RARE DISEASE
Mucopolysaccharidosis type 1
Mucopolysaccharidosis type 1
Mucopolysaccharidosis type 1
Synonyms: Alpha-L-iduronidase deficiency, MPS1, Mucopolysaccharidosis type I
Synonyms: Alpha-L-iduronidase deficiency, MPS1, Mucopolysaccharidosis type I
Synonyms: Alpha-L-iduronidase deficiency, MPS1, Mucopolysaccharidosis type I
Drug discovery
26
drugs
With orphan designations
Overview
Mucopolysaccharidosis type 1 (MPS I) is an autosomal recessive lysosomal storage disorder caused by α-L-iduronidase deficiency, leading to systemic accumulation of glycosaminoglycans (GAGs). The disease spectrum includes severe (Hurler syndrome), intermediate (Hurler-Scheie), and attenuated (Scheie) forms, with multi-organ involvement ranging from skeletal dysplasia and neurocognitive decline in severe cases to corneal clouding and cardiorespiratory complications in milder forms [1][6][10]. Current management relies on early hematopoietic stem cell transplantation (HSCT) for neuroprotection in severe cases and enzyme replacement therapy (ERT) for somatic symptoms [1][9][15].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
639 drug discovery papers about Mucopolysaccharidosis type 1, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
639 drug discovery papers about Mucopolysaccharidosis type 1, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-25 | RNA activation as a precision dosing modality: MTL-CEBPA for controlled enzyme elevation in MPS I-H.
Gene therapy and hematopoietic stem cell transplantation (HSCT) have transformed outcomes for severe mucopolysaccharidosis type I (MPS I-H), yet a critical unmet need remains. Children with MPS I-H frequently experience progressive skeletal, cardiac, and other complications despite timely HSCT, largely because enzyme activity cannot be safely and precisely titrated over time. Irreversible genetic modification via integrating vectors offers supra-physiological enzyme levels but carries long-term safety and re-dosing liabilities in patients treated early in life. We investigated RNA activation (RNAa) as a precision dosing strategy to enhance endogenous IDUA expression without permanent genome alteration. Using MTL-CEBPA, a small activating RNA that upregulates CEBPA transcription factor, we characterized CEBPA-IDUA relationships in vitro, in vivo, and in legacy clinical samples from cancer patients. CCAAT enhancer binding protein alpha activation consistently increased IDUA mRNA across A549, IMR90, and mesenchymal stem cells. In wild-type mice, two intravenous MTL-CEBPA doses produced a ∼2-fold, durable increase in bone marrow IDUA mRNA and plasma enzyme activity, sustained for up to 4 weeks. In humanized bone marrow-transplanted MPS I-H mice, repeated dosing with MTL-CEBPA led to an approximately 2-fold increase in circulating IDUA activity compared with controls over the 3-weeks treatment period. The largest apparent separation from controls was observed in the homozygous cohort, although these genotype-specific differences should be interpreted cautiously given the limited subgroup sizes. In cancer patient-derived monocytes, increased CEBPA protein levels correlated with higher IDUA levels (R2 = 0.571). Consistent with this, approximately half of evaluable patients exhibited increased plasma IDUA activity following treatment. These translational data demonstrate that MTL-CEBPA delivers controlled, reversible enhancement of IDUA in the context of HSCT, providing robust pharmacodynamic proof-of-concept rather than definitive evidence of durable efficacy. By enabling titratable enzyme elevation without integrating vectors, RNAa therapeutics address a key unmet need in Hurler syndrome: safe fine-tuning of residual enzyme activity over a patient's lifetime. With scalable, cost-effective oligonucleotide manufacturing, MTL-CEBPA and related RNAa therapeutics represent a clinically relevant adjuvant strategy for HSCT-treated MPS I-H, with potential for other enzyme deficiency disorders.
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.
2025-08-21 | RNA Activation of CEBPA in PBMCs Enhances α-L-Iduronidase Expression A Translational Adjuvant Therapy for MPS I After Bone Marrow Transplantation
Background Hurler syndrome, the most severe form of mucopolysaccharidosis type I (MPS I), is a rare genetic disorder caused by mutations in the IDUA gene, leading to a deficiency of the α-L-iduronidase enzyme. While current treatments offer some benefits, there remains a significant unmet medical need. We have identified a potential new therapeutic approach using MTL-CEBPA, a drug that upregulates the transcription factor CEBPA, which in turn regulates IDUA expression. Results In vitro studies demonstrated significant upregulation of IDUA in various cell lines following MTL-CEBPA treatment. In vivo experiments in both wild-type and MPS I mouse models showed a two-fold increased IDUA expression and enzyme activity for up to four weeks after a single dose. Analysis of archival samples from cancer patients treated with MTL-CEBPA revealed a correlation between increased CEBPA expression and IDUA expression, with approximately half of the patients showing elevated plasma IDUA enzyme activity post-treatment. Conclusions These findings provide proof-of-concept evidence supporting the potential use of MTL-CEBPA as a treatment for MPS I patients. We propose that this therapeutic oligonucleotide approach offers a favourable safety profile, allowing for multiple dosing to maintain elevated IDUA enzyme activity in bone marrow transplanted patients over extended periods, potentially addressing the limitations of current treatments and improving patient outcomes.
2025-04-28 | Genetic variations in the IDUA gene in Tunisian MPS I families: Identification of a novel microdeletion disrupting substrate binding and structural insights.
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by a deficiency in alpha-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans. MPS I presents with a broad spectrum of clinical phenotypes, ranging from severe to mild. This study aimed to identify genetic mutations in the IDUA gene among Tunisian families and assess their structural and functional implications. Genomic DNA was extracted from blood samples of four patients including two siblings from three Tunisian families. Polymerase chain reaction (PCR) followed by Sanger sequencing was performed to identify mutations in the IDUA gene. Bioinformatics tools, including the SWISS-MODEL server and DynaMut, were used for structural modeling and to predict the impact of the mutations on protein stability and flexibility. Two mutations in the IDUA gene were identified. A novel deletion mutation p.His356_Gln362del was discovered in two patients with severe MPS I phenotypes, while a previously reported missense mutation p.Pro533Arg was found in two patients with intermediate and mild phenotypes. Structural analysis revealed that the novel deletion disrupts the protein's substrate-binding site. This deletion causes structural deformation and leads to the elimination of the substrate binding site, resulting in a complete loss of enzymatic activity.The missense mutation p.Pro533Arg affects the stability and flexibility of the protein, likely reducing substrate affinity. This substitution results in the introduction of a bulkier amino acid, requiring more space in the contact region between the β-sheet structure and the substrate-bound helix. This study reports a novel deletion mutation in the IDUA gene in Tunisian MPS I patients, alongside a previously described mutation. The findings enhance understanding of the molecular basis of MPS I and provide insights into the structural effects of these mutations, which could aid in future diagnosis and therapeutic strategies. Future studies should explore the prevalence of the reported mutations in larger cohorts and investigate targeted therapies, such as pharmacological chaperones, to rescue enzymatic activity in patients carrying such mutations.
2025-01-01 | Bilateral Foveal Cysts in Mucopolysaccharidosis Type I (Hurler Syndrome): Response to Acetazolamide With Insights From Multimodal Retinal Imaging and Electrophysiology
Objective The aim of this study is to report a case of bilateral foveal cysts in MPS I‐H resolving with oral acetazolamide and to highlight the diagnostic value of multimodal retinal imaging and electrophysiological testing. Introduction Hurler syndrome (mucopolysaccharidosis Type I‐H) is a lysosomal storage disorder that can cause progressive multisystem complications. Retinal involvement often mimics retinitis pigmentosa (RP), and pathology may progress even after early hematopoietic stem cell transplantation (HSCT) due to limited enzyme penetration into ocular tissues. Case Summary A 17‐year‐old female with MPS I‐H, post‐HSCT at 21 months, presented with bilateral visual decline despite a normal clinical fundus exam. Evaluation included spectral‐domain OCT (SD‐OCT), fundus autofluorescence (FAF), multifocal electroretinography (mfERG), full‐field ERG (ffERG), and visual evoked potential. SD‐OCT revealed bilateral intraretinal foveal cysts without leakage on fluorescein angiography. FAF showed a bull′s eye maculopathy pattern; mfERG showed bilateral macular dysfunction. ffERG revealed rod–cone dystrophy. Two 3‐month courses of oral acetazolamide (125 mg three times daily) led to complete cyst resolution and visual improvement. Conclusion This case supports the role of systemic carbonic anhydrase inhibitors in treating nonleaking macular cysts in MPS I, similar to RP‐related cystoid macular pathologies, and highlights the value of integrating electrophysiological and multimodal imaging, especially in occult retinal disease.
cell therapies
2026-08-05 | First bone marrow transplantation for mucopolysaccharidosis type I in Vietnam: a case report.
Mucopolysaccharidosis type I (MPS-I) is an inherited lysosomal storage disorder characterized by alpha-L-iduronidase deficiency, leading to progressive multi-organ damage and fatal complications. Early treatment is crucial to improve outcomes, particularly in patients with severe phenotypes. We present the first case of successful allogeneic bone marrow transplantation (BMT) for MPS-I in Vietnam. A 10-month-old girl experienced coarse facial features, congenital dermal melanocytosis spots, kyphoscoliosis developmental delay. Laboratory analyses revealed reduced alpha-L-iduronidase activity and elevated urinary glycosaminoglycans, genetic mutations identified two heterozygous mutations in the IDUA gene, confirmed the diagnosis of MPS-I. At 3 years old, she underwent allogeneic BMT from an HLA-matched sibling donor following conditioning regimen with busulfan, cyclophosphamide, antithymocyte globulin. Neutrophil engraftment was achieved on day +24, and platelet engrafted on day +32. The post-transplant course was complicated by respiratory deterioration requiring 5 days of mechanical ventilation, which was promptly managed and resolved. No graft-versus-host disease occurred. Post-transplant chimerism showed 95.77% donor-derived cells on day +30 and remained stable at 100% from 2 months. The patient demonstrated improvement in clinical symptoms, accompanied by alpha-L-iduronidase activity returned to normal range, urinary glycosaminoglycan levels decreased and remained stable during follow-up. At 12 months, she demonstrated complete immune reconstitution. This case suggests that allogeneic BMT may be a therapeutic approach for patients with MPS-I in resource-limited settings.
2026-02-09 | Carpal tunnel syndrome in mucopolysaccharidosis type I: clinical, surgical and histopathological findings.
Mucopolysaccharidosis type I is a rare metabolic disorder characterized by the accumulation of glycosaminoglycans, leading to musculoskeletal disorders such as carpal tunnel syndrome. This retrospective cohort study was performed to determine the prevalence and timing of the development of carpal tunnel syndrome, assess the efficacy of surgery on recurrence and the effect of haematopoietic stem cell transplantation in resolving accumulated degradation products. Thirty-three mucopolysaccharidosis type I patients, born between 2001 and 2023, were included in this study. They received annual screening and treatment at our specialist hospital. Patient demographics, clinical symptoms of carpal tunnel syndrome pre- and post-carpal tunnel release and histopathological sections of the flexor retinaculum were collected. Regression analyses were conducted to assess cumulative risks and determine hazard ratios and survival curves were plotted. Twenty-seven of 33 mucopolysaccharidosis type I patients, with a median age at the latest follow-up of 13 years (IQR 7.7 to 18.3), were diagnosed with carpal tunnel syndrome on electrophysiological tests or ultrasound at a median age of 3.6 years (IQR 2.8 to 5.2). Only a few patients exhibited clinical symptoms. Twenty-one patients underwent carpal tunnel release and 13 patients experienced recurrence. The highest risk of developing carpal tunnel syndrome was within the first 6 years of life. Eight of the 11 patients accumulated degradation products within lysosomes despite successful haematopoietic stem cell transplantation. In this study, 27 mucopolysaccharidosis type I patients were diagnosed with carpal tunnel syndrome, showing a high-risk window from 0 to 6 years of age. Recurrence of carpal tunnel syndrome after carpal tunnel release surgery was common, occurring in 61.9% of patients. III.
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.
2025-01-07 | Human iPSC-derived neural stem cells engraft and improve pathophysiology of MPS I mice.
Mucopolysaccharidosis type I (MPS I) is a metabolic disorder characterized by a deficiency in α-l-iduronidase (IDUA), leading to impaired glycosaminoglycan degradation. Current approved treatments seek to restore IDUA levels via enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). The effectiveness of these treatment strategies in preventing neurodegeneration is limited due to the inability of ERT to penetrate the blood-brain barrier (BBB) and HSCT's limited CNS reconstitution of IDUA levels. We reprogrammed human cord blood cells into induced pluripotent stem cells (iPSCs), differentiated them into human induced neural stem cells (hiNSCs), and sorted them using fluorescence-activated cell sorting (FACS). Our in vitro studies showed that these hiNSCs can migrate and cross-correct IDUA deficiency. Purified hiNSCs were then transplanted into neonatal immunodeficient MPS I mice (Idua -/- ). Analysis of brain tissue obtained 8 months after transplantation showed partially restored IDUA activity, with distribution and differentiation of engrafted hiNSCs throughout the brain into glial cell types. The presence of engrafted hiNSCs was associated with decreased levels of biomarkers commonly elevated in the Idua -/- mouse brain, such as β-hexosaminidase, CD68, and LAMP1, suggesting physiological efficacy. These results highlight the potential of hiNSCs for use as a patient-specific cellular therapy for MPS I.
2024-11-13 | Prolonged catamnesis of a child with type I mucopolysaccharidosis, Gurler syndrome, receiving enzyme replacement therapy
Hereditary pathology makes up a significant part of the structure of childhood morbidity, disability and mortality. Mucopolysaccharidosis type I is a hereditary lysosomal accumulation disease, with an autosomal recessive type of inheritance. At birth, children with Gurler syndrome look normal, but in the future, they develop symptoms characteristic of mucopolysaccharidosis, and the first clinical manifestations of the disease are often hernias and hepatosplenomegaly. The presented clinical case demonstrates the difficulties of early diagnosis of mucopolysaccharidosis type I, which lead to a later prescription of enzyme replacement therapy and the inability to use a more effective method of therapy – hematopoietic stem cell transplantation, due to the development of serious manifestations of the cardiovascular system. While the positive effects of enzyme replacement therapy in the early stages of treatment may seem promising, it does not guarantee a favorable prognosis for the future. Conclusion. Currently, early diagnosis of mucopolysaccharidosis type I is difficult due to the lack of early manifestations. Often, the progression of clinical manifestations leads to disability, and in severe cases, to death. Therefore, it is important to have early diagnosis and appropriate treatment.
gene therapies
2026-03-28 | Liposomal CRISPR/Cas9-Mediated Local Genome Editing for Joint Disease in Mucopolysaccharidosis Type I.
Background/Objectives: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase (IDUA) deficiency, leading to progressive glycosaminoglycan (GAG) accumulation and severe joint involvement. Gene editing represents a promising alternative to restore localized enzyme production. Therefore, this study aimed to evaluate the feasibility, efficacy, and safety of in situ genome editing through intra-articular administration of a nonviral CRISPR/Cas9 system to increase localized IDUA expression in an MPS I mouse model. Methods: Cationic liposomes were formulated to deliver plasmids encoding the CRISPR/Cas9 system targeted to the ROSA26 locus along with an IDUA donor sequence. In vitro assays were performed in fibroblast-like synoviocytes (FLSs) isolated from MPS I mice to assess cytotoxicity, gene editing efficiency, and IDUA activity. In vivo, MPS I mice received intra-articular injections in the knee joints, either as a single dose (short-term study) or monthly for three months (long-term study). IDUA activity, GAG levels, and genome editing efficiency were evaluated in joint tissues, synovial fluid, serum, and major organs. Results: Gene-edited FLS showed sustained IDUA activity for up to 30 days with low cytotoxicity. In vivo, intra-articular administration resulted in a significant increase in IDUA activity in joint tissue and synovial fluid without detectable systemic IDUA. Long-term treatment led to persistent joint-localized IDUA activity, significant reductions (>50%) in GAG levels, and detectable genome editing in joint DNA. Conclusions: Intra-articular delivery of CRISPR/Cas9 via cationic liposomes enables safe and effective localized genome editing, representing a promising strategy for treating joint manifestations of MPS I.
2025-12-11 | Comparative evaluation of liver-directed knockin strategies with viral and nonviral vectors in mouse inherited disease models.
CRISPR-Cas9-mediated gene knockin has emerged as a promising strategy for early-onset genetic disease intervention. However, the therapeutic efficacy and editing outcomes of different knockin strategies remain incompletely understood. Here, we systematically evaluated three major liver-directed knockin strategies, namely homology-directed repair (HDR), homology-independent targeted integration (HITI), and homology-mediated end joining (HMEJ), using neonatal mouse models of mucopolysaccharidosis type I and hemophilia B. Although all three approaches effectively rescued disease phenotypes, we observed distinct editing outcomes. Notably, the HMEJ approach, delivered via a combined adeno-associated virus-lipid nanoparticle (AAV-LNP) system, exhibited superior integration efficiency (5.8%-5.9%) and fidelity (97%-98%) compared with HDR and HITI. In contrast, whole-genome sequencing indicated that HITI induced a higher risk of random AAV donor integration than HDR or HMEJ. Furthermore, long-read sequencing analyses revealed that the frequencies of inverted terminal repeat (ITR)-mediated transgene integration differed between the 5' and 3' genomic junctions among the three strategies. Specifically, in HDR- and HMEJ-treated mice, ITR-mediated integration events were 7.7- to 19.7-fold more common at the 3' junctions than at the 5' junctions. These findings highlight the comprehensive advantages of the AAV-LNP-mediated HMEJ approach for liver-directed knockin therapy and suggest its strong potential for clinical translation.
2025-11-21 | New approaches to the diagnosis and treatment of mucopolysaccharidos type I in children: A clinical case of Hurler syndrome in a young child
Hurler syndrome is the most severe form of mucopolysaccharidosis type I (MPS I). This is a metabolic genetic disorder caused by mutations in the IDUA gene, which encodes the α-L-iduronidase enzyme. Despite its rarity, timely diagnosis is critical. Current treatments for MPS I include enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (HSCT). Intravenous ERT, such as laronidase, although being widely used, exhibits limited effectiveness due to its inability to cross the blood–brain barrier, thus failing to halt neurological deterioration. HSCT remains the gold standard, particularly when performed before age 2, prior to developing severe clinical manifestations. Early HSCT allows better preservation of cognitive functions and mitigation of somatic symptoms, although carrying risks of complications and not guaranteeing complete recovery. These limitations underscore the need for innovative strategies, including improved early screening methods and genetic engineering technologies. Gene therapy (GT) is a promising approach, having the potential for sustained enzyme production to address the underlying deficiency.
2025-09-29 | Non-neurological, non-skeletal outcomes after hematopoietic stem and progenitor cell-gene therapy (OTL-203) for Hurler syndrome.
Patients with mucopolysaccharidosis type I Hurler (MPSIH) experience multisystem clinical manifestations, which are only partially addressed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study evaluated outcomes from a lentiviral vector-mediated hematopoietic stem and progenitor cell-gene therapy (HSPC-GT) trial (NCT03488394) in eight MPSIH patients followed up to 4 years post-treatment. Key findings included corneal clouding, hearing loss (HL), carpal tunnel syndrome (CTS), and cardiac evaluations. A retrospective comparison with an external cohort of nine MPSIH patients undergoing allo-HSCT was performed. All patients are alive at last follow-up, show stable engraftment without graft failure, insertional oncogenesis, or immune responses to the transgene. Notably, at last follow-up 3/8 HSPC-GT patients experienced corneal clouding resolution, while all allo-HSCT patients maintained moderate corneal clouding; 4/8 HSPC-GT patients showed normal hearing function at last follow-up due to improvement (n = 3) or stabilization (n = 1); 7/9 allo-HSCT patients had mild or moderate HL at baseline, while 2/9 showed moderate HL at last follow-up. No HSPC-GT patients required surgery for CTS developed after HSPC-GT, while 7/9 patients needed such surgery after allo-HSCT. No HSPC-GT patients developed severe cardiomyopathy or valvular disease, while in the HSCT cohort 4/9 patients experienced progression of valvular insufficiency although not requiring valve replacement. Our results indicate a favorable effect of HSPC-GT on MPSIH multisystemic manifestations up to 4 years after treatment; long-term, prospective comparative studies are warranted for definitive conclusions.
2025-08-18 | Neonatal gene therapy effectively prevents disease manifestations in a murine model of Mucopolysaccharidosis type I.
Mucopolysaccharidosis type I (MPS-I) is a rare pediatric disease caused by mutations in the α-L-iduronidase (IDUA) gene encoding for a lysosomal enzyme involved in glycosaminoglycan metabolism. While newborns with the severe Hurler variant are usually asymptomatic at birth, progressive disease manifestations emerge early in life. Since previous studies on lentiviral vector gene therapy (GT) in Hurler patients have demonstrated superior metabolic correction and early beneficial clinical effects, we investigated whether applying this GT approach during the neonatal period could be effective in preventing disease pathology before it becomes irreversible. Thus, newborn MPS-I mice were transplanted with affected bone marrow-derived progenitor cells transduced with an IDUA-encoding lentiviral vector. Treated animals displayed increased IDUA levels, significantly reducing substrate accumulation in analyzed organs, indicating metabolic correction. Skeletal manifestations, typically resistant to conventional therapies, showed improvements at radiographic and histological levels post-treatment. Additionally, a decrease in brain cortex vacuolization and inflammation suggested neurological amelioration. Overall, this study provides a proof of principle demonstrating the effectiveness of neonatal ex vivo GT in MPS-I mice and supports its potential for further optimization at the pre-clinical level.
proteins
2026-07-04 | Systemic and Orofacial Manifestations of Hurler Syndrome: A Short Communication
Hurler syndrome (mucopolysaccharidosis type I) is a rare autosomal recessive lysosomal storage disorder resulting from deficiency of the enzyme α-L-iduronidase, leading to systemic accumulation of glycosaminoglycans. The disorder manifests early in childhood with progressive multisystem involvement, including characteristic craniofacial features, skeletal abnormalities, cardiopulmonary compromise, and neurological issues. From a dental perspective, patients commonly present with macroglossia, thick lips, delayed tooth eruption, hypoplastic and peg-shaped teeth, gingival hyperplasia, malocclusion, and increased risk of dental caries. These oral findings, combined with airway narrowing, cervical spine instability, and cardiac involvement, pose significant challenges during dental treatment. Diagnosis is based on clinical features, enzyme activity assays, urinary glycosaminoglycan analysis, and molecular genetic testing, with prenatal diagnosis possible. Management requires a multidisciplinary approach involving enzyme replacement therapy, hematopoietic stem cell transplantation, and supportive surgical and rehabilitative care. Dental management emphasizes preventive strategies, early intervention, and careful treatment planning, often necessitating sedation or general anesthesia under strict medical supervision. This short communication aims to highlight the key oral and systemic features of Hurler syndrome and underscores the critical role of dentists in early recognition, prevention, and safe dental management of affected children.
2026-06-21 | Oral nanoparticle-encapsulated enzyme replacement therapy for mucopolysaccharidosis type I (MPS-I): a proof of concept study.
Mucopolysaccharidosis type I (MPS-I) is a rare, multisystemic lysosomal storage disease (LSD) caused by mutations in the IDUA gene, which encodes the enzyme alpha-L-iduronidase. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy (ERT), administered via weekly intravenous infusions. ERT is of limited efficacy owing to its inability to reach critical tissues such as the brain and bone. To address these limitations, this study explores a novel method to improve drug delivery to target organs and simplify administration: oral administration of enzyme encapsulated within nanostructured lipid carriers (NLC). Encapsulation of ERT within NLC enabled effective oral administration. In vitro analysis showed that our NLC formulation was as effective as intravenous ERT in correcting enzyme activity and reducing glycosaminoglycan (GAG) accumulation in fibroblasts from MPS-I patients, when administered periodically. Permeability studies confirmed passage across the intestinal barrier. Proteomic analyses demonstrated normalization of protein expression in energetic pathways related to hexose metabolism, and significant improvements in protein dysregulation in the cytoskeleton, cellular trafficking, lysosomal function, GAG biosynthesis and degradation, and the extracellular matrix. Furthermore, in vivo studies in MPS-I knockout (KO) mice demonstrated biodistribution of NLC-encapsulated enzymes to all tissues affected by the disease, including passage across the blood-brain barrier and access to poorly vascularized bone. These findings suggest that oral administration of ERT via NLC encapsulation represents a significant advancement in MPS-I treatment, enabling drug delivery to previously inaccessible areas. This study opens important avenues of research for future therapeutic strategies targeting LSDs.
2026-06-13 | Unwrapping the Lysosomal Dysfunction: Clinical Imaging of Hurler’s Multisystem Impact
Hurler's syndrome is a rare lysosomal storage disorder caused by deficiency of lysosomal enzyme α-iduronidase. It follows an autosomal recessive pattern of inheritance, leading to progressive accumulation of Glycosaminoglycans (GAGs) within lysosomes, resulting in cellular damage and multiorgan dysfunction [1]. Individuals with mucopolysaccharidosis type I (MPS-I Hurler syndrome) cannot degrade GAGs such as dermatan and heparan sulphate, important components of extracellular matrix and cartilaginous tissues including heart valves and joints. Estimated global prevalence of Hurler syndrome is 1 in 100,000 live births usually in early childhood [2,3]. It is characterised by progressive multisystem involvement causing skeletal deformities, dental irregularities, coarse facial features, organ enlargement, and cardiovascular complications [4,5].
2026-01-01 | P050: Late diagnosis of attenuated MPS I in a 35-year-old adult
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in IDUA, initially added to the US Recommended Uniform Screening Panel in 2016, and currently screened in 30 states. MPS I spans a clinical spectrum with both severe (Hurler) and attenuated (Hurler-Scheie and Scheie) forms. Attenuated MPS I typically presents as a slowly progressive, multisystem disorder with prominent musculoskeletal, cardiac, ophthalmologic, and respiratory involvement, but minimal or absent cognitive impairment, leading to significant morbidity.
2025-08-10 | Modern aspects of diagnosis and treatment of Hurler syndrome in children: achievements and prospects
Hurler syndrome is the most severe form of metabolic genetic disease, mucopolysaccharidosis (MPS) type I, caused by a mutation of the IDUA gene (the gene encoding the alpha-L-iduronidase enzyme). This year in the Omsk region, a case of MPS type I (Hurler syndrome) was diagnosed in a girl V., 2.5 years old, so far the only one in the region. Late diagnosis of MPS type I does not allow to receive the necessary amount of therapy, which leads to a more severe course of this multisystem disease with the formation of complications and a decrease in the patient’s quality of life. This fact determines the relevance of the problem. Despite the relative rarity of this pathology, timely diagnosis is very important. The gold standard of treatment is hematopoietic stem cell transplantation (HSCT). This method is associated with a number of complications, so therapy should be started before the clinically complete picture of the disease, namely, before the age of 2. The earlier HSCT is performed, the better the cognitive functions and somatic manifestations are. However, even timely treatment does not guarantee that the patient is free from the burden of the disease. Along with this, enzyme replacement therapy with laronidase is widely used, but it is ineffective in Hurler syndrome. This determines the need to consider other strategies to improve treatment outcomes. Scientific research into early screening methods and more effective therapy with genetic engineering technologies is actively ongoing.
other
2025-03-24 | Antibodies to recombinant human alpha-L-iduronidase prevent disease correction in cortical bone in MPS I mice.
Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder caused by deficiency of the enzyme α-l-iduronidase (IDUA). Failure of enzyme replacement therapy (ERT) to treat skeletal disease may be due to development of anti-IDUA antibodies, found previously to alter tissue distribution of ERT in animal models. To test this hypothesis, immunocompromised (non-obese diabetic [NOD]-severe combined immunodeficiency [SCID]) MPS I mice were treated with weekly ERT from birth (ERT alone). Some mice also received weekly injections of rabbit immunoglobulin G (IgG) against IDUA (immunized rabbit immune globulin [IRIG]) concomitant with ERT, imitating antibodies developed in patients (ERT+IRIG). Mice treated with ERT+IRIG showed lower IDUA activity and higher disease burden than mice treated with ERT alone in most tissues. Femora were harvested at 20 weeks for ex vivo microcomputed tomography (μCT). Femoral cortical bone thickness and cortical bone area in MPS I mice were greater than in unaffected mice. Mice treated with ERT alone had values that were statistically indistinguishable from carrier mice, while mice that received ERT+IRIG had no significant differences compared to vehicle-treated MPS I mice. The data suggests that immune-modulatory or immune-suppressive therapy to prevent or reduce the humoral immune response against ERT may improve treatment of skeletal disease due to MPS I.
2024-11-21 | Development of a novel tool for individual treatment trials in mucopolysaccharidosis
Mucopolysaccharidosis (MPS) encompasses a group of genetic lysosomal storage disorders, linked to reduced life expectancy and a significant lack of effective treatment options. Immunomodulatory drugs could have the potential to be a relevant medical approach, as the accumulation of undegraded substances initiates an innate immune response, which leads to inflammation and clinical deterioration. However, immunomodulators are not licensed for this indication. Consequently, we aim to provide evidence advocating fast access to innovative individual treatment trials (ITTs) with immunomodulatory drugs and high-quality evaluation of drug effects by implementing a risk-benefit model tailored for MPS. The iterative methodology of our novel decision analysis framework (DAF) involves three key steps: (i) literature review on promising treatment targets and immunomodulators in MPS; (ii) quantitative risk-benefit assessment (RBA) of selected molecules; (iii) assigning phenotypic profiles and quantitative evaluations. The results facilitate a personalized application of the model and are based on published evidence as well as interdisciplinary experts' consensus and patient perspectives. Four promising immunomodulators have been identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra is anticipated as a treatment of choice for neuronopathic MPS patients. Nevertheless, a comprehensive RBA should always be completed on an individual basis. Our evidence-based DAF tool for ITTs directly addresses the substantial unmet medical need in MPS and characterizes an initial stride toward precision medicine with immunomodulators.
2024-01-19 | Evaluation of etanercept (a tumor necrosis factor alpha inhibitor) as an effective treatment for joint disease in mucopolysaccharidosis type I. A case report with whole-body magnetic resonance imaging
Summary A 12-year-old girl with mucopolysaccharidosis (MPS) type I (Gurler-Scheie syndrome, Q70X/del C683 of the IDUA gene in the compound heterozygous state) regularly received enzyme replacement therapy (laronidase) since the preclinical stage (6 months old) due to positive family history, and started etanercept treatment due to progression of joint pain and decreasing capability to walk. The patient had a significant reduction of pain in the joints and an expansion of daily physical activity without adverse events. A decrease in bone marrow edema without foci progression compared to baseline assessment was observed in the whole-body MRI. During the treatment (baseline/6 months/12 months) the following was observed: childhood health assessment questionnaire (CHAQ) index of 1.88/2.13/1.63 points; patient’s pediatric quality of life inventory (PedsQL) of 37/30/31 points; parental PedsQL of 26/27/34 points; and patient’s pain visual-analog scale (VAS) of 75/45/40, with no VAS recorded for the mother. Juvenile arthritis functional assessment report (JAFAR) scores of 35/34/8 points were observed. A significant reduction in the taking of NSAIDs was observed. In the second half of the year, the nasal breathing became normal, and remission in chronic rhinitis and adenoiditis was achieved (no infection episodes) without otitis episodes. Conclusion Etanercept in mucopolysaccharidosis type 1 is safe and well tolerated. The reduction of joint pain and increased walking capacity were observed. A decreased number of respiratory infection episodes and nasal breathing improvement were noted during the treatment. The observation shows the role of inflammation in the different aspects of MPS. Further investigations on immune system dysregulation in patients with MPS I are needed. Additional studies on the efficacy and safety of anti-rheumatic biological drugs in patients with MPSI are required.
2022-04-21 | B-cell depletion abrogates immune mediated cytopenia and rejection of cord blood transplantation in Hurler syndrome.
Umbilical cord blood is the preferred donor cell source for children with Inherited Metabolic disorders undergoing Hematopoietic Cell Transplant (HCT), and its use has been associated with improved "engrafted survival" and higher donor chimerism compared to other cell sources. However, as in other pediatric cord blood transplants for non-malignant disease, immune-mediated cytopenia and primary graft failure limit its use, and the latter remains the commonest cause of death following cord blood transplant for non-malignant disease. We have previously shown an association between immune-mediated cytopenia and graft failure in inherited metabolic diseases suggesting that both immune-mediated cytopenia and graft failure could be mediated by antibodies from the residual recipient B cells. Since rituximab is effective in depletion of B cells and management of refractory immune-mediated cytopenia following HCT, we have added rituximab to the conditioning regimen. We studied 57 patients in 2 centers who received myeloablative conditioning for cord blood transplant in Hurler syndrome, and report a significant improvement in event-free survival with reduced incidence of graft failure and without any evidence of immune-mediated cytopenia in those patients that had received rituximab.
2019-06-01 | Strategies for the Induction of Immune Tolerance to Enzyme Replacement Therapy in Mucopolysaccharidosis Type I
Enzyme replacement therapy with laronidase is an established treatment for Mucopolysaccharidosis type I (MPS I), but its efficacy may be limited by the development of anti-drug antibodies, which inhibit cellular uptake of the enzyme. In a related disorder, infantile Pompe disease, immune tolerance induction with low-dose, short-course methotrexate appears to reduce antibody formation. We investigated a similar regimen using oral methotrexate in three MPS I patients. All patients developed anti-laronidase immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, and they had clinically relevant levels of cellular uptake inhibition. We then explored several immune tolerance induction strategies in MPS I mice: (1) methotrexate, (2) combination of non-depleting anti-CD4 and anti-CD8 monoclonal antibodies, (3) methotrexate with anti-CD4 and anti-CD8 monoclonals, (4) anti-CD4 monoclonal, and (5) anti-CD8 monoclonal. Treated mice received 10 weekly laronidase injections, and laronidase was delivered with adjuvant on day 49 to further challenge the immune system. Most regimens were only partially effective at reducing antibody responses, but two courses of non-depleting anti-CD4 monoclonal antibody (mAb) ablated immune responses to laronidase in seven of eight MPS I mice (87.5%), even after adjuvant stimulation. Immune tolerance induction with methotrexate does not appear to be effective in MPS I patients, but use of non-depleting anti-CD4 monoclonal is a promising strategy. Enzyme replacement therapy with laronidase is an established treatment for Mucopolysaccharidosis type I (MPS I), but its efficacy may be limited by the development of anti-drug antibodies, which inhibit cellular uptake of the enzyme. In a related disorder, infantile Pompe disease, immune tolerance induction with low-dose, short-course methotrexate appears to reduce antibody formation. We investigated a similar regimen using oral methotrexate in three MPS I patients. All patients developed anti-laronidase immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, and they had clinically relevant levels of cellular uptake inhibition. We then explored several immune tolerance induction strategies in MPS I mice: (1) methotrexate, (2) combination of non-depleting anti-CD4 and anti-CD8 monoclonal antibodies, (3) methotrexate with anti-CD4 and anti-CD8 monoclonals, (4) anti-CD4 monoclonal, and (5) anti-CD8 monoclonal. Treated mice received 10 weekly laronidase injections, and laronidase was delivered with adjuvant on day 49 to further challenge the immune system. Most regimens were only partially effective at reducing antibody responses, but two courses of non-depleting anti-CD4 monoclonal antibody (mAb) ablated immune responses to laronidase in seven of eight MPS I mice (87.5%), even after adjuvant stimulation. Immune tolerance induction with methotrexate does not appear to be effective in MPS I patients, but use of non-depleting anti-CD4 monoclonal is a promising strategy.
small molecules
2026-05-25 | RNA activation as a precision dosing modality: MTL-CEBPA for controlled enzyme elevation in MPS I-H.
Gene therapy and hematopoietic stem cell transplantation (HSCT) have transformed outcomes for severe mucopolysaccharidosis type I (MPS I-H), yet a critical unmet need remains. Children with MPS I-H frequently experience progressive skeletal, cardiac, and other complications despite timely HSCT, largely because enzyme activity cannot be safely and precisely titrated over time. Irreversible genetic modification via integrating vectors offers supra-physiological enzyme levels but carries long-term safety and re-dosing liabilities in patients treated early in life. We investigated RNA activation (RNAa) as a precision dosing strategy to enhance endogenous IDUA expression without permanent genome alteration. Using MTL-CEBPA, a small activating RNA that upregulates CEBPA transcription factor, we characterized CEBPA-IDUA relationships in vitro, in vivo, and in legacy clinical samples from cancer patients. CCAAT enhancer binding protein alpha activation consistently increased IDUA mRNA across A549, IMR90, and mesenchymal stem cells. In wild-type mice, two intravenous MTL-CEBPA doses produced a ∼2-fold, durable increase in bone marrow IDUA mRNA and plasma enzyme activity, sustained for up to 4 weeks. In humanized bone marrow-transplanted MPS I-H mice, repeated dosing with MTL-CEBPA led to an approximately 2-fold increase in circulating IDUA activity compared with controls over the 3-weeks treatment period. The largest apparent separation from controls was observed in the homozygous cohort, although these genotype-specific differences should be interpreted cautiously given the limited subgroup sizes. In cancer patient-derived monocytes, increased CEBPA protein levels correlated with higher IDUA levels (R2 = 0.571). Consistent with this, approximately half of evaluable patients exhibited increased plasma IDUA activity following treatment. These translational data demonstrate that MTL-CEBPA delivers controlled, reversible enhancement of IDUA in the context of HSCT, providing robust pharmacodynamic proof-of-concept rather than definitive evidence of durable efficacy. By enabling titratable enzyme elevation without integrating vectors, RNAa therapeutics address a key unmet need in Hurler syndrome: safe fine-tuning of residual enzyme activity over a patient's lifetime. With scalable, cost-effective oligonucleotide manufacturing, MTL-CEBPA and related RNAa therapeutics represent a clinically relevant adjuvant strategy for HSCT-treated MPS I-H, with potential for other enzyme deficiency disorders.
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.
2025-08-21 | RNA Activation of CEBPA in PBMCs Enhances α-L-Iduronidase Expression A Translational Adjuvant Therapy for MPS I After Bone Marrow Transplantation
Background Hurler syndrome, the most severe form of mucopolysaccharidosis type I (MPS I), is a rare genetic disorder caused by mutations in the IDUA gene, leading to a deficiency of the α-L-iduronidase enzyme. While current treatments offer some benefits, there remains a significant unmet medical need. We have identified a potential new therapeutic approach using MTL-CEBPA, a drug that upregulates the transcription factor CEBPA, which in turn regulates IDUA expression. Results In vitro studies demonstrated significant upregulation of IDUA in various cell lines following MTL-CEBPA treatment. In vivo experiments in both wild-type and MPS I mouse models showed a two-fold increased IDUA expression and enzyme activity for up to four weeks after a single dose. Analysis of archival samples from cancer patients treated with MTL-CEBPA revealed a correlation between increased CEBPA expression and IDUA expression, with approximately half of the patients showing elevated plasma IDUA enzyme activity post-treatment. Conclusions These findings provide proof-of-concept evidence supporting the potential use of MTL-CEBPA as a treatment for MPS I patients. We propose that this therapeutic oligonucleotide approach offers a favourable safety profile, allowing for multiple dosing to maintain elevated IDUA enzyme activity in bone marrow transplanted patients over extended periods, potentially addressing the limitations of current treatments and improving patient outcomes.
2025-04-28 | Genetic variations in the IDUA gene in Tunisian MPS I families: Identification of a novel microdeletion disrupting substrate binding and structural insights.
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by a deficiency in alpha-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans. MPS I presents with a broad spectrum of clinical phenotypes, ranging from severe to mild. This study aimed to identify genetic mutations in the IDUA gene among Tunisian families and assess their structural and functional implications. Genomic DNA was extracted from blood samples of four patients including two siblings from three Tunisian families. Polymerase chain reaction (PCR) followed by Sanger sequencing was performed to identify mutations in the IDUA gene. Bioinformatics tools, including the SWISS-MODEL server and DynaMut, were used for structural modeling and to predict the impact of the mutations on protein stability and flexibility. Two mutations in the IDUA gene were identified. A novel deletion mutation p.His356_Gln362del was discovered in two patients with severe MPS I phenotypes, while a previously reported missense mutation p.Pro533Arg was found in two patients with intermediate and mild phenotypes. Structural analysis revealed that the novel deletion disrupts the protein's substrate-binding site. This deletion causes structural deformation and leads to the elimination of the substrate binding site, resulting in a complete loss of enzymatic activity.The missense mutation p.Pro533Arg affects the stability and flexibility of the protein, likely reducing substrate affinity. This substitution results in the introduction of a bulkier amino acid, requiring more space in the contact region between the β-sheet structure and the substrate-bound helix. This study reports a novel deletion mutation in the IDUA gene in Tunisian MPS I patients, alongside a previously described mutation. The findings enhance understanding of the molecular basis of MPS I and provide insights into the structural effects of these mutations, which could aid in future diagnosis and therapeutic strategies. Future studies should explore the prevalence of the reported mutations in larger cohorts and investigate targeted therapies, such as pharmacological chaperones, to rescue enzymatic activity in patients carrying such mutations.
2025-01-01 | Bilateral Foveal Cysts in Mucopolysaccharidosis Type I (Hurler Syndrome): Response to Acetazolamide With Insights From Multimodal Retinal Imaging and Electrophysiology
Objective The aim of this study is to report a case of bilateral foveal cysts in MPS I‐H resolving with oral acetazolamide and to highlight the diagnostic value of multimodal retinal imaging and electrophysiological testing. Introduction Hurler syndrome (mucopolysaccharidosis Type I‐H) is a lysosomal storage disorder that can cause progressive multisystem complications. Retinal involvement often mimics retinitis pigmentosa (RP), and pathology may progress even after early hematopoietic stem cell transplantation (HSCT) due to limited enzyme penetration into ocular tissues. Case Summary A 17‐year‐old female with MPS I‐H, post‐HSCT at 21 months, presented with bilateral visual decline despite a normal clinical fundus exam. Evaluation included spectral‐domain OCT (SD‐OCT), fundus autofluorescence (FAF), multifocal electroretinography (mfERG), full‐field ERG (ffERG), and visual evoked potential. SD‐OCT revealed bilateral intraretinal foveal cysts without leakage on fluorescein angiography. FAF showed a bull′s eye maculopathy pattern; mfERG showed bilateral macular dysfunction. ffERG revealed rod–cone dystrophy. Two 3‐month courses of oral acetazolamide (125 mg three times daily) led to complete cyst resolution and visual improvement. Conclusion This case supports the role of systemic carbonic anhydrase inhibitors in treating nonleaking macular cysts in MPS I, similar to RP‐related cystoid macular pathologies, and highlights the value of integrating electrophysiological and multimodal imaging, especially in occult retinal disease.
cell therapies
2026-08-05 | First bone marrow transplantation for mucopolysaccharidosis type I in Vietnam: a case report.
Mucopolysaccharidosis type I (MPS-I) is an inherited lysosomal storage disorder characterized by alpha-L-iduronidase deficiency, leading to progressive multi-organ damage and fatal complications. Early treatment is crucial to improve outcomes, particularly in patients with severe phenotypes. We present the first case of successful allogeneic bone marrow transplantation (BMT) for MPS-I in Vietnam. A 10-month-old girl experienced coarse facial features, congenital dermal melanocytosis spots, kyphoscoliosis developmental delay. Laboratory analyses revealed reduced alpha-L-iduronidase activity and elevated urinary glycosaminoglycans, genetic mutations identified two heterozygous mutations in the IDUA gene, confirmed the diagnosis of MPS-I. At 3 years old, she underwent allogeneic BMT from an HLA-matched sibling donor following conditioning regimen with busulfan, cyclophosphamide, antithymocyte globulin. Neutrophil engraftment was achieved on day +24, and platelet engrafted on day +32. The post-transplant course was complicated by respiratory deterioration requiring 5 days of mechanical ventilation, which was promptly managed and resolved. No graft-versus-host disease occurred. Post-transplant chimerism showed 95.77% donor-derived cells on day +30 and remained stable at 100% from 2 months. The patient demonstrated improvement in clinical symptoms, accompanied by alpha-L-iduronidase activity returned to normal range, urinary glycosaminoglycan levels decreased and remained stable during follow-up. At 12 months, she demonstrated complete immune reconstitution. This case suggests that allogeneic BMT may be a therapeutic approach for patients with MPS-I in resource-limited settings.
2026-02-09 | Carpal tunnel syndrome in mucopolysaccharidosis type I: clinical, surgical and histopathological findings.
Mucopolysaccharidosis type I is a rare metabolic disorder characterized by the accumulation of glycosaminoglycans, leading to musculoskeletal disorders such as carpal tunnel syndrome. This retrospective cohort study was performed to determine the prevalence and timing of the development of carpal tunnel syndrome, assess the efficacy of surgery on recurrence and the effect of haematopoietic stem cell transplantation in resolving accumulated degradation products. Thirty-three mucopolysaccharidosis type I patients, born between 2001 and 2023, were included in this study. They received annual screening and treatment at our specialist hospital. Patient demographics, clinical symptoms of carpal tunnel syndrome pre- and post-carpal tunnel release and histopathological sections of the flexor retinaculum were collected. Regression analyses were conducted to assess cumulative risks and determine hazard ratios and survival curves were plotted. Twenty-seven of 33 mucopolysaccharidosis type I patients, with a median age at the latest follow-up of 13 years (IQR 7.7 to 18.3), were diagnosed with carpal tunnel syndrome on electrophysiological tests or ultrasound at a median age of 3.6 years (IQR 2.8 to 5.2). Only a few patients exhibited clinical symptoms. Twenty-one patients underwent carpal tunnel release and 13 patients experienced recurrence. The highest risk of developing carpal tunnel syndrome was within the first 6 years of life. Eight of the 11 patients accumulated degradation products within lysosomes despite successful haematopoietic stem cell transplantation. In this study, 27 mucopolysaccharidosis type I patients were diagnosed with carpal tunnel syndrome, showing a high-risk window from 0 to 6 years of age. Recurrence of carpal tunnel syndrome after carpal tunnel release surgery was common, occurring in 61.9% of patients. III.
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.
2025-01-07 | Human iPSC-derived neural stem cells engraft and improve pathophysiology of MPS I mice.
Mucopolysaccharidosis type I (MPS I) is a metabolic disorder characterized by a deficiency in α-l-iduronidase (IDUA), leading to impaired glycosaminoglycan degradation. Current approved treatments seek to restore IDUA levels via enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). The effectiveness of these treatment strategies in preventing neurodegeneration is limited due to the inability of ERT to penetrate the blood-brain barrier (BBB) and HSCT's limited CNS reconstitution of IDUA levels. We reprogrammed human cord blood cells into induced pluripotent stem cells (iPSCs), differentiated them into human induced neural stem cells (hiNSCs), and sorted them using fluorescence-activated cell sorting (FACS). Our in vitro studies showed that these hiNSCs can migrate and cross-correct IDUA deficiency. Purified hiNSCs were then transplanted into neonatal immunodeficient MPS I mice (Idua -/- ). Analysis of brain tissue obtained 8 months after transplantation showed partially restored IDUA activity, with distribution and differentiation of engrafted hiNSCs throughout the brain into glial cell types. The presence of engrafted hiNSCs was associated with decreased levels of biomarkers commonly elevated in the Idua -/- mouse brain, such as β-hexosaminidase, CD68, and LAMP1, suggesting physiological efficacy. These results highlight the potential of hiNSCs for use as a patient-specific cellular therapy for MPS I.
2024-11-13 | Prolonged catamnesis of a child with type I mucopolysaccharidosis, Gurler syndrome, receiving enzyme replacement therapy
Hereditary pathology makes up a significant part of the structure of childhood morbidity, disability and mortality. Mucopolysaccharidosis type I is a hereditary lysosomal accumulation disease, with an autosomal recessive type of inheritance. At birth, children with Gurler syndrome look normal, but in the future, they develop symptoms characteristic of mucopolysaccharidosis, and the first clinical manifestations of the disease are often hernias and hepatosplenomegaly. The presented clinical case demonstrates the difficulties of early diagnosis of mucopolysaccharidosis type I, which lead to a later prescription of enzyme replacement therapy and the inability to use a more effective method of therapy – hematopoietic stem cell transplantation, due to the development of serious manifestations of the cardiovascular system. While the positive effects of enzyme replacement therapy in the early stages of treatment may seem promising, it does not guarantee a favorable prognosis for the future. Conclusion. Currently, early diagnosis of mucopolysaccharidosis type I is difficult due to the lack of early manifestations. Often, the progression of clinical manifestations leads to disability, and in severe cases, to death. Therefore, it is important to have early diagnosis and appropriate treatment.
gene therapies
2026-03-28 | Liposomal CRISPR/Cas9-Mediated Local Genome Editing for Joint Disease in Mucopolysaccharidosis Type I.
Background/Objectives: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase (IDUA) deficiency, leading to progressive glycosaminoglycan (GAG) accumulation and severe joint involvement. Gene editing represents a promising alternative to restore localized enzyme production. Therefore, this study aimed to evaluate the feasibility, efficacy, and safety of in situ genome editing through intra-articular administration of a nonviral CRISPR/Cas9 system to increase localized IDUA expression in an MPS I mouse model. Methods: Cationic liposomes were formulated to deliver plasmids encoding the CRISPR/Cas9 system targeted to the ROSA26 locus along with an IDUA donor sequence. In vitro assays were performed in fibroblast-like synoviocytes (FLSs) isolated from MPS I mice to assess cytotoxicity, gene editing efficiency, and IDUA activity. In vivo, MPS I mice received intra-articular injections in the knee joints, either as a single dose (short-term study) or monthly for three months (long-term study). IDUA activity, GAG levels, and genome editing efficiency were evaluated in joint tissues, synovial fluid, serum, and major organs. Results: Gene-edited FLS showed sustained IDUA activity for up to 30 days with low cytotoxicity. In vivo, intra-articular administration resulted in a significant increase in IDUA activity in joint tissue and synovial fluid without detectable systemic IDUA. Long-term treatment led to persistent joint-localized IDUA activity, significant reductions (>50%) in GAG levels, and detectable genome editing in joint DNA. Conclusions: Intra-articular delivery of CRISPR/Cas9 via cationic liposomes enables safe and effective localized genome editing, representing a promising strategy for treating joint manifestations of MPS I.
2025-12-11 | Comparative evaluation of liver-directed knockin strategies with viral and nonviral vectors in mouse inherited disease models.
CRISPR-Cas9-mediated gene knockin has emerged as a promising strategy for early-onset genetic disease intervention. However, the therapeutic efficacy and editing outcomes of different knockin strategies remain incompletely understood. Here, we systematically evaluated three major liver-directed knockin strategies, namely homology-directed repair (HDR), homology-independent targeted integration (HITI), and homology-mediated end joining (HMEJ), using neonatal mouse models of mucopolysaccharidosis type I and hemophilia B. Although all three approaches effectively rescued disease phenotypes, we observed distinct editing outcomes. Notably, the HMEJ approach, delivered via a combined adeno-associated virus-lipid nanoparticle (AAV-LNP) system, exhibited superior integration efficiency (5.8%-5.9%) and fidelity (97%-98%) compared with HDR and HITI. In contrast, whole-genome sequencing indicated that HITI induced a higher risk of random AAV donor integration than HDR or HMEJ. Furthermore, long-read sequencing analyses revealed that the frequencies of inverted terminal repeat (ITR)-mediated transgene integration differed between the 5' and 3' genomic junctions among the three strategies. Specifically, in HDR- and HMEJ-treated mice, ITR-mediated integration events were 7.7- to 19.7-fold more common at the 3' junctions than at the 5' junctions. These findings highlight the comprehensive advantages of the AAV-LNP-mediated HMEJ approach for liver-directed knockin therapy and suggest its strong potential for clinical translation.
2025-11-21 | New approaches to the diagnosis and treatment of mucopolysaccharidos type I in children: A clinical case of Hurler syndrome in a young child
Hurler syndrome is the most severe form of mucopolysaccharidosis type I (MPS I). This is a metabolic genetic disorder caused by mutations in the IDUA gene, which encodes the α-L-iduronidase enzyme. Despite its rarity, timely diagnosis is critical. Current treatments for MPS I include enzyme replacement therapy (ERT) and allogeneic hematopoietic stem cell transplantation (HSCT). Intravenous ERT, such as laronidase, although being widely used, exhibits limited effectiveness due to its inability to cross the blood–brain barrier, thus failing to halt neurological deterioration. HSCT remains the gold standard, particularly when performed before age 2, prior to developing severe clinical manifestations. Early HSCT allows better preservation of cognitive functions and mitigation of somatic symptoms, although carrying risks of complications and not guaranteeing complete recovery. These limitations underscore the need for innovative strategies, including improved early screening methods and genetic engineering technologies. Gene therapy (GT) is a promising approach, having the potential for sustained enzyme production to address the underlying deficiency.
2025-09-29 | Non-neurological, non-skeletal outcomes after hematopoietic stem and progenitor cell-gene therapy (OTL-203) for Hurler syndrome.
Patients with mucopolysaccharidosis type I Hurler (MPSIH) experience multisystem clinical manifestations, which are only partially addressed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study evaluated outcomes from a lentiviral vector-mediated hematopoietic stem and progenitor cell-gene therapy (HSPC-GT) trial (NCT03488394) in eight MPSIH patients followed up to 4 years post-treatment. Key findings included corneal clouding, hearing loss (HL), carpal tunnel syndrome (CTS), and cardiac evaluations. A retrospective comparison with an external cohort of nine MPSIH patients undergoing allo-HSCT was performed. All patients are alive at last follow-up, show stable engraftment without graft failure, insertional oncogenesis, or immune responses to the transgene. Notably, at last follow-up 3/8 HSPC-GT patients experienced corneal clouding resolution, while all allo-HSCT patients maintained moderate corneal clouding; 4/8 HSPC-GT patients showed normal hearing function at last follow-up due to improvement (n = 3) or stabilization (n = 1); 7/9 allo-HSCT patients had mild or moderate HL at baseline, while 2/9 showed moderate HL at last follow-up. No HSPC-GT patients required surgery for CTS developed after HSPC-GT, while 7/9 patients needed such surgery after allo-HSCT. No HSPC-GT patients developed severe cardiomyopathy or valvular disease, while in the HSCT cohort 4/9 patients experienced progression of valvular insufficiency although not requiring valve replacement. Our results indicate a favorable effect of HSPC-GT on MPSIH multisystemic manifestations up to 4 years after treatment; long-term, prospective comparative studies are warranted for definitive conclusions.
2025-08-18 | Neonatal gene therapy effectively prevents disease manifestations in a murine model of Mucopolysaccharidosis type I.
Mucopolysaccharidosis type I (MPS-I) is a rare pediatric disease caused by mutations in the α-L-iduronidase (IDUA) gene encoding for a lysosomal enzyme involved in glycosaminoglycan metabolism. While newborns with the severe Hurler variant are usually asymptomatic at birth, progressive disease manifestations emerge early in life. Since previous studies on lentiviral vector gene therapy (GT) in Hurler patients have demonstrated superior metabolic correction and early beneficial clinical effects, we investigated whether applying this GT approach during the neonatal period could be effective in preventing disease pathology before it becomes irreversible. Thus, newborn MPS-I mice were transplanted with affected bone marrow-derived progenitor cells transduced with an IDUA-encoding lentiviral vector. Treated animals displayed increased IDUA levels, significantly reducing substrate accumulation in analyzed organs, indicating metabolic correction. Skeletal manifestations, typically resistant to conventional therapies, showed improvements at radiographic and histological levels post-treatment. Additionally, a decrease in brain cortex vacuolization and inflammation suggested neurological amelioration. Overall, this study provides a proof of principle demonstrating the effectiveness of neonatal ex vivo GT in MPS-I mice and supports its potential for further optimization at the pre-clinical level.
proteins
2026-07-04 | Systemic and Orofacial Manifestations of Hurler Syndrome: A Short Communication
Hurler syndrome (mucopolysaccharidosis type I) is a rare autosomal recessive lysosomal storage disorder resulting from deficiency of the enzyme α-L-iduronidase, leading to systemic accumulation of glycosaminoglycans. The disorder manifests early in childhood with progressive multisystem involvement, including characteristic craniofacial features, skeletal abnormalities, cardiopulmonary compromise, and neurological issues. From a dental perspective, patients commonly present with macroglossia, thick lips, delayed tooth eruption, hypoplastic and peg-shaped teeth, gingival hyperplasia, malocclusion, and increased risk of dental caries. These oral findings, combined with airway narrowing, cervical spine instability, and cardiac involvement, pose significant challenges during dental treatment. Diagnosis is based on clinical features, enzyme activity assays, urinary glycosaminoglycan analysis, and molecular genetic testing, with prenatal diagnosis possible. Management requires a multidisciplinary approach involving enzyme replacement therapy, hematopoietic stem cell transplantation, and supportive surgical and rehabilitative care. Dental management emphasizes preventive strategies, early intervention, and careful treatment planning, often necessitating sedation or general anesthesia under strict medical supervision. This short communication aims to highlight the key oral and systemic features of Hurler syndrome and underscores the critical role of dentists in early recognition, prevention, and safe dental management of affected children.
2026-06-21 | Oral nanoparticle-encapsulated enzyme replacement therapy for mucopolysaccharidosis type I (MPS-I): a proof of concept study.
Mucopolysaccharidosis type I (MPS-I) is a rare, multisystemic lysosomal storage disease (LSD) caused by mutations in the IDUA gene, which encodes the enzyme alpha-L-iduronidase. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy (ERT), administered via weekly intravenous infusions. ERT is of limited efficacy owing to its inability to reach critical tissues such as the brain and bone. To address these limitations, this study explores a novel method to improve drug delivery to target organs and simplify administration: oral administration of enzyme encapsulated within nanostructured lipid carriers (NLC). Encapsulation of ERT within NLC enabled effective oral administration. In vitro analysis showed that our NLC formulation was as effective as intravenous ERT in correcting enzyme activity and reducing glycosaminoglycan (GAG) accumulation in fibroblasts from MPS-I patients, when administered periodically. Permeability studies confirmed passage across the intestinal barrier. Proteomic analyses demonstrated normalization of protein expression in energetic pathways related to hexose metabolism, and significant improvements in protein dysregulation in the cytoskeleton, cellular trafficking, lysosomal function, GAG biosynthesis and degradation, and the extracellular matrix. Furthermore, in vivo studies in MPS-I knockout (KO) mice demonstrated biodistribution of NLC-encapsulated enzymes to all tissues affected by the disease, including passage across the blood-brain barrier and access to poorly vascularized bone. These findings suggest that oral administration of ERT via NLC encapsulation represents a significant advancement in MPS-I treatment, enabling drug delivery to previously inaccessible areas. This study opens important avenues of research for future therapeutic strategies targeting LSDs.
2026-06-13 | Unwrapping the Lysosomal Dysfunction: Clinical Imaging of Hurler’s Multisystem Impact
Hurler's syndrome is a rare lysosomal storage disorder caused by deficiency of lysosomal enzyme α-iduronidase. It follows an autosomal recessive pattern of inheritance, leading to progressive accumulation of Glycosaminoglycans (GAGs) within lysosomes, resulting in cellular damage and multiorgan dysfunction [1]. Individuals with mucopolysaccharidosis type I (MPS-I Hurler syndrome) cannot degrade GAGs such as dermatan and heparan sulphate, important components of extracellular matrix and cartilaginous tissues including heart valves and joints. Estimated global prevalence of Hurler syndrome is 1 in 100,000 live births usually in early childhood [2,3]. It is characterised by progressive multisystem involvement causing skeletal deformities, dental irregularities, coarse facial features, organ enlargement, and cardiovascular complications [4,5].
2026-01-01 | P050: Late diagnosis of attenuated MPS I in a 35-year-old adult
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in IDUA, initially added to the US Recommended Uniform Screening Panel in 2016, and currently screened in 30 states. MPS I spans a clinical spectrum with both severe (Hurler) and attenuated (Hurler-Scheie and Scheie) forms. Attenuated MPS I typically presents as a slowly progressive, multisystem disorder with prominent musculoskeletal, cardiac, ophthalmologic, and respiratory involvement, but minimal or absent cognitive impairment, leading to significant morbidity.
2025-08-10 | Modern aspects of diagnosis and treatment of Hurler syndrome in children: achievements and prospects
Hurler syndrome is the most severe form of metabolic genetic disease, mucopolysaccharidosis (MPS) type I, caused by a mutation of the IDUA gene (the gene encoding the alpha-L-iduronidase enzyme). This year in the Omsk region, a case of MPS type I (Hurler syndrome) was diagnosed in a girl V., 2.5 years old, so far the only one in the region. Late diagnosis of MPS type I does not allow to receive the necessary amount of therapy, which leads to a more severe course of this multisystem disease with the formation of complications and a decrease in the patient’s quality of life. This fact determines the relevance of the problem. Despite the relative rarity of this pathology, timely diagnosis is very important. The gold standard of treatment is hematopoietic stem cell transplantation (HSCT). This method is associated with a number of complications, so therapy should be started before the clinically complete picture of the disease, namely, before the age of 2. The earlier HSCT is performed, the better the cognitive functions and somatic manifestations are. However, even timely treatment does not guarantee that the patient is free from the burden of the disease. Along with this, enzyme replacement therapy with laronidase is widely used, but it is ineffective in Hurler syndrome. This determines the need to consider other strategies to improve treatment outcomes. Scientific research into early screening methods and more effective therapy with genetic engineering technologies is actively ongoing.
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2025-03-24 | Antibodies to recombinant human alpha-L-iduronidase prevent disease correction in cortical bone in MPS I mice.
Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder caused by deficiency of the enzyme α-l-iduronidase (IDUA). Failure of enzyme replacement therapy (ERT) to treat skeletal disease may be due to development of anti-IDUA antibodies, found previously to alter tissue distribution of ERT in animal models. To test this hypothesis, immunocompromised (non-obese diabetic [NOD]-severe combined immunodeficiency [SCID]) MPS I mice were treated with weekly ERT from birth (ERT alone). Some mice also received weekly injections of rabbit immunoglobulin G (IgG) against IDUA (immunized rabbit immune globulin [IRIG]) concomitant with ERT, imitating antibodies developed in patients (ERT+IRIG). Mice treated with ERT+IRIG showed lower IDUA activity and higher disease burden than mice treated with ERT alone in most tissues. Femora were harvested at 20 weeks for ex vivo microcomputed tomography (μCT). Femoral cortical bone thickness and cortical bone area in MPS I mice were greater than in unaffected mice. Mice treated with ERT alone had values that were statistically indistinguishable from carrier mice, while mice that received ERT+IRIG had no significant differences compared to vehicle-treated MPS I mice. The data suggests that immune-modulatory or immune-suppressive therapy to prevent or reduce the humoral immune response against ERT may improve treatment of skeletal disease due to MPS I.
2024-11-21 | Development of a novel tool for individual treatment trials in mucopolysaccharidosis
Mucopolysaccharidosis (MPS) encompasses a group of genetic lysosomal storage disorders, linked to reduced life expectancy and a significant lack of effective treatment options. Immunomodulatory drugs could have the potential to be a relevant medical approach, as the accumulation of undegraded substances initiates an innate immune response, which leads to inflammation and clinical deterioration. However, immunomodulators are not licensed for this indication. Consequently, we aim to provide evidence advocating fast access to innovative individual treatment trials (ITTs) with immunomodulatory drugs and high-quality evaluation of drug effects by implementing a risk-benefit model tailored for MPS. The iterative methodology of our novel decision analysis framework (DAF) involves three key steps: (i) literature review on promising treatment targets and immunomodulators in MPS; (ii) quantitative risk-benefit assessment (RBA) of selected molecules; (iii) assigning phenotypic profiles and quantitative evaluations. The results facilitate a personalized application of the model and are based on published evidence as well as interdisciplinary experts' consensus and patient perspectives. Four promising immunomodulators have been identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra is anticipated as a treatment of choice for neuronopathic MPS patients. Nevertheless, a comprehensive RBA should always be completed on an individual basis. Our evidence-based DAF tool for ITTs directly addresses the substantial unmet medical need in MPS and characterizes an initial stride toward precision medicine with immunomodulators.
2024-01-19 | Evaluation of etanercept (a tumor necrosis factor alpha inhibitor) as an effective treatment for joint disease in mucopolysaccharidosis type I. A case report with whole-body magnetic resonance imaging
Summary A 12-year-old girl with mucopolysaccharidosis (MPS) type I (Gurler-Scheie syndrome, Q70X/del C683 of the IDUA gene in the compound heterozygous state) regularly received enzyme replacement therapy (laronidase) since the preclinical stage (6 months old) due to positive family history, and started etanercept treatment due to progression of joint pain and decreasing capability to walk. The patient had a significant reduction of pain in the joints and an expansion of daily physical activity without adverse events. A decrease in bone marrow edema without foci progression compared to baseline assessment was observed in the whole-body MRI. During the treatment (baseline/6 months/12 months) the following was observed: childhood health assessment questionnaire (CHAQ) index of 1.88/2.13/1.63 points; patient’s pediatric quality of life inventory (PedsQL) of 37/30/31 points; parental PedsQL of 26/27/34 points; and patient’s pain visual-analog scale (VAS) of 75/45/40, with no VAS recorded for the mother. Juvenile arthritis functional assessment report (JAFAR) scores of 35/34/8 points were observed. A significant reduction in the taking of NSAIDs was observed. In the second half of the year, the nasal breathing became normal, and remission in chronic rhinitis and adenoiditis was achieved (no infection episodes) without otitis episodes. Conclusion Etanercept in mucopolysaccharidosis type 1 is safe and well tolerated. The reduction of joint pain and increased walking capacity were observed. A decreased number of respiratory infection episodes and nasal breathing improvement were noted during the treatment. The observation shows the role of inflammation in the different aspects of MPS. Further investigations on immune system dysregulation in patients with MPS I are needed. Additional studies on the efficacy and safety of anti-rheumatic biological drugs in patients with MPSI are required.
2022-04-21 | B-cell depletion abrogates immune mediated cytopenia and rejection of cord blood transplantation in Hurler syndrome.
Umbilical cord blood is the preferred donor cell source for children with Inherited Metabolic disorders undergoing Hematopoietic Cell Transplant (HCT), and its use has been associated with improved "engrafted survival" and higher donor chimerism compared to other cell sources. However, as in other pediatric cord blood transplants for non-malignant disease, immune-mediated cytopenia and primary graft failure limit its use, and the latter remains the commonest cause of death following cord blood transplant for non-malignant disease. We have previously shown an association between immune-mediated cytopenia and graft failure in inherited metabolic diseases suggesting that both immune-mediated cytopenia and graft failure could be mediated by antibodies from the residual recipient B cells. Since rituximab is effective in depletion of B cells and management of refractory immune-mediated cytopenia following HCT, we have added rituximab to the conditioning regimen. We studied 57 patients in 2 centers who received myeloablative conditioning for cord blood transplant in Hurler syndrome, and report a significant improvement in event-free survival with reduced incidence of graft failure and without any evidence of immune-mediated cytopenia in those patients that had received rituximab.
2019-06-01 | Strategies for the Induction of Immune Tolerance to Enzyme Replacement Therapy in Mucopolysaccharidosis Type I
Enzyme replacement therapy with laronidase is an established treatment for Mucopolysaccharidosis type I (MPS I), but its efficacy may be limited by the development of anti-drug antibodies, which inhibit cellular uptake of the enzyme. In a related disorder, infantile Pompe disease, immune tolerance induction with low-dose, short-course methotrexate appears to reduce antibody formation. We investigated a similar regimen using oral methotrexate in three MPS I patients. All patients developed anti-laronidase immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, and they had clinically relevant levels of cellular uptake inhibition. We then explored several immune tolerance induction strategies in MPS I mice: (1) methotrexate, (2) combination of non-depleting anti-CD4 and anti-CD8 monoclonal antibodies, (3) methotrexate with anti-CD4 and anti-CD8 monoclonals, (4) anti-CD4 monoclonal, and (5) anti-CD8 monoclonal. Treated mice received 10 weekly laronidase injections, and laronidase was delivered with adjuvant on day 49 to further challenge the immune system. Most regimens were only partially effective at reducing antibody responses, but two courses of non-depleting anti-CD4 monoclonal antibody (mAb) ablated immune responses to laronidase in seven of eight MPS I mice (87.5%), even after adjuvant stimulation. Immune tolerance induction with methotrexate does not appear to be effective in MPS I patients, but use of non-depleting anti-CD4 monoclonal is a promising strategy. Enzyme replacement therapy with laronidase is an established treatment for Mucopolysaccharidosis type I (MPS I), but its efficacy may be limited by the development of anti-drug antibodies, which inhibit cellular uptake of the enzyme. In a related disorder, infantile Pompe disease, immune tolerance induction with low-dose, short-course methotrexate appears to reduce antibody formation. We investigated a similar regimen using oral methotrexate in three MPS I patients. All patients developed anti-laronidase immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies, and they had clinically relevant levels of cellular uptake inhibition. We then explored several immune tolerance induction strategies in MPS I mice: (1) methotrexate, (2) combination of non-depleting anti-CD4 and anti-CD8 monoclonal antibodies, (3) methotrexate with anti-CD4 and anti-CD8 monoclonals, (4) anti-CD4 monoclonal, and (5) anti-CD8 monoclonal. Treated mice received 10 weekly laronidase injections, and laronidase was delivered with adjuvant on day 49 to further challenge the immune system. Most regimens were only partially effective at reducing antibody responses, but two courses of non-depleting anti-CD4 monoclonal antibody (mAb) ablated immune responses to laronidase in seven of eight MPS I mice (87.5%), even after adjuvant stimulation. Immune tolerance induction with methotrexate does not appear to be effective in MPS I patients, but use of non-depleting anti-CD4 monoclonal is a promising strategy.
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Drug Discovery Landscape
26 orphan drug designations for Mucopolysaccharidosis type 1, including 1 approved therapy.
26 orphan drug designations for Mucopolysaccharidosis type 1, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Self-complementary adeno-associated virus serotype 9 vector harboring a miniaturized codon-optimized human IDUA gene | gene therapies | FDA | 2024-04-08 | — | NeuroGT, Inc. |
alpha-L-iduronidase (IDUA) - ricin transport subunit B (RTB) lectin protein fusion | proteins | FDA | 2022-07-01 | — | BioStrategies LC |
Allogeneic retinal pigment epithelial cells genetically modified with a non-viral vector to express human alpha-L-iduronidase | cell therapies | EMA | 2021-10-15 | — | [INACTIVE] TMC Pharma (EU) Limited |
Alpha-L-iduronidase fused to Fab fragment of a humanised monoclonal antibody targeting human transferrin receptor | proteins | EMA | 2021-03-26 | — | JCR Europe B.V. |
Recombinant fusion protein of human alpha-L-iduronidase (IDUA) and Fab fragment of a humanized monoclonal antibody targeting human transferrin receptor (hTfR). | proteins | FDA | 2021-02-08 | — | JCR Pharmaceuticals Co., Ltd. |
Cultured human retinal pigment epithelial cells (ARPE-19) genetically modified with a non-viral vector to express human native alpha-L-iduronidase enzyme (hIDUA), encapsulated within two-layer modified alginate spheres | cell therapies | FDA | 2020-12-14 | — | Sigilon Therapeutics, Inc. |
a single-stranded adeno-associated virus serotype 8 gene therapy containing codon optimized human alpha-1-iduronidase cDNA. | gene therapies | FDA | 2020-10-22 | — | Rain Bio, Inc. |
Autologous CD34+ enriched cell population that contains hematopoietic stem and progenitor cells transduced ex-vivo using a lentiviral vector encoding alpha-L-iduronidase gene | gene therapies | FDA | 2020-06-22 | — | Orchard Therapeutics (Europe) Limited |
pentosan polysulfate | small molecules | FDA | 2020-04-28 | — | Paradigm Biopharmaceuticals Ltd. |
Autologous CD34+ haematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the alpha-L-iduronidase cDNA | gene therapies | EMA | 2018-10-26 | — | Orchard Therapeutics (Netherlands) B.V. |
Recombinant adeno-associated viral vector serotype 9 containing human iduronidase gene | gene therapies | EMA | 2018-06-27 | — | Regenxbio EU Limited |
Sleeping Beauty Transposon-Engineered Autologous Plasmablasts for Expression and Delivery of Alpha-L-Iduronidase | cell therapies | FDA | 2018-03-19 | — | Immusoft Corporation |
Devafidugene civaparvovec | gene therapies | EMA | 2018-01-17 | — | Sangamo Therapeutics France S.A.S. |
adeno-associated virus serotype 2/6 (rAAV2/6) vectors encoding zinc finger nucleases (ZFNs) and the human alpha-L-iduronidase (hIDUA) gene | gene therapies | FDA | 2017-01-09 | — | Sangamo Therapeutics, Inc. |
6-(R)-Methyl-5-O-(5-amino-5,6-dideoxy-a-L-talofuranosyl)- paromamine sulfate | small molecules | FDA | 2016-10-18 | — | Eloxx Pharmaceuticals, Ltd. |
6'-(R)-methyl-5-O-(5-amino-5,6-dideoxy-α-L-talofuranosyl)-paromamine sulfate | small molecules | EMA | 2016-08-29 | — | FGK Representative Service GmbH |
aden-associated virus vector serotype 9 expressing human a-L-iduronidase | gene therapies | FDA | 2015-09-29 | — | REGENXBIO, Inc. |
ataluren | small molecules | FDA | 2014-12-10 | — | PTC Therapeutics, Inc. |
Ataluren [Translarna] | small molecules | EMA | 2014-11-19 | — | PTC Therapeutics International Limited |
Pentosan polysulfate sodium | small molecules | EMA | 2014-11-19 | — | Paradigm Biopharmaceuticals (Ireland) Limited |
Valanafusp alfa [AGT-181] | proteins | EMA | 2014-10-15 | — | Voisin Consulting Life Sciences |
iduvec | gene therapies | FDA | 2011-01-21 | — | Zebraic Corporation |
IDUA-HIRMAb fusion protein | proteins | FDA | 2008-01-10 | — | ArmaGen Technologies, Inc. |
Recombinant human highly phosphorylated alpha-L-iduronidase (rhHP-IDUA) | proteins | FDA | 2001-04-11 | — | Novazyme Pharmaceuticals, Inc. |
Laronidase [Aldurazyme] | proteins | EMA | 2001-02-14 | — | [INACTIVE] Sanofi B.V. |
laronidase [Aldurazyme] | proteins | FDA | 1997-09-24 | 2003-04-30 | BioMarin Pharmaceutical, Inc. |
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