disease that affects the skeleton. The affected person develops various skeletal abnormalities, including height, protruding chest, scoliosis, deformed knees, and curvature of both lower limbs, which may be in Kubjata. Kubjata is one of the Vataja Nanatmaja Vikara; this comes under Janmabala Pravrutta Vyadhi. In this case Abhyanga, Swedana, Mridu Virechana and Basti for 25 days along with a combination of oral medicines such as Trayodashanga guggulu-500 mg, Dashmool kwatha 20 ml, Shiva gutika 500 mg twice per day have been showing that Ayurvedic herbs along with Panchakarma, can play a major role in the management of Morquio syndrome to improve the quality of life and prognosis of the disease.
2024-02-19 | Evidence of epigenetic landscape shifts in mucopolysaccharidosis IIIB and IVA.
Lysosomal storage diseases (LSDs) are a group of monogenic diseases characterized by mutations in genes coding for proteins associated with the lysosomal function. Despite the monogenic nature, LSDs patients exhibit variable and heterogeneous clinical manifestations, prompting investigations into epigenetic factors underlying this phenotypic diversity. In this study, we focused on the potential role of epigenetic mechanisms in the pathogenesis of mucopolysaccharidosis IIIB (MPS IIIB) and mucopolysaccharidosis IVA (MPS IVA). We analyzed DNA methylation (5mC) and histone modifications (H3K14 acetylation and H3K9 trimethylation) in MPS IIIB and MPS IVA patients' fibroblasts and healthy controls. The findings revealed that global DNA hypomethylation is present in cell lines for both diseases. At the same time, histone acetylation was increased in MPS IIIB and MPS IVA cells in a donor-dependent way, further indicating a shift towards relaxed open chromatin in these MPS. Finally, the constitutive heterochromatin marker, histone H3K9 trimethylation, only showed reduced clustering in MPS IIIB cells, suggesting limited alterations in heterochromatin organization. These findings collectively emphasize the significance of epigenetic mechanisms in modulating the phenotypic variations observed in LSDs. While global DNA hypomethylation could contribute to the MPS pathogenesis, the study also highlights individual-specific epigenetic responses that might contribute to phenotypic heterogeneity. Further research into the specific genes and pathways affected by these epigenetic changes could provide insights into potential therapeutic interventions for these MPS and other LSDs.
gene therapies
2026-03-05 | Development and characterization of a model of mucopolysaccharidosis type IVA for evaluating therapies targeting bone disease.
Mucopolysaccharidosis type IVA (MPSIVA) is a lysosomal storage disease (LSD) caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which causes the accumulation of keratan sulphate (KS) and chondroitin sulphate (CS). Patients with MPSIVA typically present with severe skeletal and joint disorders, which are not addressed by conventional therapies. Currently, no animal model accurately replicates the human disease, hindering the development of novel therapeutic interventions. To overcome this limitation, we established, by CRISPR-Cas9 technology, a Galns-/- mouse model that expresses a non-functional enzyme and accumulates CS and KS in the urine, plasma and distinct tissues, and glycosaminoglycans in the spleen. The mice exhibit shortened long bones, trabecular bone alterations and skeletal abnormalities in the growth plate. Additionally, we observed increased levels of inflammatory and oxidative markers in visceral organs and plasma. Our newly developed model of MPSIVA demonstrates clear and quantifiable signs of skeletal alterations, providing novel means of assessment of the safety and efficacy of innovative therapies, including hematopoietic stem and progenitor cell gene therapy, which has recently been shown to provide a beneficial effect on skeletal alterations in Hurler syndrome.
2026-01-30 | Collagen Type II-Targeting Lentiviral Gene Therapy for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis (MPS IVA) is caused by pathogenic variations in the GALNS gene, leading to the accumulation of glycosaminoglycans in tissues and causing progressive skeletal lesions. While conventional lentiviral vectors (LVs) provide long-term stable expression, they do not deliver therapeutic levels to bone and cartilage. We hypothesized that engineering the LV envelope with a collagen type II-targeting peptide (WYRGRL) increases the binding affinity of the LVs for bone and cartilage. These modified vectors carrying the CBh and COL2A1 promoters delivered the GALNS gene to MPS IVA newborn mice via intravenous (IV) or intraarticular (IA) administration. The peptide-modified LVs exhibited markedly increased uptake in the liver when administered IV, but lower enzyme activity than that of the conventional vector. The modified WYRGRL-LV-COL2A1 vector elevated GALNS activity in other tissues, suggesting systemic benefits. When administered IA, the modified vectors showed potential for local treatment due to the WYRGRL peptide-mediated uptake. Additionally, there was a reduction in keratan sulfate glycosaminoglycan levels in plasma and tissues, indicating that this peptide can be a suitable candidate for disease modification. These findings pave the way for further preclinical and clinical studies, offering new possibilities for the development of targeted therapies for skeletal diseases.
2025-11-22 | "Comprehensive Clinical Evaluation And Management Of Congenital Mucopolysacchariodosos type IVA: A Case Report"
This report outlines a brief clinical description of a 2-year-old boy diagnosed with Morquio syndrome (Mucopolysaccharidosis type IVA), a rare autosomal recessive lysosomal storage disorder. The disease results from a deficiency of the N-acetyl-galactosamine-6-sulfatase enzyme, causing the buildup of glycosaminoglycans. This accumulation leads to congenital malformations, disproportionate short stature, significant skeletal deformities, and multisystem involvement, while cognitive function generally remains intact. The case underscores the significance of early recognition, treatment options such as enzyme replacement therapy with Elosulfase alfa, and the necessity of comprehensive multidisciplinary management, genetic counseling, and regular follow-up. It further discusses diagnostic difficulties and explores emerging treatment strategies like gene therapy for managing these progressive hereditary metabolic conditions.
2025-10-15 | Recent advances in mucopolysaccharidosis IVA treatment.
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare lysosomal storage disorder caused by mutations in the GALNS gene, resulting in N-acetylgalactosamine-6-sulfatase (GALNS) deficiency and accumulation of keratan sulfate and chondroitin-6-sulfate. MPS IVA primarily affects the skeletal system, leading to progressive dysplasia and multi-organ involvement. Although enzyme replacement therapy (ERT) with elosulfase alfa is currently the only approved treatment, its clinical benefit on bone pathology is limited due to rapid clearance and poor penetration into avascular cartilage. Strategies to enhance enzyme stability and targeting, such as PEGylated hydrogels and extracellular vesicles, have shown promise in enhancing the biodistribution and stability of GALNS, while pharmacological chaperones, including ezetimibe, pranlukast, and bromocriptine, seem to stabilize GALNS in vitro. Promisingly, gene therapy (GT) has demonstrated significant preclinical progress using adeno-associated virus (AAV), lentiviral (LV), and CRISPR/Cas9 platforms. For instance, AAV vectors employing bone-targeting peptides and tandem promoters improve skeletal manifestations in murine and rat models. Similarly, recent ex vivo LV-based GT studies have opened new avenues in the treatment of MPS IVA. Furthermore, CRISPR/nCas9-based strategies targeting safe harbor loci have successfully restored GALNS activity in MPS IVA fibroblasts and mouse models supporting the notion that gene editing may represent a potential therapeutic approach. On the other hand, antisense-based therapies using modified U7 small nuclear RNAs and circular RNAs offer novel approaches to correct pseudoexon activation from deep-intronic variants while expanding the therapeutic alternatives in MPS IVA. Importantly, recent evidence revealed that mitochondrial dysfunction in chondrocytes may contribute to the pathology of MPS IVA, uncovering new targets beyond GALNS enzyme activity recovery. This review highlights recent advances in the treatment of MPS IVA and discusses new directions to improve outcomes in MPS IVA treatment.
2025-07-29 | Integrase-Deficient Lentiviral Vector as a Platform for Efficient CRISPR/Cas9-Mediated Gene Editing for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder causing systemic skeletal dysplasia due to a deficiency of N-acetyl-galactosamine-6-sulfate sulfatase (GALNS) enzyme activity, leading to the impaired degradation and accumulation of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate. While treatments such as enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available, they have significant limitations regarding efficacy in skeletal tissues and long-term safety, highlighting the need for more effective therapies. We evaluated a novel gene therapy approach using a dual Integrase-deficient lentiviral vector (IDLV) to deliver an expression cassette that includes human GALNS cDNA and Cas9 sgRNA, targeting the upstream region of the mouse Galns initial codon. This approach leverages the endogenous promoter to drive transgene expression. We assessed in vitro transduction, editing, and functional correction in NIH3T3 and MPS IVA mouse fibroblasts. In vivo efficacy was successfully evaluated via the facial vein injection in MPS IVA newborn mice. In vitro, this IDLV platform demonstrated supraphysiological GALNS activity in cell lysate, resulting in the normalization of KS levels. In vivo direct IDLV platform in newborn MPS IVA mice led to sustained plasma GALNS activity, reduced plasma KS, and favorable biodistribution. Partial correction of heart and bone pathology was observed, with no vector toxicity and minimal antibody responses. This dual IDLV-CRISPR/Cas9 approach effectively mediated targeted GALNS knock-in, yielding sustained enzyme activity, reduced KS storage, and partial pathological amelioration in MPS IVA mice. In conclusion, IDLVs represent an efficient, safe platform for delivering the CRISPR/Cas9 gene editing system for MPS IVA.
proteins
2026-07-27 | Early Versus Late Enzyme Replacement Therapy in Siblings With Morquio A Syndrome: Insights Into Therapeutic Timing.
Enzyme replacement therapy (ERT) with elosulfase alfa is the only approved treatment for mucopolysaccharidosis type IVA. This case report delineates the 5-year outcomes of ERT in two Korean siblings with mucopolysaccharidosis type IVA, with the younger sibling initiating treatment at 0.8 years of age and the older one at 5.4 years. Both patients exhibited a progressive decline in their height standard deviation scores, with trajectories paralleling the natural history curves of the disease. At 5.2 years of age, persistent skeletal dysplasia was evident in both siblings. However, the younger sibling demonstrated attenuated disease severity, lacking cervical myelopathy or spinal stenosis requiring C1 laminoplasty. Cardiorespiratory assessment revealed normalized left ventricular mass index z-scores, stable ejection fractions, and the absence of valvular pathology. Overall, these findings suggest that early ERT attenuates severe spinal and upper body manifestations but does not prevent lower limb skeletal progression, highlighting the need for early therapeutic initiation along with orthopedic intervention to preserve cardiorespiratory parameters and functional independence.
2026-03-14 | AAV Gene Therapy for MPS IVA with Induction of Immune Tolerance via Oral Administration of Epitope Peptides of N-Acetylgalactosamine-6-sulfate Sulfatase.
Mucopolysaccharidosis IVA (MPS IVA) is caused by the accumulation of undegraded glycosaminoglycans due to the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme. MPS IVA manifests as progressive systemic skeletal dysplasia. Gene therapy (GT) is potentially a one-time treatment in which the enzyme is continuously produced, circulated, and delivered to target tissues. However, immune responses to gene products can diminish therapeutic efficacy. We hypothesized that oral delivery of tolerogenic peptides induces immune tolerance to human GALNS (hGALNS) in MPS IVA mice, enhancing therapeutic efficacy. Neonatal mice deficient in mouse GALNS (mGALNS) were treated orally with three T-cell/B-cell epitope peptides or hGALNS protein on alternate days from day 3 after birth to day 20 before intravenous injection with AAV9 vectors encoding human GALNS on day 30. The results are encouraging, with anti-hGALNS antibodies undetectable in the plasma of orally administered peptide groups. hGALNS enzyme activities in plasma and tissues were higher in the orally treated groups than in the non-tolerized control group. Keratan sulfate levels in plasma, liver, and bone were normalized. Complete correction for heart vacuolization was achieved in peptide-treated groups, and partial correction for bone pathology was observed in all GT-treated groups. Overall, oral tolerance induction using immunodominant peptides promises to significantly enhance the efficacy of AAV-GT for MPS IVA.
2026-01-01 | Development of national biobank for lysosomal storage disorders in India- a step towards advancing research and precision medicine
Abstract Background Lysosomal storage disorders (LSDs) are a diverse group of over 70 rare, inherited metabolic conditions that present significant diagnostic and therapeutic challenges, especially in genetically diverse and resource-limited settings like India. To address the lack of a centralized clinical and genomic data registry for LSDs, we established the first government-supported national LSDs biobank in India. This study describes the infrastructure, sample collection, storage procedures, ethical framework, and expected impact of the biobank on research, diagnostics, and patient care. Methods The study includes biological samples and clinical-genetic data from 530 patients, (526 unrelated individuals and 2 sibling pairs), over a 17-year period (2008–2025). Biological samples including genomic DNA from blood, plasma, and urine precipitate were processed for enzyme and genetic investigations. A centralized webpage has been established to manage the biological sample data including clinical, enzyme and genetic data. Results The LSD biobank cohort encompasses 8 LSD subgroups across 27 disorders, with the most common being Gaucher disease (n = 70), Tay-Sachs disease (n = 62), Mucolipidosis (ML) II/III (n = 44), and Morquio-A (n = 40). Samples originated from 15 Indian states, with a predominance of pediatric cases. Detailed phenotypic, enzymatic, and genomic profiles were generated. Enzyme assays confirmed markedly reduced activity in most cases, with variable residual activity noted in few LSDs. Genetic analyses using Sanger sequencing, PCR-RFLP, targeted gene panel sequencing, and/ or whole exome sequencing detected causative variants. Notably, c.1469T > C in the IDUA gene (29.4% in Hurler disease), c.230 C > G in the GALNS gene (22.5% in Morquio-A disease), c.1448T > C in the GBA1 gene (56% in Gaucher disease), and c.1385 C > T and c.964G > T in the HEXA gene (11.3% and 8.1% respectively in Tay-Sachs disease) were the most common variants. Several novel, private mutations were also identified, broadening the mutational landscape of LSDs. Conclusion The present study represents a scalable model for rare disease research in low- and middle-income countries. This resource lays the foundation for genotype–phenotype correlation studies, natural history analyses, and future precision medicine strategies tailored to the Indian population.
2024-07-18 | Abbreviation of Desensitization Protocol for Pediatric Patients with Lysosomal Storage Diseases Receiving Enzyme Replacement Therapy.
Lysosomal storage diseases (LSDs) constitute a group of metabolic disorders characterized by the accumulation of substrates within lysosomes. For their treatment, disease-specific enzyme replacement therapy (ERT) is employed. In cases of hypersensitivity reactions that may occur during these treatments, desensitization of enzyme therapy becomes necessary. Repeated desensitization procedures may result some degree of tolerance. This study presents cases of patients received abbreviated desensitization protocols following repeated desensitization procedures. During the period between September 2019 and January 2024, pediatric patients who experienced anaphylactic reactions to ERT and whose desensitization protocols were abbreviated after receiving uneventful treatment with desensitization for at least a year were included in the study. Six patients, four with Pompe disease, one with mucopolysaccharidosis type 2, and one with mucopolysaccharidosis type 4, had been receiving uninterrupted ERT by desensitization for at least 1 year. The mean age of the patients was 117.6 months (median: 104.5, IQR: 85.2-144). All patients experienced anaphylaxis as the initial reaction. Skin and intradermal tests were repeated on patients prior to protocol abbreviation. Premedication previously given to all patients was discontinued, and desensitization protocols were subsequently shortened by increasing the infusion rate and/or reducing the number of steps. The study investigated patients whose desensitization protocols were abbreviated. It demonstrated that some level of tolerance could be attained through repeated applications. This approach aims to identify concise, safe, and efficient protocols, thereby reducing hospitalizations, nosocomial infections, and treatment expenses.
2021-03-08 | Morquio B Disease. Disease Characteristics and Treatment Options of a Distinct GLB1-Related Dysostosis Multiplex.
Morquio B disease (MBD) is an autosomal recessive GLB1-gene-related lysosomal storage disease, presenting with a peculiar type of dysostosis multiplex which is also observed in GALNS-related Morquio A disease. MBD may present as pure skeletal phenotype (pure MBD) or in combination with the neuronopathic manifestations seen in type 2 (juvenile) or type 3 (late onset) GM1 gangliosidosis (MBD plus). The main skeletal features are progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly and odontoid hypoplasia. The main neuronopathic features are dystonia, ataxia, and intellectual/developmental/speech delay. Spinal cord compression occurs as a complication of spinal dysostosis. Chronic pain is reported, along with mobility issues and challenges with daily living and self-care activities, as the most common health concern. The most commonly reported orthopedic surgeries are hip and knee replacements. Keratan sulphate-derived oligosaccharides are characteristic biomarkers. Residual β-galactosidase activities measured against synthetic substrates do not correlate with the phenotype. W273 L and T500A are the most frequently observed GLB1 variants in MBD, W273L being invariably associated with pure MBD. Cytokines play a role in joint destruction and pain, providing a promising treatment target. In the future, patients may benefit from small molecule therapies, and gene and enzyme replacement therapies, which are currently being developed for GM1 gangliosidosis.
other
2024-07-31 | 14 A precision medicine tool for high utilization and quality of individual treatment trials with immunomodulatory drugs in mucopolysaccharidosis
The growing understanding of the innate immune response in Mucopolysaccharidosis (MPS) revealed potential targets for intervening, including the repurposing of immunomodulatory drugs. Individual treatment trials (ITT) could efficiently translate this knowledge into clinical use. However, despite the limited efficacy of approved drugs and the high level of suffering this has so far hardly been used - at least these are not reported or published. We analysed the subjective need for, utilisation of and barriers to ITT by an international MPS-expert survey. Based on that and by adapting a validated decision analysis framework (DAF) we developed an innovative, quantitative, personalizable benefit-risk assessment model to overcome barriers to ITT in MPS. Our strategy is based on the following steps i) MPS-expert survey on ITT in MPS, (ii) systematic literature review regarding relevant targets and clinical pharmacology of immunomodulatory drugs, (iii) quantitative DAF data acquisition with the creation of a framed decision context and assigning weights to relevant outcomes, (iv) enabling personali-zability by phenotypic profiling and assessing specific probabilities of expected beneficial out-comes, (v) an assessment standard for ITT with immunomodulatory drugs in MPS. These steps are in accordance with an international, interdisciplinary board of experts as well as patient representatives. Our survey (n=27) demonstrated that the majority of MPS-experts is familiar with the concept of ITT (73%), however only few ever conducted (35%) or published those (6%) reported those. A free service for data-driven treatment choices is expected to in-crease the utilization and quality of ITT by 85%. We identified Anakinra, Adalimumab, Abatacept and Cladribine as top candidates and defined first and second choices for different phenotypes. Our developed evidence-based, personalizable, quantitative DAF model for ITT characterizes the first step towards precision medicine with immunomodulatory drugs in MPS.
cell therapies
2026-09-11 | Haematopoietic stem cell transplant in a case of mucopolysaccharidosis IV with Fanconi anaemia and bone marrow failure.
Mucopolysaccharidosis type IV (MPS IV; Morquio syndrome) is a rare lysosomal storage disorder characterised by skeletal dysplasia and multisystem involvement, while Fanconi anaemia (FA) is an inherited bone marrow failure syndrome associated with chromosomal instability and hypersensitivity to conditioning agents. The coexistence of these two disorders poses a unique therapeutic challenge, particularly when haematopoietic stem cell transplantation (HSCT) is indicated. We report a child with MPS IV and FA who underwent HSCT with a non-myeloablative conditioning regimen. The procedure was carefully individualised to balance engraftment success with minimisation of toxicity. This case highlights the complexities of managing overlapping genetic conditions requiring HSCT and demonstrates the value of multidisciplinary planning and personalised transplant strategies in achieving favourable clinical outcomes.
2026-04-28 | Long-Term Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Mucopolysaccharidosis IVA: A 10-Year Follow-Up from a Single-Center Experience in China.
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potential approach for pediatric mucopolysaccharidosis IVA (MPS IVA). However, delayed diagnosis and higher transplant-related complications have limited its broader use. This study investigated treatment-related benefit and up to 10-year outcomes following HSCT in children with MPS IVA. Study Design We retrospectively analyzed 19 pediatric patients with a severe phenotype of MPS IVA who underwent HSCT between January 2015 and July 2025. N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity, height growth, and organ dysfunction (cardiac, auditory, and visual) was evaluated to analyze the benefit of HSCT. The donor sources include human leukocyte antigen (HLA)-matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT, n = 5), HLA-matched unrelated donor PBSCT (MUD-PBSCT, n = 7), and single-unit unrelated umbilical cord blood transplantation (UD-UCBT, n = 7). The overall survival rate was 94.7% (18/19), apart from 1 mortality due to pulmonary infection. All surviving patients achieved full donor engraftment and durable restoration of GALNS activity. There is no severe graft-versus-host disease (GVHD) was observed. The majority of patients exhibited no deterioration in auditory, visual, respiratory, or cardiac function. During the long-term follow-up period, our cases showed a continued linear growth post-HSCT. Here we demonstrated the data of our HSCT experience in MPS IVA with the safety and efficacy of HSCT. More data with an expanded patient cohort are imperative to delineate the capacity of HSCT to repair severe skeletal manifestations in MPS IVA.
2026-01-31 | Allogeneic Hematopoietic Cell Transplantation for Morquio A Syndrome: An International Retrospective Study.
Mucopolysaccharidosis IV A (MPS IVA) or Morquio A syndrome is a lysosomal storage disorder that results from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), causing deposition of glycosaminoglycans, keratan sulfate, and chondroitin-6-sulfate in multiple organs. The main clinical manifestations include severe short stature, severe cervical spine stenosis, and progressive skeletal dysplasia, which leads to severe mobility limitation resulting in patients becoming wheelchair-bound in their second decade of life, and overall shortened life span. The current standard of care for Morquio A is weekly enzyme replacement therapy (ERT). However, ERT is expensive, not widely available worldwide, and offers limited long-term benefits. Allogeneic hematopoietic cell transplantation (HCT) is a way to provide a life-long endogenous enzyme and has the potential to improve outcomes. The main objectives of this study were to investigate the safety and assess the benefits of allogeneic HCT in the treatment of patients with Morquio A. We performed a retrospective study of 41 patients who underwent allogeneic HCT at 9 international centers. Forty-one patients with Morquio A received allogeneic HCT. Three patients experienced graft failure and underwent second transplants. Most (77%) of the transplants were performed using either matched or mismatched unrelated donors, and 71% of the transplants utilized peripheral blood stem cells as the graft source. The overall 3-year survival rate was 90.5%. Graft-versus-host disease (GVHD) was a direct or indirect contributor to mortality in 3 out of 4 patients. The median myeloid engraftment was 100% at the last follow-up, with a median follow-up of 3 years; the median times for neutrophil and platelet engraftment were 12 and 13 days, respectively. The incidence of grade II to IV acute GVHD was 35.5%. Interestingly, in patients who had received pretransplant ERT, the incidence of acute grade II to IV GVHD was 14.9%, compared to 45% in those who had not received pretransplant ERT (P = .075). The incidence of grades III to IV acute and chronic GVHD was 14.2% and 12.7%, respectively. When available, disease-specific outcomes showed complete to near normalization of metabolic biomarkers, as well as improvement in movement scores, stability of heart function, eyes, and cervical spine stenosis. Notably, in patients transplanted below the age of 3 years, growth continued in 6 out of 8 patients, while this effect was less notable in the older cohort. Allogeneic HCT for patients with Morquio A is safe and feasible. This treatment can potentially lead to significantly improved biochemical markers of the disease, preservation of organs, and better clinical manifestations. Additionally, when performed at a young age, ideally before the age of 3 years, allogeneic HCT may result in improved growth. The use of bone marrow as a stem cell source whenever possible, combined with effective GVHD prophylaxis, may enhance transplant success and disease-related outcomes. Long-term benefits and risks require further investigation.
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.
2024-10-15 | Hematopoietic stem cell transplantation in children with mucopolysaccharidosis IVA: single center experience.
Mucopolysaccharidosis IVA (MPS IVA; Morquio syndrome) is a lysosomal storage disorder and features systemic skeletal dysplasia that is caused by defective Nacetylgalactosamine-6-sulfate sulfatase (GALNS). Although there are convincing data for hematopoietic stem cell transplantation (HSCT) in certain types of MPS, the studies are limited for MPS IVA and more data is still pending to show the efficacy/safety of HSCT. This study included 3 girls and 7 boys, with a median age of 75,5 months (35-186 months), who underwent allogeneic HSCT for severe MPS IVA between February 12, 2021, and March 10, 2023. Enzyme levels, height growth, the most involved organs (ear, eye, and heart), and the activities of daily living (ADL) scoring system were monitored to assess the benefit of HSCT. In a median follow-up of 20 months (9-34 months), there is no severe transplant-related adverse event was observed. In all cases, normal enzyme levels were reached after HSCT. During the short follow-up period, our cases showed an increase in stature and improvement in daily activity functions. Here we present the data of our HSCT experience in MPS IVA with promising results regarding both safety and efficacy. Although there are signs of amelioration with HSCT, we need more data and long-term follow-up to comment properly on the benefits of HSCT in MPS IVA.
small molecules
2026-05-04 | Development of Small-Molecule Allosteric Modulators of Beta-Galactosidase (β-Gal) for the Treatment of GM1 Gangliosidosis and Morquio B.
GM1 gangliosidosis and Morquio B are rare lysosomal storage disorders (LSDs) with significant unmet medical needs. These disorders result from mutations in the galactosidase beta 1 (GLB1) gene, leading to impaired β-galactosidase (β-Gal) activity and toxic substrate accumulation. The lack of approved disease-modifying therapies for GM1 gangliosidosis and Morquio B, along with the challenges of achieving effective central nervous system delivery, has driven interest in small-molecule pharmacological chaperones (PCs) to restore β-Gal stability and function. Using Gain Therapeutics' Magellan™ platform, a novel allosteric binding site on β-Gal was identified, enabling the discovery of a new class of Structurally Targeted Allosteric Regulators (STARs). Medicinal chemistry optimization produced a structurally unique STAR compound series, demonstrating broad β-Gal stabilizing effects. The therapeutic potential of these compounds was evaluated in vitro using a canine fibroblast model of GM1 gangliosidosis, where they were shown to significantly reduce toxic GM1 ganglioside accumulation. Immunocytochemistry-based assays confirmed substrate clearance and provided reliable structure-activity relationships, guiding further compound development. Notably, STARs achieved greater substrate clearance than the competitive PC N-nonyl-deoxygalactonojirimycin (NN-DGJ) under the conditions tested, as demonstrated by immunocytochemistry-based assays. While these findings are encouraging, further in vivo studies are required to validate the therapeutic efficacy of these few STAR compounds, particularly in addressing the neurodegenerative aspects of GM1 gangliosidosis. This study underscores the potential of the Magellan platform in identifying STAR molecules and provides a strong foundation for further optimization and preclinical validation in GLB1-related disorders, particularly GM1 gangliosidosis.
2026-03-30 | 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.
2025-03-17 | Cathepsin B inhibition blocks amyloidogenesis in the mouse models of neurological lysosomal diseases MPS IIIC and sialidosis.
Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs), including mucopolysaccharidoses (MPS); however, the molecular mechanism underlying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3- to 5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-Geo and Hgsnat P304L ) and sialidosis (Neu1 ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC, and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing thioflavin-S+, β-amyloid+ aggregates consistent with a pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (Hgsnat P304L /Ctsb -/- ) mice as well as Hgsnat P304L and Neu1 ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor E64 showed a drastic reduction in neuronal thioflavin-S+/APP+ deposits. Neurons of Hgsnat P304L /Ctsb -/- mice and E64-treated Hgsnat P304L mice also showed reduced levels of P62+, LC3+ puncta, GM2 ganglioside, and misfolded subunit C of mitochondrial ATP synthase, consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat P304L mice, implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.
2024-09-16 | AYURVEDIC MANAGEMENT OF MORQUIO SYNDROME IN A PEDIATRIC PA-TIENT – A CASE STUDY
Mucopolysaccharidosis type IV, also known as Morquio syndrome, a rare hereditary disease of autosomal recessive storage that is a progressive disease that affects the skeleton. The affected person develops various skeletal abnormalities, including height, protruding chest, scoliosis, deformed knees, and curvature of both lower limbs, which may be in Kubjata. Kubjata is one of the Vataja Nanatmaja Vikara; this comes under Janmabala Pravrutta Vyadhi. In this case Abhyanga, Swedana, Mridu Virechana and Basti for 25 days along with a combination of oral medicines such as Trayodashanga guggulu-500 mg, Dashmool kwatha 20 ml, Shiva gutika 500 mg twice per day have been showing that Ayurvedic herbs along with Panchakarma, can play a major role in the management of Morquio syndrome to improve the quality of life and prognosis of the disease.
2024-02-19 | Evidence of epigenetic landscape shifts in mucopolysaccharidosis IIIB and IVA.
Lysosomal storage diseases (LSDs) are a group of monogenic diseases characterized by mutations in genes coding for proteins associated with the lysosomal function. Despite the monogenic nature, LSDs patients exhibit variable and heterogeneous clinical manifestations, prompting investigations into epigenetic factors underlying this phenotypic diversity. In this study, we focused on the potential role of epigenetic mechanisms in the pathogenesis of mucopolysaccharidosis IIIB (MPS IIIB) and mucopolysaccharidosis IVA (MPS IVA). We analyzed DNA methylation (5mC) and histone modifications (H3K14 acetylation and H3K9 trimethylation) in MPS IIIB and MPS IVA patients' fibroblasts and healthy controls. The findings revealed that global DNA hypomethylation is present in cell lines for both diseases. At the same time, histone acetylation was increased in MPS IIIB and MPS IVA cells in a donor-dependent way, further indicating a shift towards relaxed open chromatin in these MPS. Finally, the constitutive heterochromatin marker, histone H3K9 trimethylation, only showed reduced clustering in MPS IIIB cells, suggesting limited alterations in heterochromatin organization. These findings collectively emphasize the significance of epigenetic mechanisms in modulating the phenotypic variations observed in LSDs. While global DNA hypomethylation could contribute to the MPS pathogenesis, the study also highlights individual-specific epigenetic responses that might contribute to phenotypic heterogeneity. Further research into the specific genes and pathways affected by these epigenetic changes could provide insights into potential therapeutic interventions for these MPS and other LSDs.
gene therapies
2026-03-05 | Development and characterization of a model of mucopolysaccharidosis type IVA for evaluating therapies targeting bone disease.
Mucopolysaccharidosis type IVA (MPSIVA) is a lysosomal storage disease (LSD) caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which causes the accumulation of keratan sulphate (KS) and chondroitin sulphate (CS). Patients with MPSIVA typically present with severe skeletal and joint disorders, which are not addressed by conventional therapies. Currently, no animal model accurately replicates the human disease, hindering the development of novel therapeutic interventions. To overcome this limitation, we established, by CRISPR-Cas9 technology, a Galns-/- mouse model that expresses a non-functional enzyme and accumulates CS and KS in the urine, plasma and distinct tissues, and glycosaminoglycans in the spleen. The mice exhibit shortened long bones, trabecular bone alterations and skeletal abnormalities in the growth plate. Additionally, we observed increased levels of inflammatory and oxidative markers in visceral organs and plasma. Our newly developed model of MPSIVA demonstrates clear and quantifiable signs of skeletal alterations, providing novel means of assessment of the safety and efficacy of innovative therapies, including hematopoietic stem and progenitor cell gene therapy, which has recently been shown to provide a beneficial effect on skeletal alterations in Hurler syndrome.
2026-01-30 | Collagen Type II-Targeting Lentiviral Gene Therapy for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis (MPS IVA) is caused by pathogenic variations in the GALNS gene, leading to the accumulation of glycosaminoglycans in tissues and causing progressive skeletal lesions. While conventional lentiviral vectors (LVs) provide long-term stable expression, they do not deliver therapeutic levels to bone and cartilage. We hypothesized that engineering the LV envelope with a collagen type II-targeting peptide (WYRGRL) increases the binding affinity of the LVs for bone and cartilage. These modified vectors carrying the CBh and COL2A1 promoters delivered the GALNS gene to MPS IVA newborn mice via intravenous (IV) or intraarticular (IA) administration. The peptide-modified LVs exhibited markedly increased uptake in the liver when administered IV, but lower enzyme activity than that of the conventional vector. The modified WYRGRL-LV-COL2A1 vector elevated GALNS activity in other tissues, suggesting systemic benefits. When administered IA, the modified vectors showed potential for local treatment due to the WYRGRL peptide-mediated uptake. Additionally, there was a reduction in keratan sulfate glycosaminoglycan levels in plasma and tissues, indicating that this peptide can be a suitable candidate for disease modification. These findings pave the way for further preclinical and clinical studies, offering new possibilities for the development of targeted therapies for skeletal diseases.
2025-11-22 | "Comprehensive Clinical Evaluation And Management Of Congenital Mucopolysacchariodosos type IVA: A Case Report"
This report outlines a brief clinical description of a 2-year-old boy diagnosed with Morquio syndrome (Mucopolysaccharidosis type IVA), a rare autosomal recessive lysosomal storage disorder. The disease results from a deficiency of the N-acetyl-galactosamine-6-sulfatase enzyme, causing the buildup of glycosaminoglycans. This accumulation leads to congenital malformations, disproportionate short stature, significant skeletal deformities, and multisystem involvement, while cognitive function generally remains intact. The case underscores the significance of early recognition, treatment options such as enzyme replacement therapy with Elosulfase alfa, and the necessity of comprehensive multidisciplinary management, genetic counseling, and regular follow-up. It further discusses diagnostic difficulties and explores emerging treatment strategies like gene therapy for managing these progressive hereditary metabolic conditions.
2025-10-15 | Recent advances in mucopolysaccharidosis IVA treatment.
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare lysosomal storage disorder caused by mutations in the GALNS gene, resulting in N-acetylgalactosamine-6-sulfatase (GALNS) deficiency and accumulation of keratan sulfate and chondroitin-6-sulfate. MPS IVA primarily affects the skeletal system, leading to progressive dysplasia and multi-organ involvement. Although enzyme replacement therapy (ERT) with elosulfase alfa is currently the only approved treatment, its clinical benefit on bone pathology is limited due to rapid clearance and poor penetration into avascular cartilage. Strategies to enhance enzyme stability and targeting, such as PEGylated hydrogels and extracellular vesicles, have shown promise in enhancing the biodistribution and stability of GALNS, while pharmacological chaperones, including ezetimibe, pranlukast, and bromocriptine, seem to stabilize GALNS in vitro. Promisingly, gene therapy (GT) has demonstrated significant preclinical progress using adeno-associated virus (AAV), lentiviral (LV), and CRISPR/Cas9 platforms. For instance, AAV vectors employing bone-targeting peptides and tandem promoters improve skeletal manifestations in murine and rat models. Similarly, recent ex vivo LV-based GT studies have opened new avenues in the treatment of MPS IVA. Furthermore, CRISPR/nCas9-based strategies targeting safe harbor loci have successfully restored GALNS activity in MPS IVA fibroblasts and mouse models supporting the notion that gene editing may represent a potential therapeutic approach. On the other hand, antisense-based therapies using modified U7 small nuclear RNAs and circular RNAs offer novel approaches to correct pseudoexon activation from deep-intronic variants while expanding the therapeutic alternatives in MPS IVA. Importantly, recent evidence revealed that mitochondrial dysfunction in chondrocytes may contribute to the pathology of MPS IVA, uncovering new targets beyond GALNS enzyme activity recovery. This review highlights recent advances in the treatment of MPS IVA and discusses new directions to improve outcomes in MPS IVA treatment.
2025-07-29 | Integrase-Deficient Lentiviral Vector as a Platform for Efficient CRISPR/Cas9-Mediated Gene Editing for Mucopolysaccharidosis IVA.
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder causing systemic skeletal dysplasia due to a deficiency of N-acetyl-galactosamine-6-sulfate sulfatase (GALNS) enzyme activity, leading to the impaired degradation and accumulation of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate. While treatments such as enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available, they have significant limitations regarding efficacy in skeletal tissues and long-term safety, highlighting the need for more effective therapies. We evaluated a novel gene therapy approach using a dual Integrase-deficient lentiviral vector (IDLV) to deliver an expression cassette that includes human GALNS cDNA and Cas9 sgRNA, targeting the upstream region of the mouse Galns initial codon. This approach leverages the endogenous promoter to drive transgene expression. We assessed in vitro transduction, editing, and functional correction in NIH3T3 and MPS IVA mouse fibroblasts. In vivo efficacy was successfully evaluated via the facial vein injection in MPS IVA newborn mice. In vitro, this IDLV platform demonstrated supraphysiological GALNS activity in cell lysate, resulting in the normalization of KS levels. In vivo direct IDLV platform in newborn MPS IVA mice led to sustained plasma GALNS activity, reduced plasma KS, and favorable biodistribution. Partial correction of heart and bone pathology was observed, with no vector toxicity and minimal antibody responses. This dual IDLV-CRISPR/Cas9 approach effectively mediated targeted GALNS knock-in, yielding sustained enzyme activity, reduced KS storage, and partial pathological amelioration in MPS IVA mice. In conclusion, IDLVs represent an efficient, safe platform for delivering the CRISPR/Cas9 gene editing system for MPS IVA.
proteins
2026-07-27 | Early Versus Late Enzyme Replacement Therapy in Siblings With Morquio A Syndrome: Insights Into Therapeutic Timing.
Enzyme replacement therapy (ERT) with elosulfase alfa is the only approved treatment for mucopolysaccharidosis type IVA. This case report delineates the 5-year outcomes of ERT in two Korean siblings with mucopolysaccharidosis type IVA, with the younger sibling initiating treatment at 0.8 years of age and the older one at 5.4 years. Both patients exhibited a progressive decline in their height standard deviation scores, with trajectories paralleling the natural history curves of the disease. At 5.2 years of age, persistent skeletal dysplasia was evident in both siblings. However, the younger sibling demonstrated attenuated disease severity, lacking cervical myelopathy or spinal stenosis requiring C1 laminoplasty. Cardiorespiratory assessment revealed normalized left ventricular mass index z-scores, stable ejection fractions, and the absence of valvular pathology. Overall, these findings suggest that early ERT attenuates severe spinal and upper body manifestations but does not prevent lower limb skeletal progression, highlighting the need for early therapeutic initiation along with orthopedic intervention to preserve cardiorespiratory parameters and functional independence.
2026-03-14 | AAV Gene Therapy for MPS IVA with Induction of Immune Tolerance via Oral Administration of Epitope Peptides of N-Acetylgalactosamine-6-sulfate Sulfatase.
Mucopolysaccharidosis IVA (MPS IVA) is caused by the accumulation of undegraded glycosaminoglycans due to the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme. MPS IVA manifests as progressive systemic skeletal dysplasia. Gene therapy (GT) is potentially a one-time treatment in which the enzyme is continuously produced, circulated, and delivered to target tissues. However, immune responses to gene products can diminish therapeutic efficacy. We hypothesized that oral delivery of tolerogenic peptides induces immune tolerance to human GALNS (hGALNS) in MPS IVA mice, enhancing therapeutic efficacy. Neonatal mice deficient in mouse GALNS (mGALNS) were treated orally with three T-cell/B-cell epitope peptides or hGALNS protein on alternate days from day 3 after birth to day 20 before intravenous injection with AAV9 vectors encoding human GALNS on day 30. The results are encouraging, with anti-hGALNS antibodies undetectable in the plasma of orally administered peptide groups. hGALNS enzyme activities in plasma and tissues were higher in the orally treated groups than in the non-tolerized control group. Keratan sulfate levels in plasma, liver, and bone were normalized. Complete correction for heart vacuolization was achieved in peptide-treated groups, and partial correction for bone pathology was observed in all GT-treated groups. Overall, oral tolerance induction using immunodominant peptides promises to significantly enhance the efficacy of AAV-GT for MPS IVA.
2026-01-01 | Development of national biobank for lysosomal storage disorders in India- a step towards advancing research and precision medicine
Abstract Background Lysosomal storage disorders (LSDs) are a diverse group of over 70 rare, inherited metabolic conditions that present significant diagnostic and therapeutic challenges, especially in genetically diverse and resource-limited settings like India. To address the lack of a centralized clinical and genomic data registry for LSDs, we established the first government-supported national LSDs biobank in India. This study describes the infrastructure, sample collection, storage procedures, ethical framework, and expected impact of the biobank on research, diagnostics, and patient care. Methods The study includes biological samples and clinical-genetic data from 530 patients, (526 unrelated individuals and 2 sibling pairs), over a 17-year period (2008–2025). Biological samples including genomic DNA from blood, plasma, and urine precipitate were processed for enzyme and genetic investigations. A centralized webpage has been established to manage the biological sample data including clinical, enzyme and genetic data. Results The LSD biobank cohort encompasses 8 LSD subgroups across 27 disorders, with the most common being Gaucher disease (n = 70), Tay-Sachs disease (n = 62), Mucolipidosis (ML) II/III (n = 44), and Morquio-A (n = 40). Samples originated from 15 Indian states, with a predominance of pediatric cases. Detailed phenotypic, enzymatic, and genomic profiles were generated. Enzyme assays confirmed markedly reduced activity in most cases, with variable residual activity noted in few LSDs. Genetic analyses using Sanger sequencing, PCR-RFLP, targeted gene panel sequencing, and/ or whole exome sequencing detected causative variants. Notably, c.1469T > C in the IDUA gene (29.4% in Hurler disease), c.230 C > G in the GALNS gene (22.5% in Morquio-A disease), c.1448T > C in the GBA1 gene (56% in Gaucher disease), and c.1385 C > T and c.964G > T in the HEXA gene (11.3% and 8.1% respectively in Tay-Sachs disease) were the most common variants. Several novel, private mutations were also identified, broadening the mutational landscape of LSDs. Conclusion The present study represents a scalable model for rare disease research in low- and middle-income countries. This resource lays the foundation for genotype–phenotype correlation studies, natural history analyses, and future precision medicine strategies tailored to the Indian population.
2024-07-18 | Abbreviation of Desensitization Protocol for Pediatric Patients with Lysosomal Storage Diseases Receiving Enzyme Replacement Therapy.
Lysosomal storage diseases (LSDs) constitute a group of metabolic disorders characterized by the accumulation of substrates within lysosomes. For their treatment, disease-specific enzyme replacement therapy (ERT) is employed. In cases of hypersensitivity reactions that may occur during these treatments, desensitization of enzyme therapy becomes necessary. Repeated desensitization procedures may result some degree of tolerance. This study presents cases of patients received abbreviated desensitization protocols following repeated desensitization procedures. During the period between September 2019 and January 2024, pediatric patients who experienced anaphylactic reactions to ERT and whose desensitization protocols were abbreviated after receiving uneventful treatment with desensitization for at least a year were included in the study. Six patients, four with Pompe disease, one with mucopolysaccharidosis type 2, and one with mucopolysaccharidosis type 4, had been receiving uninterrupted ERT by desensitization for at least 1 year. The mean age of the patients was 117.6 months (median: 104.5, IQR: 85.2-144). All patients experienced anaphylaxis as the initial reaction. Skin and intradermal tests were repeated on patients prior to protocol abbreviation. Premedication previously given to all patients was discontinued, and desensitization protocols were subsequently shortened by increasing the infusion rate and/or reducing the number of steps. The study investigated patients whose desensitization protocols were abbreviated. It demonstrated that some level of tolerance could be attained through repeated applications. This approach aims to identify concise, safe, and efficient protocols, thereby reducing hospitalizations, nosocomial infections, and treatment expenses.
2021-03-08 | Morquio B Disease. Disease Characteristics and Treatment Options of a Distinct GLB1-Related Dysostosis Multiplex.
Morquio B disease (MBD) is an autosomal recessive GLB1-gene-related lysosomal storage disease, presenting with a peculiar type of dysostosis multiplex which is also observed in GALNS-related Morquio A disease. MBD may present as pure skeletal phenotype (pure MBD) or in combination with the neuronopathic manifestations seen in type 2 (juvenile) or type 3 (late onset) GM1 gangliosidosis (MBD plus). The main skeletal features are progressive growth impairment, kyphoscoliosis, coxa/genua valga, joint laxity, platyspondyly and odontoid hypoplasia. The main neuronopathic features are dystonia, ataxia, and intellectual/developmental/speech delay. Spinal cord compression occurs as a complication of spinal dysostosis. Chronic pain is reported, along with mobility issues and challenges with daily living and self-care activities, as the most common health concern. The most commonly reported orthopedic surgeries are hip and knee replacements. Keratan sulphate-derived oligosaccharides are characteristic biomarkers. Residual β-galactosidase activities measured against synthetic substrates do not correlate with the phenotype. W273 L and T500A are the most frequently observed GLB1 variants in MBD, W273L being invariably associated with pure MBD. Cytokines play a role in joint destruction and pain, providing a promising treatment target. In the future, patients may benefit from small molecule therapies, and gene and enzyme replacement therapies, which are currently being developed for GM1 gangliosidosis.
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2024-07-31 | 14 A precision medicine tool for high utilization and quality of individual treatment trials with immunomodulatory drugs in mucopolysaccharidosis
The growing understanding of the innate immune response in Mucopolysaccharidosis (MPS) revealed potential targets for intervening, including the repurposing of immunomodulatory drugs. Individual treatment trials (ITT) could efficiently translate this knowledge into clinical use. However, despite the limited efficacy of approved drugs and the high level of suffering this has so far hardly been used - at least these are not reported or published. We analysed the subjective need for, utilisation of and barriers to ITT by an international MPS-expert survey. Based on that and by adapting a validated decision analysis framework (DAF) we developed an innovative, quantitative, personalizable benefit-risk assessment model to overcome barriers to ITT in MPS. Our strategy is based on the following steps i) MPS-expert survey on ITT in MPS, (ii) systematic literature review regarding relevant targets and clinical pharmacology of immunomodulatory drugs, (iii) quantitative DAF data acquisition with the creation of a framed decision context and assigning weights to relevant outcomes, (iv) enabling personali-zability by phenotypic profiling and assessing specific probabilities of expected beneficial out-comes, (v) an assessment standard for ITT with immunomodulatory drugs in MPS. These steps are in accordance with an international, interdisciplinary board of experts as well as patient representatives. Our survey (n=27) demonstrated that the majority of MPS-experts is familiar with the concept of ITT (73%), however only few ever conducted (35%) or published those (6%) reported those. A free service for data-driven treatment choices is expected to in-crease the utilization and quality of ITT by 85%. We identified Anakinra, Adalimumab, Abatacept and Cladribine as top candidates and defined first and second choices for different phenotypes. Our developed evidence-based, personalizable, quantitative DAF model for ITT characterizes the first step towards precision medicine with immunomodulatory drugs in MPS.
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Drug Discovery Landscape
1 orphan drug designation for Mucopolysaccharidosis type 4.
1 orphan drug designation for Mucopolysaccharidosis type 4.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase | proteins | FDA | — | Vivendy Therapeutics LTD |
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