RARE DISEASE
Mucopolysaccharidosis type 2
Mucopolysaccharidosis type 2
Mucopolysaccharidosis type 2
Synonyms: Hunter syndrome, Iduronate 2-sulfatase deficiency, MPS2, MPSII, Mucopolysaccharidosis type II
Synonyms: Hunter syndrome, Iduronate 2-sulfatase deficiency, MPS2, MPSII, Mucopolysaccharidosis type II
Synonyms: Hunter syndrome, Iduronate 2-sulfatase deficiency, MPS2, MPSII, Mucopolysaccharidosis type II
Drug discovery
24
drugs
With orphan designations
Overview
Mucopolysaccharidosis type II (MPS II/Hunter syndrome) is an X-linked lysosomal storage disorder caused by IDS gene mutations, resulting in iduronate-2-sulfatase deficiency and systemic glycosaminoglycan accumulation. It manifests with coarse facial features, skeletal abnormalities (dysostosis multiplex), organomegaly, airway obstruction, and progressive neurodegeneration in severe forms. Two subtypes exist: neuropathic (rapid cognitive decline) and non-neuropathic. Diagnosis involves enzyme activity assays, urinary GAG analysis, and genetic testing [1,2,6].
Population
Almost exclusively affects males (X-linked recessive)
Birth prevalence: 1/100,000-1/170,000 males [1,2,12]
Symptom onset typically between 18 months-4 years [2,6]
Burden
Median lifespan: 10-20 years (severe neuropathic); 20-60 years (attenuated) [2,7]
Major morbidity: Cardiorespiratory failure, spinal cord compression, and progressive physical disability [1,16]
High economic burden: Annual costs exceed $500,000/patient for ERT, with frequent hospitalizations [4,11]
Emerging therapies include intrathecal ERT, gene therapy, and substrate reduction therapy currently in clinical trials [3,13].
Therapies
Enzyme replacement therapy (ERT): Weekly intravenous idursulfase improves somatic symptoms but lacks CNS efficacy [3,8,13]
Hematopoietic stem cell transplantation (HSCT): Considered for early neuropathic cases, with variable outcomes [3,19]
Supportive care: Surgical interventions (airway management, hernia repair), anti-inflammatory agents, and multidisciplinary monitoring [2,8]
Categories: rare bone diseases, rare cardiac diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare skin diseases, rare transplant-related disorders
Research Papers
559 drug discovery papers about Mucopolysaccharidosis type 2, with 2 first-in-class and 19 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
559 drug discovery papers about Mucopolysaccharidosis type 2, with 2 first-in-class and 19 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-16 | Breaking Biological Barriers: Engineering Nanocarriers for Efficient Drug and Gene Delivery through Nano-Bio Interfaces and Biophysical Design.
A persistent challenge in nanomedicine is achieving functional delivery of therapeutic molecules across physiological barriers. Organs impose distinct transport constraints, including the blood-brain barrier, renal filtration, hepatic sequestration, and pulmonary clearance. Although substantial effort has focused on engineering particle structure and surface chemistry, therapeutic performance also depends on dynamic interactions at the nano-bio interface. This structured critical narrative review compares how nanoparticle design variables interact with organ-specific transport mechanisms, prioritizing mechanistic primary studies and direct clinical or regulatory evidence while preserving study-specific experimental conditions. Most review papers focus on a single disease or summarize the progress of a specific nanoparticle type. In contrast, this review addresses the heterogeneity of biological filters by proposing a barrier-specific engineering framework. We evaluate diverse high-barrier environments with distinct restrictive mechanisms and describe the strategies used to overcome them in nanoparticle design. Specifically, we focus on how matching physicochemical properties to these environments can bypass physiological constraints. Using a comparative analysis methodology, we evaluate how design parameters, including size, morphology, and surface functionalization, interact with the mechanisms of major organ systems. Applying this framework across biological barriers distinguishes study-specific relationships from potentially transferable design principles. Its clinical and translational relevance is illustrated by engineered blood-brain barrier shuttles for Hunter syndrome and Alzheimer disease, lipid nanoparticle platforms for mRNA vaccination, and inhaled liposomal therapies.
2026-09-11 | Longitudinal Assessment of Cognitive Development in 23 Patients With Mucopolysaccharidosis (MPS) Type II: Results of up to 14 Years of Follow-Up.
This study investigated long-term cognitive development and genotype-phenotype relationships in patients with Mucopolysaccharidosis Type II (MPS II). A nationwide prospective cohort study was conducted in the Netherlands with cognitive follow-up since 2007. Patients were classified as neuronopathic or non-neuronopathic based on iduronate-2-sulphatase (IDS) genotype; novel variants based on age and intelligence quotient (IQ). IQ and Mental Age (MA) were analysed individually and, using linear mixed-effect models, at group level to compare trajectories by genotype and phenotype. Twenty-three male patients (22 children, 1 adult) underwent 136 cognitive assessments, beginning at a median age of 2.9 years with a median follow-up of 6.3 (range 0-13.5) years. IQ and MA trajectories significantly differed between neuronopathic and non-neuronopathic patients (p < 0.001). Non-neuronopathic patients (n = 5) showed normal or mildly impaired cognition. Neuronopathic patients (n = 18) initially developed normally, then stagnated, plateaued, and declined; IQ fell below 70 at a median age of 4 years. Patients with deletions (n = 3) experienced the earliest, most severe impairment (p < 0.001), while those with other IDS variants showed more variable trajectories. Neurocognitive patterns diverge early in MPS II, highlighting the importance of understanding genotype-specific developmental trajectories. This insight is essential for guiding timely brain-targeted interventions, ideally initiated before neurocognitive decline begins.
2026-06-22 | Clinical Outcomes of Ayurvedic Management in Hunter Syndrome: A Case Report
Introduction: Hunter Syndrome, otherwise called Mucopolysaccharidosis Type II, is a rare X- linked Lysosomal Storage disorder, occurring due to the deficiency of Iduronate-2-sulfatase enzyme (I2S). This leads to impaired Glycosaminoglycans catabolism (GAGs), resulting in the pathological accumulation of Heparan sulfate and Dermatan sulfate in multiple tissues and organs. It manifests as a progressive, multisystemic, genetic metabolic disorder. In Ayurveda, Hunter Syndrome is correlated with Sahaja Vyadhi (genetic disease) arising due to genetic defects, manifesting with persistent, impaired metabolism, coarse facies, hirsutism, multiple joint contractures, short stature, hyperactivity, and subnormal cognitive development. Methods: A single case study of a 4-year-old boy with Hunter syndrome was evaluated to analyze the efficacy of ayurvedic therapies on the quality of life. The child was managed with symptomatic treatment and rejuvenation therapy. Oral medicines were targeted for Deepana (appetite stimulant), and Pachana (digestive) to rectify metabolism and to improve cognitive abilities. Procedure-based therapies were targeted to treat physical impairments. Results: After five months of exclusive oral medications and one course of external therapies, the child showed improvement in metabolic activity, cognitive abilities and joint mobility, marking overall well-being and enhanced quality of life. Conclusion: Hunter syndrome is an early onset, progressive disorder, with high morbidity and poor life expectancy, making it a Sahaja Vata Pradhana Tridoshaja Vyadhi. Early diagnosis, genetic counseling, and an integrative approach combining contemporary and traditional therapeutic strategies may reduce mortality and improve long- term health outcomes in affected children.
2026-06-15 | Synthesis of a C-2 Functionalized l-Iduronic Acid Derivative as a Candidate Pharmacological Chaperone for MPS II (Hunter Syndrome).
A C-2 functionalized l-IdoA derivative was designed as a potential pharmacological chaperone for MPS II, and several routes to its synthesis were investigated. Successful synthesis proceeded via an oxidation/Horner-Wadsworth-Emmons sequence, overcoming significant challenges with competing elimination reactions to give alkene derivatives in good overall yields. Catalytic hydrogenation of the double bonds proceeded stereoselectively in high yield to give the desired L-ido-configured products, confirmed by x-ray crystallographic analysis. These were subsequently elaborated to the target dicarboxylate prodrug 1 in good overall yield. Molecular docking studies suggest the parent compound engages with the active site and makes several H-bonding interactions with key active site residues. Target prodrug 1 and known chaperone D2S0 were evaluated against two MPS II cell lines, but neither compound was able to reduce HS substrate levels at the doses tested.
2026-05-10 | Treosulfan-based conditioning for hematopoietic stem cell transplantation in mucopolysaccharidosis: a pilot study.
Treosulfan (Treo), a prodrug of a bifunctional alkylating agent, has been used in conditioning regimens to reduce the risk of hepatic sinusoidal obstruction syndrome. We aimed to establish a Treo-based conditioning regimen for mucopolysaccharidosis (MPS) as a phase 1 study. The regimen included thoracoabdominal irradiation, Treo, fludarabine, and antithymocyte globulin. Antithymocyte globulin was omitted in cord blood transplantation. Five patients with MPS II, aged 8 months to 21 years, were enrolled. Stem cell sources were HLA-C-mismatched unrelated bone marrow in one patient and HLA 1 to 3 allele-mismatched cord blood in four. No patients experienced grade 4 toxicities. Absolute neutrophil count > 500/µL was achieved at a median of 16 days. A pharmacokinetic study showed that AUC0-12h was 50% higher in children than in adults. Bone marrow donor chimerism at 4 weeks post-transplant was 100% in two patients and 96.7% to 98.1% in three; at 8 weeks, it was 100% in four patients and 77.1% in one who received a reduced dose of Treo. Three patients are alive, but two died at 415 and 767 days post-transplant due to factors unrelated to the conditioning regimen. Treo remains a valuable agent for conditioning regimens in MPS.
cell therapies
2024-08-09 | [Clinical phenotype, genetic characteristics, and creation of immortalized cell lines for patients from a pedigree affected with Hunter syndrome].
To explore the clinical phenotype and genetic variant in a Chinese pedigree affected with Hunter syndrome and create immortalized cell lines for the affected pedigree members. A pedigree of six members who had visited Xi'an Children's Hospital in July 2022 was selected as the study subject. Clinical data was collected. Whole exome sequencing was carried out for the pedigree members. Candidate variant was verified by Sanger sequencing. In addition, peripheral B lymphocytes were transfected with Epstein-Barr virus to create immortalized cell lines, which were then subjected to enzyme activity analysis. The patient, a five-year-and-seven-month-old boy, had exhibited stiff limbs and enlarged joints. He had developed hernia, scaphocephaly, and barrel chest from 3 months of age. His uncle also had stiff limbs, poor hearing, blindness, and right oblique inguinal hernia. Above features had resembled those of Hunter syndrome. Genetic testing revealed that both the child and his uncle had harbored an IDS (NM_000202.8): c.823G>A (p.D275N) variant, which was unreported previously. Bioinformatic analysis indicated that the D275 to be a highly conserved site, and the D275N variant may affect the stability of the protein's spatial conformation, thereby decrease the catalytic activity of the enzyme. The successfully constructed immortalized lymphoblastoid cell lines for the child and his parents showed increased volume, irregular shape, burr structure and cluster growth. And the value of IDS activity of the patient's immortalized lymphoblastoid cells was below the limit of detection. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PS3+PM2_Supporting+PM5+PP1+PP3). Above finding has enriched the phenotypic and mutational spectra of Hunter syndrome, and provided a basis for the genetic counseling for this pedigree. The creation of immortalized cell lines has offered a model for further investigation of the impact of variant on the function of IDS and development of targeted drugs.
2024-03-29 | Modeling Lysosomal Storage Disorders in an Innovative Way: Establishment and Characterization of Stem Cell Lines from Human Exfoliated Deciduous Teeth of Mucopolysaccharidosis Type II Patients.
Among the many lysosomal storage disorders (LSDs) that would benefit from the establishment of novel cell models, either patient-derived or genetically engineered, is mucopolysaccharidosis type II (MPS II). Here, we present our results on the establishment and characterization of two MPS II patient-derived stem cell line(s) from deciduous baby teeth. To the best of our knowledge, this is the first time a stem cell population has been isolated from LSD patient samples obtained from the dental pulp. Taking into account our results on the molecular and biochemical characterization of those cells and the fact that they exhibit visible and measurable disease phenotypes, we consider these cells may qualify as a valuable disease model, which may be useful for both pathophysiological assessments and in vitro screenings. Ultimately, we believe that patient-derived dental pulp stem cells (DPSCs), particularly those isolated from human exfoliated deciduous teeth (SHEDs), may represent a feasible alternative to induced pluripotent stem cells (iPSCs) in many labs with standard cell culture conditions and limited (human and economic) resources.
2023-04-25 | Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II.
Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS-/- NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.
2019-02-01 | Platform technology for treatment of the brain in lysosomal disorders: Application to Tay-Sachs disease
Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS−/− NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.
2012-09-07 | Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: A nationwide survey in Japan
Hematopoietic stem cell transplantation (HSCT) has not been indicated for patients with mucopolysaccharidosis II (MPS II, Hunter syndrome), while it is indicated for mucopolysaccharidosis I (MPS I) patients < 2 years of age and an intelligence quotient (IQ) of ≥ 70. Even after the approval of enzyme replacement therapy for both of MPS I and II, HSCT is still indicated for patients with MPS I severe form (Hurler syndrome). To evaluate the efficacy and benefit of HSCT in MPS II patients, we carried out a nationwide retrospective study in Japan. Activities of daily living (ADL), IQ, brain magnetic resonance image (MRI) lesions, cardiac valvular regurgitation, and urinary glycosaminoglycan (GAG) were analyzed at baseline and at the most recent visit. We also performed a questionnaire analysis about ADL for an HSCT-treated cohort and an untreated cohort (natural history). Records of 21 patients were collected from eight hospitals. The follow-up period in the retrospective study was 9.6 ± 3.5 years. ADL was maintained around baseline levels. Cribriform changes and ventricular dilatation on brain MRI were improved in 9/17 and 4/17 patients, respectively. Stabilization of brain atrophy was shown in 11/17 patients. Cardiac valvular regurgitation was diminished in 20/63 valves. Urinary GAG concentration was remarkably lower in HSCT-treated patients than age-matched untreated patients. In the questionnaire analysis, speech deterioration was observed in 12/19 patients in the untreated cohort and 1/7 patient in HSCT-treated cohort. HSCT showed effectiveness towards brain or heart involvement, when performed before signs of brain atrophy or valvular regurgitation appear. We consider HSCT is worthwhile in early stages of the disease for patients with MPS II.
proteins
2026-09-01 | Interim analysis of post-marketing surveillance study of intracerebroventricular idursulfase therapy for neuronopathic mucopolysaccharidosis type II: Safety and effectiveness in clinical practice in Japan.
Mucopolysaccharidosis type II (MPS II) results from iduronate-2-sulfatase (IDS) enzyme deficiency due to IDS gene mutations. Most patients with neuronopathic MPS II experience progressive neurological decline; however, effectiveness of standard treatment, intravenous idursulfase, is limited by blood-brain barrier transfer. Intracerebroventricular (ICV) idursulfase beta, approved in Japan in 2021, directly delivers idursulfase beta into cerebral ventricles. This post-marketing surveillance reports long-term effectiveness and safety of ICV idursulfase beta (30 mg every 4 weeks) in all treated patients from April 2021 through August 2024. Outcomes included cerebrospinal fluid (CSF) heparan sulfate (HS) levels (quarterly), developmental age (DA; Kyoto Scale of Psychological Development, annually), and safety. Thirty-seven Japanese male patients across 21 sites were enrolled (safety population n = 36; effectiveness population n = 35). Mean CSF HS concentrations decreased from 7.36 to 3.19 μg/mL from baseline to week 24, with reduction sustained through week 100. Patients who initiated treatment within 3 years of age had DA progression aligned with healthy cohorts, regardless of mutation type; however, those starting later had no comparable benefit. Adverse events (AEs) occurred in 20 patients (55.6%). Procedure-related serious AEs (SAEs) occurred in 2 patients (bacterial meningitis, device-related infection, pyrexia). Treatment-related AEs affected 14 patients (38.9%), mainly pyrexia (27.8%, including one SAE). One SAE (membranous glomerulonephritis) was not intervention related. No deaths, anaphylaxis, or anti-IDS antibodies in CSF were detected. ICV idursulfase beta demonstrated sustained CSF HS reduction with no new safety signals. Earlier treatment initiation (≤3 years) was associated with improved neurodevelopmental outcomes, regardless of mutation type.
2026-08-14 | PRE-CONGRESS «CURRENT ISSUES IN THE DIAGNOSIS AND THERAPY OF HUNTER SYNDROME» OF THE VIII ALL-RUSSIAN SCIENTIFIC AND PRACTICAL CONGRESS WITH INTERNATIONAL PARTICIPATION «ORPHAN DISEASES»
Pre-Congress «Current Issues in the Diagnosis and Therapy of Hunter Syndrome» of the VIII All-Russian Scientific and Practical Congress with International Participation «Orphan Diseases». Pediatria n.a. G.N. Speransky. 2026; 105 (4): 151–153. DOI: 10.24110/0031-403X-2026-105-4-151-153.
2026-08-09 | The IDS Gene Variant c.851C>T, p.P284L: More Evidence Against its Role as a Pathogenic Mutation in Mucopolysaccharidosis Type II
The Data of research The IDS Gene Variant c.851C>T, p.P284L: More Evidence Against its Role as a Pathogenic Mutation in Mucopolysaccharidosis Type II
2026-07-30 | Treatment outcomes maintained in Hunter syndrome patients: a case series on switching from idursulfase to idursulfase beta in Belarus.
Hunter syndrome (Mucopolysaccharidosis type II, MPS II) is a rare X-linked lysosomal storage disorder caused by iduronate-2-sulfatase deficiency, leading to glycosaminoglycan accumulation. Enzyme replacement therapy (ERT) with idursulfase is a standard treatment, although supply shortages may disrupt continuity of care. This retrospective case series describes clinical and biochemical outcomes in seven patients with Hunter syndrome in Belarus who were switched from idursulfase (Elaprase®) to idursulfase beta (Hunterase®). Patients were evaluated before and after the switch using urinary GAG levels, 6-minute walking test (6MWT), liver and spleen size, and safety parameters. Following the transition, patients maintained or improved clinical outcomes, with continued reductions in urinary GAG levels, stable or improved 6MWT performance, and further decreases in organ enlargement. No new safety concerns were identified. These findings suggest that switching to idursulfase beta may preserve therapeutic benefits and support treatment continuity in real-world settings.
2026-07-09 | Sustained clinical benefit of idursulfase beta in mucopolysaccharidosis II: two-year experience from a phase 3 extension study including patients switched from idursulfase.
Long-term safety and efficacy data on enzyme replacement therapy, particularly switching between recombinant iduronate-2-sulfatase formulations, remain limited in mucopolysaccharidosis II (MPS II). This open-label extension study included male patients with MPS II who completed a 52-week, phase 3 trial and either continued idursulfase beta (maintenance group, n = 22) or switched from idursulfase (switch group, n = 6). Participants received weekly intravenous idursulfase beta (0.5 mg/kg) for an additional 52 weeks. Safety, immunogenicity, six-minute walk test (6-MWT), and urinary glycosaminoglycan (GAG) levels were evaluated longitudinally for two years. Changes over time were analyzed using descriptive statistics and mixed models for repeated measures. Over the two-year treatment period, no new safety signals were identified in both groups. In the maintenance group, the incidence of adverse drug reactions decreased in the second year compared with the first year (from 54.5% to 13.6%); anti-drug antibody positivity peaked within the first six months and subsequently declined, with a low prevalence of neutralizing antibodies (4.5-22.7%). At Month 24, least-square mean changes from baseline demonstrated a 23.1% increase in 6-MWT distance and a 73.1% reduction in urinary total GAG levels in the maintenance group. Patients switching from idursulfase showed comparable safety profiles and sustained functional and biochemical improvements. These results demonstrate that idursulfase beta is safe and efficacious in the long-term management of MPS II. Additionally, switching from idursulfase to idursulfase beta preserved therapeutic efficacy without additional safety or immunogenicity concerns, supporting idursulfase beta as a viable option following prior idursulfase therapy. The study was registered at ClinicalTrials.gov (identifier, NCT07344376 date of registration, 7 January 2026).
gene therapies
2025-12-29 | Intravenous Delivery of a Gene Therapy Vector that Expresses an Antitransferrin Receptor 1 Nanobody-I2S Fusion Protein Rescued Central Nervous System Lysosomal Burden in Mucopolysaccharidosis II Mice.
Hunter syndrome, also known as mucopolysaccharidosis type II, is an X-linked lysosomal storage disease caused by the deficiency of functional iduronate-2-sulfatase (I2S) enzyme, leading to the accumulation of lysosomal glycosaminoglycans (GAGs) affecting multiple organs. Two-thirds of patients have central nervous system (CNS) manifestations. The current standard of care, enzyme replacement therapy (ERT) via weekly intravenous delivery of recombinant human I2S (rhI2S), does not address the neuropathy in the CNS due to its inability to cross the blood-brain barrier (BBB). Next-generation ERTs consisting of systemically administered rhI2S linked to antibodies that target the transferrin receptor (TfR) have shown clinical efficacy in addressing CNS and peripheral manifestations of disease. We demonstrate here that systemic administration of recombinant AAV9 gene therapy vectors encoding human I2S fusion protein with a TfR1-targeted Variable Heavy chain domain of Heavy chain (VHH) nanobody at the N-terminus normalized brain and cerebrospinal fluid GAGs in symptomatic Ids knockout (Ids KO) mice. This ability to correct toxic substrate accumulation in the CNS was superior to gene therapy vectors expressing I2S with a C-terminal VHH tag or untagged I2S control. The VHH-I2S transgene product demonstrated a broader distribution in the brain parenchyma, coincident with a significant reduction of lysosomal-associated membrane protein 1 immunoreactivity, unlike untagged I2S and I2S-VHH transgene products. These data illuminate strategies to enhance AAV gene therapy vector design and leverage receptor-mediated transcytosis to strategize BBB-penetrating gene therapy for addressing the unmet medical needs of neuronopathic Hunter syndrome.
2025-09-30 | Domain-substituted IGF2 tag modulates targeting of lentiviral gene therapy for Hunter syndrome.
We present the SWAP design, a novel, structurally cohesive IGF2-based tag for modular receptor targeting during gene therapy for lysosomal storage disorders (LSDs). We found that IGF2's central loop is critical for high-affinity binding to the insulin receptor (IR) and IGF1 receptor (IGF1R)-both involved in glucose homeostasis-but is not required for interaction with the cation independent mannose 6-phosphate/IGF2 receptor (CI-M6P/IGF2R)-a key target for lysosomal delivery. This formed the basis for designing the Substitution of the central-loop With Augmenting Peptides (SWAP) tag. By replacing the central loop with alternative epitopes, SWAP ensures high-affinity multimodal receptor targeting while maintaining structural integrity. In vivo, lentiviral gene therapy employing IDS fused to SWAP variants containing ApoE and RAP12x2 inserts corrected Hunter disease pathology across multiple tissues, including liver, spleen, heart, bone, and brain, matching the efficacy of the traditional IGF2 tag. These findings position SWAP as a novel and effective tag design for IGF2-based therapeutics with a more favourable ligand-receptor interaction.
2025-09-20 | Rescue of neurologic disease in mucopolysaccharidosis type II mice via AAV-mediated liver delivery of brain-penetrating iduronate-2-sulfatase.
Mucopolysaccharidosis type II (MPS II) is a neurodegenerative lysosomal storage disorder (LSD) caused by inherited mutations in the iduronate-2-sulfatase (IDS) gene. Approximately two-thirds of patients exhibit severe central nervous system (CNS) involvement and cognitive impairment, which remain unaddressed by conventional enzyme replacement therapy (ERT) due to the inability of wild-type IDS to cross the blood-brain barrier (BBB). To overcome this limitation, we engineered a brain-penetrant IDS variant, eBT-IDS4, which retained enzymatic activity and demonstrated enhanced BBB transcytosis in vitro. We then evaluated a liver-directed gene therapy approach using an adeno-associated virus 8 (AAV8) vector encoding eBT-IDS4 under the control of a liver-specific promoter (LSP) in an adult MPS II mouse model. Intravenous administration of AAV8.LSP.IVS2.eBT-IDS4 resulted in sustained supraphysiological IDS activity and normalization of glycosaminoglycan (GAG) levels in peripheral tissues. Notably, this strategy achieved 89 % of wild-type IDS activity in the brain, leading to complete correction of neuropathology and reversal of cognitive deficits in 8-month-old MPS II mice. These findings support a promising, minimally invasive gene therapy strategy for treating MPS II and other neurodegenerative LSDs.
2024-03-27 | Cellular Organelle-Related Transcriptomic Profile Abnormalities in Neuronopathic Types of Mucopolysaccharidosis: A Comparison with Other Neurodegenerative Diseases.
Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG) degradation. As a result, GAGs accumulate in lysosomes, impairing the proper functioning of entire cells and tissues. There are 14 types/subtypes of MPS, which are differentiated by the kind(s) of accumulated GAG(s) and the type of a non-functional lysosomal enzyme. Some of these types (severe forms of MPS types I and II, MPS III, and MPS VII) are characterized by extensive central nervous system disorders. The aim of this work was to identify, using transcriptomic methods, organelle-related genes whose expression levels are changed in neuronopathic types of MPS compared to healthy cells while remaining unchanged in non-neuronopathic types of MPS. The study was conducted with fibroblast lines derived from patients with neuronopathic and non-neuronopathic types of MPS and control (healthy) fibroblasts. Transcriptomic analysis has identified genes related to cellular organelles whose expression is altered. Then, using fluorescence and electron microscopy, we assessed the morphology of selected structures. Our analyses indicated that the genes whose expression is affected in neuronopathic MPS are often associated with the structures or functions of the cell nucleus, endoplasmic reticulum, or Golgi apparatus. Electron microscopic studies confirmed disruptions in the structures of these organelles. Special attention was paid to up-regulated genes, such as PDIA3 and MFGE8, and down-regulated genes, such as ARL6IP6, ABHD5, PDE4DIP, YIPF5, and CLDN11. Of particular interest is also the GM130 (GOLGA2) gene, which encodes golgin A2, which revealed an increased expression in neuronopathic MPS types. We propose to consider the levels of mRNAs of these genes as candidates for biomarkers of neurodegeneration in MPS. These genes may also become potential targets for therapies under development for neurological disorders associated with MPS and candidates for markers of the effectiveness of these therapies. Although fibroblasts rather than nerve cells were used in this study, it is worth noting that potential genetic markers characteristic solely of neurons would be impractical in testing patients, contrary to somatic cells that can be relatively easily obtained from assessed persons.
2021-11-02 | Programmable large DNA deletion, replacement, integration, and inversion with twin prime editing and site-specific recombinases
Summary The targeted deletion, replacement, integration, or inversion of DNA sequences at specified locations in the genome could be used to study or treat many human genetic diseases. Here, we describe twin prime editing (twinPE), a method for the programmable replacement or excision of DNA sequence at endogenous human genomic sites without requiring double-strand DNA breaks. TwinPE uses a prime editor (PE) protein and two prime editing guide RNAs (pegRNAs) that template the synthesis of complementary DNA flaps on opposing strands of genomic DNA, resulting in the replacement of endogenous DNA sequence between the PE-induced nick sites with pegRNA-encoded sequences. We show that twinPE in human cells can perform precise deletions of at least 780 bp and precise replacements of genomic DNA sequence with new sequences of at least 108 bp. By combining single or multiplexed twinPE with site-specific serine recombinases either in separate steps or in a single step, we demonstrate targeted integration of gene-sized DNA plasmids (>5,000 bp) into safe-harbor loci including AAVS1 , CCR5, and ALB in human cells. To our knowledge, these results represent the first RNA-programmable insertion of gene-sized DNA sequences into targeted genomic sites of unmodified human cells without requiring double-strand breaks or homology-directed repair. Twin PE combined with recombinases also mediated a 40,167-bp inversion at IDS that corrects a common Hunter syndrome allele. TwinPE expands the capabilities of precision gene editing without requiring double-strand DNA breaks and synergizes with other tools to enable the correction or complementation of large or complex pathogenic alleles in human cells.
other
2026-07-21 | New Paradigms in Management of Central Nervous System Damage in Patients with Hunter Syndrome
Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a progressive lysosomal storage disease with X-linked recessive inheritance. This disease is caused by pathogenic or probably pathogenic variants in the IDS gene encoding iduronate 2-sulfatase. This enzyme insufficiency leads to glycosaminoglycans accumulation in cells of various organs and tissues, which underlies the multisystem lesion. There is neuropathic form of MPS II with progressive central nervous system (CNS) damage and behavioral disorders, and milder form without any intellectual disorders. There are methods of effective pathogenetic therapy for this disease, however, they do not affect CNS manifestations. Thus, there is topical issue in management of neuropathic MPS II forms on transporting enzyme-replacement medications through the blood-brain barrier (BBB). Development of pabinafusp alfa (JR-141), innovative drug penetrating the BBB via transcytosis mediated by the transferrin receptor, became one of the approaches to solve this problem. This publication provides the literature review on the pabinafusp alfa administration for management of neuropathic MPS II forms focusing its efficacy and safety.
2025-02-07 | Bodyweight and Absolute Lymphocyte Count-Based Dosing of Rabbit Anti-thymocyte Globulin Results in Early CD4+ Immune Reconstitution in Patients with Inborn Errors of Metabolism Undergoing Umbilical Cord Blood Transplantation.
Rabbit anti-thymocyte globulin (rATG) decreases the risk of graft failure and graft-versus-host disease (GVHD) in a setting of allogenic hematopoietic cell transplantation (HCT) but has highly variable pharmacokinetics. Recently, it was shown that a dosing nomogram based on recipient bodyweight and absolute lymphocyte count reduced rATG overexposure, which led to faster immune reconstitution. The aim of this study is to evaluate the feasibility and benefits of using an rATG dosing nomogram to achieve early CD4+ immune reconstitution in pediatric patients with inborn errors of metabolism (IEM) undergoing umbilical cord blood transplantation. The rATG dosing nomogram in pediatric patients with IEM receiving an umbilical cord blood transplant with busulfan-based myeloablative conditioning at the University of Minnesota Masonic Children's Hospital was used prospectively since 2017. The primary endpoint was CD4+ immune reconstitution (>50 CD4+ T-cells/mL) within 100 days after HCT. Secondary endpoints included overall survival, graft failure, acute and chronic GVHD, and viral reactivations. A total of 27 patients were included in the study. Median follow-up time was 31 months (interquartile range [IQR], 22-38) and median age was 1.5 years (IQR, 0.7-3.9). The underlying disease was Hurler syndrome in 17 (63%), Hunter syndrome in 4 (15%), and cerebral adrenoleukodystrophy in 4 (15%) patients; 2 patients were transplanted for other IEM. The CD4+ recovery (>50 CD4+ T cells/mL) at 100 days post-HCT was reached in 22 (85%) of 26 patients. Overall survival was 83% (95% confidence interval [CI], 67%-100%). No graft failure was observed. Two (7%) patients developed acute GVHD grade II to IV and no patients had chronic GVHD. Six patients (22%) had cytomegalovirus (CMV) viremia. One patient had Epstein-Barr virus reactivation requiring treatment. In patients with IEM, individualized dosing of rATG was associated with a robust and early CD4+ immune reconstitution, with no graft failures and low GVHD incidence.
2024-11-22 | 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.
2024-07-31 | 14 A precision medicine tool for high utilization and quality of individual treatment trials with immunomodulatory drugs in mucopolysaccharidosis
The growing understanding of the innate immune response in Mucopolysaccharidosis (MPS) revealed potential targets for intervening, including the repurposing of immunomodulatory drugs. Individual treatment trials (ITT) could efficiently translate this knowledge into clinical use. However, despite the limited efficacy of approved drugs and the high level of suffering this has so far hardly been used - at least these are not reported or published. We analysed the subjective need for, utilisation of and barriers to ITT by an international MPS-expert survey. Based on that and by adapting a validated decision analysis framework (DAF) we developed an innovative, quantitative, personalizable benefit-risk assessment model to overcome barriers to ITT in MPS. Our strategy is based on the following steps i) MPS-expert survey on ITT in MPS, (ii) systematic literature review regarding relevant targets and clinical pharmacology of immunomodulatory drugs, (iii) quantitative DAF data acquisition with the creation of a framed decision context and assigning weights to relevant outcomes, (iv) enabling personali-zability by phenotypic profiling and assessing specific probabilities of expected beneficial out-comes, (v) an assessment standard for ITT with immunomodulatory drugs in MPS. These steps are in accordance with an international, interdisciplinary board of experts as well as patient representatives. Our survey (n=27) demonstrated that the majority of MPS-experts is familiar with the concept of ITT (73%), however only few ever conducted (35%) or published those (6%) reported those. A free service for data-driven treatment choices is expected to in-crease the utilization and quality of ITT by 85%. We identified Anakinra, Adalimumab, Abatacept and Cladribine as top candidates and defined first and second choices for different phenotypes. Our developed evidence-based, personalizable, quantitative DAF model for ITT characterizes the first step towards precision medicine with immunomodulatory drugs in MPS.
2023-12-14 | Urine proteome uncover common mechanism between mucopolysaccharidosis type I and II
Abstract Mucopolysaccharidosis (MPS) type I and II are two types of rare lysosomal storage diseases, which lead to the accumulation of glycosaminoglycans due to the lack of the enzyme alpha-L-iduronidase (IDUA) and iduronate 2-sulfatase (IDS) respectively. There are some similar pathogenic mechanisms and clinical phenotypes but also some specific minute manifestations between these two subtypes. To better understand the similarities in the pathogenesis and clinical symptoms of these two diseases and the mechanism of differential symptoms, we used TMT technology to analyze the differential protein profiles in the urine of MPS I and MPS II patients. We detected the differential proteins of MPS I and MPS II compared with the control group separately. After that, we focused on 227 differentially expressed proteins (DEPs) which showed consistent changes in the urine of both MPS I and MPS II. Parallel reaction monitoring (PRM) analysis verified that up-regulated HEXB and down-regulated HBA1 showed significant difference in the urine of both subtypes. In addition, we found 391 DEPs by comparative analysis of MPS I and MPS II proteomes and found that DHRS2 contributed to the difference between the two subtypes by PRM verification. Therefore, our study demonstrates the value of multi-sample proteomics combined analysis in exploring the similarities and differences of functional proteins between MPS I and MPS II, which provides a new idea for the clinical study of the characteristics of MPS subtypes and the exploration of common treatment options.
small molecules
2026-09-16 | Breaking Biological Barriers: Engineering Nanocarriers for Efficient Drug and Gene Delivery through Nano-Bio Interfaces and Biophysical Design.
A persistent challenge in nanomedicine is achieving functional delivery of therapeutic molecules across physiological barriers. Organs impose distinct transport constraints, including the blood-brain barrier, renal filtration, hepatic sequestration, and pulmonary clearance. Although substantial effort has focused on engineering particle structure and surface chemistry, therapeutic performance also depends on dynamic interactions at the nano-bio interface. This structured critical narrative review compares how nanoparticle design variables interact with organ-specific transport mechanisms, prioritizing mechanistic primary studies and direct clinical or regulatory evidence while preserving study-specific experimental conditions. Most review papers focus on a single disease or summarize the progress of a specific nanoparticle type. In contrast, this review addresses the heterogeneity of biological filters by proposing a barrier-specific engineering framework. We evaluate diverse high-barrier environments with distinct restrictive mechanisms and describe the strategies used to overcome them in nanoparticle design. Specifically, we focus on how matching physicochemical properties to these environments can bypass physiological constraints. Using a comparative analysis methodology, we evaluate how design parameters, including size, morphology, and surface functionalization, interact with the mechanisms of major organ systems. Applying this framework across biological barriers distinguishes study-specific relationships from potentially transferable design principles. Its clinical and translational relevance is illustrated by engineered blood-brain barrier shuttles for Hunter syndrome and Alzheimer disease, lipid nanoparticle platforms for mRNA vaccination, and inhaled liposomal therapies.
2026-09-11 | Longitudinal Assessment of Cognitive Development in 23 Patients With Mucopolysaccharidosis (MPS) Type II: Results of up to 14 Years of Follow-Up.
This study investigated long-term cognitive development and genotype-phenotype relationships in patients with Mucopolysaccharidosis Type II (MPS II). A nationwide prospective cohort study was conducted in the Netherlands with cognitive follow-up since 2007. Patients were classified as neuronopathic or non-neuronopathic based on iduronate-2-sulphatase (IDS) genotype; novel variants based on age and intelligence quotient (IQ). IQ and Mental Age (MA) were analysed individually and, using linear mixed-effect models, at group level to compare trajectories by genotype and phenotype. Twenty-three male patients (22 children, 1 adult) underwent 136 cognitive assessments, beginning at a median age of 2.9 years with a median follow-up of 6.3 (range 0-13.5) years. IQ and MA trajectories significantly differed between neuronopathic and non-neuronopathic patients (p < 0.001). Non-neuronopathic patients (n = 5) showed normal or mildly impaired cognition. Neuronopathic patients (n = 18) initially developed normally, then stagnated, plateaued, and declined; IQ fell below 70 at a median age of 4 years. Patients with deletions (n = 3) experienced the earliest, most severe impairment (p < 0.001), while those with other IDS variants showed more variable trajectories. Neurocognitive patterns diverge early in MPS II, highlighting the importance of understanding genotype-specific developmental trajectories. This insight is essential for guiding timely brain-targeted interventions, ideally initiated before neurocognitive decline begins.
2026-06-22 | Clinical Outcomes of Ayurvedic Management in Hunter Syndrome: A Case Report
Introduction: Hunter Syndrome, otherwise called Mucopolysaccharidosis Type II, is a rare X- linked Lysosomal Storage disorder, occurring due to the deficiency of Iduronate-2-sulfatase enzyme (I2S). This leads to impaired Glycosaminoglycans catabolism (GAGs), resulting in the pathological accumulation of Heparan sulfate and Dermatan sulfate in multiple tissues and organs. It manifests as a progressive, multisystemic, genetic metabolic disorder. In Ayurveda, Hunter Syndrome is correlated with Sahaja Vyadhi (genetic disease) arising due to genetic defects, manifesting with persistent, impaired metabolism, coarse facies, hirsutism, multiple joint contractures, short stature, hyperactivity, and subnormal cognitive development. Methods: A single case study of a 4-year-old boy with Hunter syndrome was evaluated to analyze the efficacy of ayurvedic therapies on the quality of life. The child was managed with symptomatic treatment and rejuvenation therapy. Oral medicines were targeted for Deepana (appetite stimulant), and Pachana (digestive) to rectify metabolism and to improve cognitive abilities. Procedure-based therapies were targeted to treat physical impairments. Results: After five months of exclusive oral medications and one course of external therapies, the child showed improvement in metabolic activity, cognitive abilities and joint mobility, marking overall well-being and enhanced quality of life. Conclusion: Hunter syndrome is an early onset, progressive disorder, with high morbidity and poor life expectancy, making it a Sahaja Vata Pradhana Tridoshaja Vyadhi. Early diagnosis, genetic counseling, and an integrative approach combining contemporary and traditional therapeutic strategies may reduce mortality and improve long- term health outcomes in affected children.
2026-06-15 | Synthesis of a C-2 Functionalized l-Iduronic Acid Derivative as a Candidate Pharmacological Chaperone for MPS II (Hunter Syndrome).
A C-2 functionalized l-IdoA derivative was designed as a potential pharmacological chaperone for MPS II, and several routes to its synthesis were investigated. Successful synthesis proceeded via an oxidation/Horner-Wadsworth-Emmons sequence, overcoming significant challenges with competing elimination reactions to give alkene derivatives in good overall yields. Catalytic hydrogenation of the double bonds proceeded stereoselectively in high yield to give the desired L-ido-configured products, confirmed by x-ray crystallographic analysis. These were subsequently elaborated to the target dicarboxylate prodrug 1 in good overall yield. Molecular docking studies suggest the parent compound engages with the active site and makes several H-bonding interactions with key active site residues. Target prodrug 1 and known chaperone D2S0 were evaluated against two MPS II cell lines, but neither compound was able to reduce HS substrate levels at the doses tested.
2026-05-10 | Treosulfan-based conditioning for hematopoietic stem cell transplantation in mucopolysaccharidosis: a pilot study.
Treosulfan (Treo), a prodrug of a bifunctional alkylating agent, has been used in conditioning regimens to reduce the risk of hepatic sinusoidal obstruction syndrome. We aimed to establish a Treo-based conditioning regimen for mucopolysaccharidosis (MPS) as a phase 1 study. The regimen included thoracoabdominal irradiation, Treo, fludarabine, and antithymocyte globulin. Antithymocyte globulin was omitted in cord blood transplantation. Five patients with MPS II, aged 8 months to 21 years, were enrolled. Stem cell sources were HLA-C-mismatched unrelated bone marrow in one patient and HLA 1 to 3 allele-mismatched cord blood in four. No patients experienced grade 4 toxicities. Absolute neutrophil count > 500/µL was achieved at a median of 16 days. A pharmacokinetic study showed that AUC0-12h was 50% higher in children than in adults. Bone marrow donor chimerism at 4 weeks post-transplant was 100% in two patients and 96.7% to 98.1% in three; at 8 weeks, it was 100% in four patients and 77.1% in one who received a reduced dose of Treo. Three patients are alive, but two died at 415 and 767 days post-transplant due to factors unrelated to the conditioning regimen. Treo remains a valuable agent for conditioning regimens in MPS.
cell therapies
2024-08-09 | [Clinical phenotype, genetic characteristics, and creation of immortalized cell lines for patients from a pedigree affected with Hunter syndrome].
To explore the clinical phenotype and genetic variant in a Chinese pedigree affected with Hunter syndrome and create immortalized cell lines for the affected pedigree members. A pedigree of six members who had visited Xi'an Children's Hospital in July 2022 was selected as the study subject. Clinical data was collected. Whole exome sequencing was carried out for the pedigree members. Candidate variant was verified by Sanger sequencing. In addition, peripheral B lymphocytes were transfected with Epstein-Barr virus to create immortalized cell lines, which were then subjected to enzyme activity analysis. The patient, a five-year-and-seven-month-old boy, had exhibited stiff limbs and enlarged joints. He had developed hernia, scaphocephaly, and barrel chest from 3 months of age. His uncle also had stiff limbs, poor hearing, blindness, and right oblique inguinal hernia. Above features had resembled those of Hunter syndrome. Genetic testing revealed that both the child and his uncle had harbored an IDS (NM_000202.8): c.823G>A (p.D275N) variant, which was unreported previously. Bioinformatic analysis indicated that the D275 to be a highly conserved site, and the D275N variant may affect the stability of the protein's spatial conformation, thereby decrease the catalytic activity of the enzyme. The successfully constructed immortalized lymphoblastoid cell lines for the child and his parents showed increased volume, irregular shape, burr structure and cluster growth. And the value of IDS activity of the patient's immortalized lymphoblastoid cells was below the limit of detection. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PS3+PM2_Supporting+PM5+PP1+PP3). Above finding has enriched the phenotypic and mutational spectra of Hunter syndrome, and provided a basis for the genetic counseling for this pedigree. The creation of immortalized cell lines has offered a model for further investigation of the impact of variant on the function of IDS and development of targeted drugs.
2024-03-29 | Modeling Lysosomal Storage Disorders in an Innovative Way: Establishment and Characterization of Stem Cell Lines from Human Exfoliated Deciduous Teeth of Mucopolysaccharidosis Type II Patients.
Among the many lysosomal storage disorders (LSDs) that would benefit from the establishment of novel cell models, either patient-derived or genetically engineered, is mucopolysaccharidosis type II (MPS II). Here, we present our results on the establishment and characterization of two MPS II patient-derived stem cell line(s) from deciduous baby teeth. To the best of our knowledge, this is the first time a stem cell population has been isolated from LSD patient samples obtained from the dental pulp. Taking into account our results on the molecular and biochemical characterization of those cells and the fact that they exhibit visible and measurable disease phenotypes, we consider these cells may qualify as a valuable disease model, which may be useful for both pathophysiological assessments and in vitro screenings. Ultimately, we believe that patient-derived dental pulp stem cells (DPSCs), particularly those isolated from human exfoliated deciduous teeth (SHEDs), may represent a feasible alternative to induced pluripotent stem cells (iPSCs) in many labs with standard cell culture conditions and limited (human and economic) resources.
2023-04-25 | Generation and characterization of an immunodeficient mouse model of mucopolysaccharidosis type II.
Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS-/- NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.
2019-02-01 | Platform technology for treatment of the brain in lysosomal disorders: Application to Tay-Sachs disease
Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an inherited X-linked recessive disease caused by deficiency of iduronate-2-sulfatase (IDS), resulting in the accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfates. Mouse models of MPS II have been used in several reports to study disease pathology and to conduct preclinical studies for current and next generation therapies. Here, we report the generation and characterization of an immunodeficient mouse model of MPS II, where CRISPR/Cas9 was employed to knock out a portion of the murine IDS gene on the NOD/SCID/Il2rγ (NSG) immunodeficient background. IDS−/− NSG mice lacked detectable IDS activity in plasma and all analyzed tissues and exhibited elevated levels of GAGs in those same tissues and in the urine. Histopathology revealed vacuolized cells in both the periphery and CNS of NSG-MPS II mice. This model recapitulates skeletal disease manifestations, such as increased zygomatic arch diameter and decreased femur length. Neurocognitive deficits in spatial memory and learning were also observed in the NSG-MPS II model. We anticipate that this new immunodeficient model will be appropriate for preclinical studies involving xenotransplantation of human cell products intended for the treatment of MPS II.
2012-09-07 | Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: A nationwide survey in Japan
Hematopoietic stem cell transplantation (HSCT) has not been indicated for patients with mucopolysaccharidosis II (MPS II, Hunter syndrome), while it is indicated for mucopolysaccharidosis I (MPS I) patients < 2 years of age and an intelligence quotient (IQ) of ≥ 70. Even after the approval of enzyme replacement therapy for both of MPS I and II, HSCT is still indicated for patients with MPS I severe form (Hurler syndrome). To evaluate the efficacy and benefit of HSCT in MPS II patients, we carried out a nationwide retrospective study in Japan. Activities of daily living (ADL), IQ, brain magnetic resonance image (MRI) lesions, cardiac valvular regurgitation, and urinary glycosaminoglycan (GAG) were analyzed at baseline and at the most recent visit. We also performed a questionnaire analysis about ADL for an HSCT-treated cohort and an untreated cohort (natural history). Records of 21 patients were collected from eight hospitals. The follow-up period in the retrospective study was 9.6 ± 3.5 years. ADL was maintained around baseline levels. Cribriform changes and ventricular dilatation on brain MRI were improved in 9/17 and 4/17 patients, respectively. Stabilization of brain atrophy was shown in 11/17 patients. Cardiac valvular regurgitation was diminished in 20/63 valves. Urinary GAG concentration was remarkably lower in HSCT-treated patients than age-matched untreated patients. In the questionnaire analysis, speech deterioration was observed in 12/19 patients in the untreated cohort and 1/7 patient in HSCT-treated cohort. HSCT showed effectiveness towards brain or heart involvement, when performed before signs of brain atrophy or valvular regurgitation appear. We consider HSCT is worthwhile in early stages of the disease for patients with MPS II.
proteins
2026-09-01 | Interim analysis of post-marketing surveillance study of intracerebroventricular idursulfase therapy for neuronopathic mucopolysaccharidosis type II: Safety and effectiveness in clinical practice in Japan.
Mucopolysaccharidosis type II (MPS II) results from iduronate-2-sulfatase (IDS) enzyme deficiency due to IDS gene mutations. Most patients with neuronopathic MPS II experience progressive neurological decline; however, effectiveness of standard treatment, intravenous idursulfase, is limited by blood-brain barrier transfer. Intracerebroventricular (ICV) idursulfase beta, approved in Japan in 2021, directly delivers idursulfase beta into cerebral ventricles. This post-marketing surveillance reports long-term effectiveness and safety of ICV idursulfase beta (30 mg every 4 weeks) in all treated patients from April 2021 through August 2024. Outcomes included cerebrospinal fluid (CSF) heparan sulfate (HS) levels (quarterly), developmental age (DA; Kyoto Scale of Psychological Development, annually), and safety. Thirty-seven Japanese male patients across 21 sites were enrolled (safety population n = 36; effectiveness population n = 35). Mean CSF HS concentrations decreased from 7.36 to 3.19 μg/mL from baseline to week 24, with reduction sustained through week 100. Patients who initiated treatment within 3 years of age had DA progression aligned with healthy cohorts, regardless of mutation type; however, those starting later had no comparable benefit. Adverse events (AEs) occurred in 20 patients (55.6%). Procedure-related serious AEs (SAEs) occurred in 2 patients (bacterial meningitis, device-related infection, pyrexia). Treatment-related AEs affected 14 patients (38.9%), mainly pyrexia (27.8%, including one SAE). One SAE (membranous glomerulonephritis) was not intervention related. No deaths, anaphylaxis, or anti-IDS antibodies in CSF were detected. ICV idursulfase beta demonstrated sustained CSF HS reduction with no new safety signals. Earlier treatment initiation (≤3 years) was associated with improved neurodevelopmental outcomes, regardless of mutation type.
2026-08-14 | PRE-CONGRESS «CURRENT ISSUES IN THE DIAGNOSIS AND THERAPY OF HUNTER SYNDROME» OF THE VIII ALL-RUSSIAN SCIENTIFIC AND PRACTICAL CONGRESS WITH INTERNATIONAL PARTICIPATION «ORPHAN DISEASES»
Pre-Congress «Current Issues in the Diagnosis and Therapy of Hunter Syndrome» of the VIII All-Russian Scientific and Practical Congress with International Participation «Orphan Diseases». Pediatria n.a. G.N. Speransky. 2026; 105 (4): 151–153. DOI: 10.24110/0031-403X-2026-105-4-151-153.
2026-08-09 | The IDS Gene Variant c.851C>T, p.P284L: More Evidence Against its Role as a Pathogenic Mutation in Mucopolysaccharidosis Type II
The Data of research The IDS Gene Variant c.851C>T, p.P284L: More Evidence Against its Role as a Pathogenic Mutation in Mucopolysaccharidosis Type II
2026-07-30 | Treatment outcomes maintained in Hunter syndrome patients: a case series on switching from idursulfase to idursulfase beta in Belarus.
Hunter syndrome (Mucopolysaccharidosis type II, MPS II) is a rare X-linked lysosomal storage disorder caused by iduronate-2-sulfatase deficiency, leading to glycosaminoglycan accumulation. Enzyme replacement therapy (ERT) with idursulfase is a standard treatment, although supply shortages may disrupt continuity of care. This retrospective case series describes clinical and biochemical outcomes in seven patients with Hunter syndrome in Belarus who were switched from idursulfase (Elaprase®) to idursulfase beta (Hunterase®). Patients were evaluated before and after the switch using urinary GAG levels, 6-minute walking test (6MWT), liver and spleen size, and safety parameters. Following the transition, patients maintained or improved clinical outcomes, with continued reductions in urinary GAG levels, stable or improved 6MWT performance, and further decreases in organ enlargement. No new safety concerns were identified. These findings suggest that switching to idursulfase beta may preserve therapeutic benefits and support treatment continuity in real-world settings.
2026-07-09 | Sustained clinical benefit of idursulfase beta in mucopolysaccharidosis II: two-year experience from a phase 3 extension study including patients switched from idursulfase.
Long-term safety and efficacy data on enzyme replacement therapy, particularly switching between recombinant iduronate-2-sulfatase formulations, remain limited in mucopolysaccharidosis II (MPS II). This open-label extension study included male patients with MPS II who completed a 52-week, phase 3 trial and either continued idursulfase beta (maintenance group, n = 22) or switched from idursulfase (switch group, n = 6). Participants received weekly intravenous idursulfase beta (0.5 mg/kg) for an additional 52 weeks. Safety, immunogenicity, six-minute walk test (6-MWT), and urinary glycosaminoglycan (GAG) levels were evaluated longitudinally for two years. Changes over time were analyzed using descriptive statistics and mixed models for repeated measures. Over the two-year treatment period, no new safety signals were identified in both groups. In the maintenance group, the incidence of adverse drug reactions decreased in the second year compared with the first year (from 54.5% to 13.6%); anti-drug antibody positivity peaked within the first six months and subsequently declined, with a low prevalence of neutralizing antibodies (4.5-22.7%). At Month 24, least-square mean changes from baseline demonstrated a 23.1% increase in 6-MWT distance and a 73.1% reduction in urinary total GAG levels in the maintenance group. Patients switching from idursulfase showed comparable safety profiles and sustained functional and biochemical improvements. These results demonstrate that idursulfase beta is safe and efficacious in the long-term management of MPS II. Additionally, switching from idursulfase to idursulfase beta preserved therapeutic efficacy without additional safety or immunogenicity concerns, supporting idursulfase beta as a viable option following prior idursulfase therapy. The study was registered at ClinicalTrials.gov (identifier, NCT07344376 date of registration, 7 January 2026).
gene therapies
2025-12-29 | Intravenous Delivery of a Gene Therapy Vector that Expresses an Antitransferrin Receptor 1 Nanobody-I2S Fusion Protein Rescued Central Nervous System Lysosomal Burden in Mucopolysaccharidosis II Mice.
Hunter syndrome, also known as mucopolysaccharidosis type II, is an X-linked lysosomal storage disease caused by the deficiency of functional iduronate-2-sulfatase (I2S) enzyme, leading to the accumulation of lysosomal glycosaminoglycans (GAGs) affecting multiple organs. Two-thirds of patients have central nervous system (CNS) manifestations. The current standard of care, enzyme replacement therapy (ERT) via weekly intravenous delivery of recombinant human I2S (rhI2S), does not address the neuropathy in the CNS due to its inability to cross the blood-brain barrier (BBB). Next-generation ERTs consisting of systemically administered rhI2S linked to antibodies that target the transferrin receptor (TfR) have shown clinical efficacy in addressing CNS and peripheral manifestations of disease. We demonstrate here that systemic administration of recombinant AAV9 gene therapy vectors encoding human I2S fusion protein with a TfR1-targeted Variable Heavy chain domain of Heavy chain (VHH) nanobody at the N-terminus normalized brain and cerebrospinal fluid GAGs in symptomatic Ids knockout (Ids KO) mice. This ability to correct toxic substrate accumulation in the CNS was superior to gene therapy vectors expressing I2S with a C-terminal VHH tag or untagged I2S control. The VHH-I2S transgene product demonstrated a broader distribution in the brain parenchyma, coincident with a significant reduction of lysosomal-associated membrane protein 1 immunoreactivity, unlike untagged I2S and I2S-VHH transgene products. These data illuminate strategies to enhance AAV gene therapy vector design and leverage receptor-mediated transcytosis to strategize BBB-penetrating gene therapy for addressing the unmet medical needs of neuronopathic Hunter syndrome.
2025-09-30 | Domain-substituted IGF2 tag modulates targeting of lentiviral gene therapy for Hunter syndrome.
We present the SWAP design, a novel, structurally cohesive IGF2-based tag for modular receptor targeting during gene therapy for lysosomal storage disorders (LSDs). We found that IGF2's central loop is critical for high-affinity binding to the insulin receptor (IR) and IGF1 receptor (IGF1R)-both involved in glucose homeostasis-but is not required for interaction with the cation independent mannose 6-phosphate/IGF2 receptor (CI-M6P/IGF2R)-a key target for lysosomal delivery. This formed the basis for designing the Substitution of the central-loop With Augmenting Peptides (SWAP) tag. By replacing the central loop with alternative epitopes, SWAP ensures high-affinity multimodal receptor targeting while maintaining structural integrity. In vivo, lentiviral gene therapy employing IDS fused to SWAP variants containing ApoE and RAP12x2 inserts corrected Hunter disease pathology across multiple tissues, including liver, spleen, heart, bone, and brain, matching the efficacy of the traditional IGF2 tag. These findings position SWAP as a novel and effective tag design for IGF2-based therapeutics with a more favourable ligand-receptor interaction.
2025-09-20 | Rescue of neurologic disease in mucopolysaccharidosis type II mice via AAV-mediated liver delivery of brain-penetrating iduronate-2-sulfatase.
Mucopolysaccharidosis type II (MPS II) is a neurodegenerative lysosomal storage disorder (LSD) caused by inherited mutations in the iduronate-2-sulfatase (IDS) gene. Approximately two-thirds of patients exhibit severe central nervous system (CNS) involvement and cognitive impairment, which remain unaddressed by conventional enzyme replacement therapy (ERT) due to the inability of wild-type IDS to cross the blood-brain barrier (BBB). To overcome this limitation, we engineered a brain-penetrant IDS variant, eBT-IDS4, which retained enzymatic activity and demonstrated enhanced BBB transcytosis in vitro. We then evaluated a liver-directed gene therapy approach using an adeno-associated virus 8 (AAV8) vector encoding eBT-IDS4 under the control of a liver-specific promoter (LSP) in an adult MPS II mouse model. Intravenous administration of AAV8.LSP.IVS2.eBT-IDS4 resulted in sustained supraphysiological IDS activity and normalization of glycosaminoglycan (GAG) levels in peripheral tissues. Notably, this strategy achieved 89 % of wild-type IDS activity in the brain, leading to complete correction of neuropathology and reversal of cognitive deficits in 8-month-old MPS II mice. These findings support a promising, minimally invasive gene therapy strategy for treating MPS II and other neurodegenerative LSDs.
2024-03-27 | Cellular Organelle-Related Transcriptomic Profile Abnormalities in Neuronopathic Types of Mucopolysaccharidosis: A Comparison with Other Neurodegenerative Diseases.
Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG) degradation. As a result, GAGs accumulate in lysosomes, impairing the proper functioning of entire cells and tissues. There are 14 types/subtypes of MPS, which are differentiated by the kind(s) of accumulated GAG(s) and the type of a non-functional lysosomal enzyme. Some of these types (severe forms of MPS types I and II, MPS III, and MPS VII) are characterized by extensive central nervous system disorders. The aim of this work was to identify, using transcriptomic methods, organelle-related genes whose expression levels are changed in neuronopathic types of MPS compared to healthy cells while remaining unchanged in non-neuronopathic types of MPS. The study was conducted with fibroblast lines derived from patients with neuronopathic and non-neuronopathic types of MPS and control (healthy) fibroblasts. Transcriptomic analysis has identified genes related to cellular organelles whose expression is altered. Then, using fluorescence and electron microscopy, we assessed the morphology of selected structures. Our analyses indicated that the genes whose expression is affected in neuronopathic MPS are often associated with the structures or functions of the cell nucleus, endoplasmic reticulum, or Golgi apparatus. Electron microscopic studies confirmed disruptions in the structures of these organelles. Special attention was paid to up-regulated genes, such as PDIA3 and MFGE8, and down-regulated genes, such as ARL6IP6, ABHD5, PDE4DIP, YIPF5, and CLDN11. Of particular interest is also the GM130 (GOLGA2) gene, which encodes golgin A2, which revealed an increased expression in neuronopathic MPS types. We propose to consider the levels of mRNAs of these genes as candidates for biomarkers of neurodegeneration in MPS. These genes may also become potential targets for therapies under development for neurological disorders associated with MPS and candidates for markers of the effectiveness of these therapies. Although fibroblasts rather than nerve cells were used in this study, it is worth noting that potential genetic markers characteristic solely of neurons would be impractical in testing patients, contrary to somatic cells that can be relatively easily obtained from assessed persons.
2021-11-02 | Programmable large DNA deletion, replacement, integration, and inversion with twin prime editing and site-specific recombinases
Summary The targeted deletion, replacement, integration, or inversion of DNA sequences at specified locations in the genome could be used to study or treat many human genetic diseases. Here, we describe twin prime editing (twinPE), a method for the programmable replacement or excision of DNA sequence at endogenous human genomic sites without requiring double-strand DNA breaks. TwinPE uses a prime editor (PE) protein and two prime editing guide RNAs (pegRNAs) that template the synthesis of complementary DNA flaps on opposing strands of genomic DNA, resulting in the replacement of endogenous DNA sequence between the PE-induced nick sites with pegRNA-encoded sequences. We show that twinPE in human cells can perform precise deletions of at least 780 bp and precise replacements of genomic DNA sequence with new sequences of at least 108 bp. By combining single or multiplexed twinPE with site-specific serine recombinases either in separate steps or in a single step, we demonstrate targeted integration of gene-sized DNA plasmids (>5,000 bp) into safe-harbor loci including AAVS1 , CCR5, and ALB in human cells. To our knowledge, these results represent the first RNA-programmable insertion of gene-sized DNA sequences into targeted genomic sites of unmodified human cells without requiring double-strand breaks or homology-directed repair. Twin PE combined with recombinases also mediated a 40,167-bp inversion at IDS that corrects a common Hunter syndrome allele. TwinPE expands the capabilities of precision gene editing without requiring double-strand DNA breaks and synergizes with other tools to enable the correction or complementation of large or complex pathogenic alleles in human cells.
other
2026-07-21 | New Paradigms in Management of Central Nervous System Damage in Patients with Hunter Syndrome
Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a progressive lysosomal storage disease with X-linked recessive inheritance. This disease is caused by pathogenic or probably pathogenic variants in the IDS gene encoding iduronate 2-sulfatase. This enzyme insufficiency leads to glycosaminoglycans accumulation in cells of various organs and tissues, which underlies the multisystem lesion. There is neuropathic form of MPS II with progressive central nervous system (CNS) damage and behavioral disorders, and milder form without any intellectual disorders. There are methods of effective pathogenetic therapy for this disease, however, they do not affect CNS manifestations. Thus, there is topical issue in management of neuropathic MPS II forms on transporting enzyme-replacement medications through the blood-brain barrier (BBB). Development of pabinafusp alfa (JR-141), innovative drug penetrating the BBB via transcytosis mediated by the transferrin receptor, became one of the approaches to solve this problem. This publication provides the literature review on the pabinafusp alfa administration for management of neuropathic MPS II forms focusing its efficacy and safety.
2025-02-07 | Bodyweight and Absolute Lymphocyte Count-Based Dosing of Rabbit Anti-thymocyte Globulin Results in Early CD4+ Immune Reconstitution in Patients with Inborn Errors of Metabolism Undergoing Umbilical Cord Blood Transplantation.
Rabbit anti-thymocyte globulin (rATG) decreases the risk of graft failure and graft-versus-host disease (GVHD) in a setting of allogenic hematopoietic cell transplantation (HCT) but has highly variable pharmacokinetics. Recently, it was shown that a dosing nomogram based on recipient bodyweight and absolute lymphocyte count reduced rATG overexposure, which led to faster immune reconstitution. The aim of this study is to evaluate the feasibility and benefits of using an rATG dosing nomogram to achieve early CD4+ immune reconstitution in pediatric patients with inborn errors of metabolism (IEM) undergoing umbilical cord blood transplantation. The rATG dosing nomogram in pediatric patients with IEM receiving an umbilical cord blood transplant with busulfan-based myeloablative conditioning at the University of Minnesota Masonic Children's Hospital was used prospectively since 2017. The primary endpoint was CD4+ immune reconstitution (>50 CD4+ T-cells/mL) within 100 days after HCT. Secondary endpoints included overall survival, graft failure, acute and chronic GVHD, and viral reactivations. A total of 27 patients were included in the study. Median follow-up time was 31 months (interquartile range [IQR], 22-38) and median age was 1.5 years (IQR, 0.7-3.9). The underlying disease was Hurler syndrome in 17 (63%), Hunter syndrome in 4 (15%), and cerebral adrenoleukodystrophy in 4 (15%) patients; 2 patients were transplanted for other IEM. The CD4+ recovery (>50 CD4+ T cells/mL) at 100 days post-HCT was reached in 22 (85%) of 26 patients. Overall survival was 83% (95% confidence interval [CI], 67%-100%). No graft failure was observed. Two (7%) patients developed acute GVHD grade II to IV and no patients had chronic GVHD. Six patients (22%) had cytomegalovirus (CMV) viremia. One patient had Epstein-Barr virus reactivation requiring treatment. In patients with IEM, individualized dosing of rATG was associated with a robust and early CD4+ immune reconstitution, with no graft failures and low GVHD incidence.
2024-11-22 | 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.
2024-07-31 | 14 A precision medicine tool for high utilization and quality of individual treatment trials with immunomodulatory drugs in mucopolysaccharidosis
The growing understanding of the innate immune response in Mucopolysaccharidosis (MPS) revealed potential targets for intervening, including the repurposing of immunomodulatory drugs. Individual treatment trials (ITT) could efficiently translate this knowledge into clinical use. However, despite the limited efficacy of approved drugs and the high level of suffering this has so far hardly been used - at least these are not reported or published. We analysed the subjective need for, utilisation of and barriers to ITT by an international MPS-expert survey. Based on that and by adapting a validated decision analysis framework (DAF) we developed an innovative, quantitative, personalizable benefit-risk assessment model to overcome barriers to ITT in MPS. Our strategy is based on the following steps i) MPS-expert survey on ITT in MPS, (ii) systematic literature review regarding relevant targets and clinical pharmacology of immunomodulatory drugs, (iii) quantitative DAF data acquisition with the creation of a framed decision context and assigning weights to relevant outcomes, (iv) enabling personali-zability by phenotypic profiling and assessing specific probabilities of expected beneficial out-comes, (v) an assessment standard for ITT with immunomodulatory drugs in MPS. These steps are in accordance with an international, interdisciplinary board of experts as well as patient representatives. Our survey (n=27) demonstrated that the majority of MPS-experts is familiar with the concept of ITT (73%), however only few ever conducted (35%) or published those (6%) reported those. A free service for data-driven treatment choices is expected to in-crease the utilization and quality of ITT by 85%. We identified Anakinra, Adalimumab, Abatacept and Cladribine as top candidates and defined first and second choices for different phenotypes. Our developed evidence-based, personalizable, quantitative DAF model for ITT characterizes the first step towards precision medicine with immunomodulatory drugs in MPS.
2023-12-14 | Urine proteome uncover common mechanism between mucopolysaccharidosis type I and II
Abstract Mucopolysaccharidosis (MPS) type I and II are two types of rare lysosomal storage diseases, which lead to the accumulation of glycosaminoglycans due to the lack of the enzyme alpha-L-iduronidase (IDUA) and iduronate 2-sulfatase (IDS) respectively. There are some similar pathogenic mechanisms and clinical phenotypes but also some specific minute manifestations between these two subtypes. To better understand the similarities in the pathogenesis and clinical symptoms of these two diseases and the mechanism of differential symptoms, we used TMT technology to analyze the differential protein profiles in the urine of MPS I and MPS II patients. We detected the differential proteins of MPS I and MPS II compared with the control group separately. After that, we focused on 227 differentially expressed proteins (DEPs) which showed consistent changes in the urine of both MPS I and MPS II. Parallel reaction monitoring (PRM) analysis verified that up-regulated HEXB and down-regulated HBA1 showed significant difference in the urine of both subtypes. In addition, we found 391 DEPs by comparative analysis of MPS I and MPS II proteomes and found that DHRS2 contributed to the difference between the two subtypes by PRM verification. Therefore, our study demonstrates the value of multi-sample proteomics combined analysis in exploring the similarities and differences of functional proteins between MPS I and MPS II, which provides a new idea for the clinical study of the characteristics of MPS subtypes and the exploration of common treatment options.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
24 orphan drug designations for Mucopolysaccharidosis type 2, including 2 approved therapies.
24 orphan drug designations for Mucopolysaccharidosis type 2, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
sleeping beauty transposon-engineered autologous plasmablasts for expression and delivery of iduronate-2-sulfatase | gene therapies | FDA | — | Immusoft CA, Inc. |
Adeno-associated virus vector expressing human iduronate-2-sulfatase | gene therapies | FDA | — | NeuroGT, Inc. |
Recombinant adeno-associated virus (AAV) serotype HSC15 (rAAVHSC15) encoding human iduronate-2-sulfatase (hIDS) | gene therapies | FDA | Homology Medicines, Inc | |
Adeno-associated virus serotype HSC 15 expressing human iduronate 2-sulfatase | gene therapies | EMA | — | Propharma Group The Netherlands B.V. |
ex vivo, lentiviral vector (LV)-mediated, genetically modified autologous cell therapy intended for the stable provision of functional human iduronate?2? sulfatase (IDS) enzyme to subjects with Hunter syndrome | gene therapies | FDA | — | AVROBIO, Inc. |
Idursulfase beta | proteins | EMA | Parexel International (IRL) Limited | |
Autologous CD34+ haematopoietic stem and progenitor cells genetically modified with the lentiviral vector encoding for the human iduronate 2-sulfatase gene | cell therapies | EMA | — | University of Padua |
Idursulfase | proteins | EMA | Takeda Pharmaceuticals International AG | |
Humanised IGg1 monoclonal antibody targeting human transferrin receptor conjugated to human iduronate-2-sulfatase | proteins | EMA | JCR Europe B.V. | |
tividenofusp alfa-eknm [Avlayah] | proteins | FDA | Approved | Denali Therapeutics Inc. |
Humanized IgG-1 antibody targeting human transferrin receptor conjugated to human iduronate-2-sulfatase | antibodies | FDA | JCR Pharmaceuticals Co., Ltd. | |
Tefidsogene civaparvovec | gene therapies | EMA | Sangamo Therapeutics France S.A.S. | |
Recombinant adeno-associated viral vector serotype 9 containing human iduronate-2-sulfatase gene | gene therapies | EMA | Regenxbio EU Limited | |
Adeno-associated virus serotype 2/6 (rAAV2/6) vectors encoding zinc finger nucleases (ZFNs) and the human iduronate 2-sulfatase (hIDS) gene | gene therapies | FDA | Sangamo Therapeutics, Inc. | |
recombinant adeno-associated virus vector serotype 9 expressing human iduronate-2-sulfatase | gene therapies | FDA | — | University of North Carolina at Chapel Hill |
non-replicating recombinant adeno-associated virus (AAV) vector of serotype 9 expressing human iduronate-2-sulfatase | gene therapies | FDA | REGENXBIO, Inc. | |
Clemidsogene lanparvovec | gene therapies | EMA | Esteve Pharmaceuticals S.A. | |
adeno-associated virus serotype 9 vector containing human Iduronate-2-sulfatase transgene | gene therapies | FDA | — | Esteve Pharmaceuticals, S.A. |
Recombinant human insulin receptor monoclonal antibody-fused iduronate 2-sulfatase [AGT-182] | proteins | EMA | Voisin Consulting Life Sciences | |
HIRMAb-IDS | proteins | FDA | ArmaGen Technologies, Inc. | |
idursulfase beta | proteins | FDA | Green Cross Corp. | |
idursulfase IT | proteins | FDA | Takeda Pharmaceuticals U.S.A., Inc. | |
Idursulfase [Elaprase] | proteins | EMA | [INACTIVE] Silanes Idf S.L. | |
idursulfase [Elaprase] | proteins | FDA | Approved | Takeda Pharmaceuticals U.S.A., Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.