RARE DISEASE
Hurler syndrome
Hurler syndrome
Hurler syndrome
Synonyms: Hurler disease, MPS1H, MPSIH, Mucopolysaccharidosis type 1H, Mucopolysaccharidosis type IH
Synonyms: Hurler disease, MPS1H, MPSIH, Mucopolysaccharidosis type 1H, Mucopolysaccharidosis type IH
Synonyms: Hurler disease, MPS1H, MPSIH, Mucopolysaccharidosis type 1H, Mucopolysaccharidosis type IH
Drug discovery
1
drug
With orphan designation
Overview
Hurler syndrome (mucopolysaccharidosis type I-H) is a severe autosomal recessive lysosomal storage disorder caused by α-L-iduronidase deficiency, leading to systemic glycosaminoglycan accumulation. It manifests with neurodevelopmental deterioration, dysostosis multiplex, cardiorespiratory complications, corneal clouding, and organomegaly. Diagnosis combines enzyme activity assays, genetic testing (IDUA mutations), and newborn screening. Early hematopoietic stem cell transplantation (HSCT) before age 2 years is critical to stabilize neurocognitive decline, while enzyme replacement therapy (ERT) addresses somatic symptoms [1][3][12].
Burden
Residual morbidity: 68% develop psychiatric disorders (depression/psychosis); 30% require spinal/cardiac surgeries despite treatment [4][9]
Median survival: Untreated <10 years; post-HSCT survival to 3rd decade with chronic musculoskeletal/ocular complications [4][14][17]
Lifetime costs: HSCT + ERT exceeds $5M/patient; 82% require ≥3 specialty care teams [9][13]
Therapies
HSCT: Gold standard for severe cases (<2.5 years), preserves neurocognition but requires full-donor chimerism [3][4][12]
ERT (laronidase): Lifelong therapy for non-neurological symptoms (e.g., hepatosplenomegaly, respiratory function) [3][10][14]
Emerging therapies: Autologous stem cell gene therapy trials show promise for sustained enzyme production [8][12]
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 transplant-related disorders
Research Papers
686 drug discovery papers about Hurler syndrome, with 6 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
686 drug discovery papers about Hurler syndrome, with 6 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-11-19 | 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.
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.
2025-06-13 | 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.
2024-08-08 | Synergistic effects of resveratrol and enzyme replacement therapy in the Mucopolysaccharidosis type I.
Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder caused by mutations in the IDUA gene, leading to alpha-L-iduronidase enzyme deficiency and resulting in the accumulation of glycosaminoglycans (GAG; heparan and dermatan sulfate) in lysosomes. The consequent GAG accumulation within cells leads to organ dysfunction and a range of debilitating symptoms. Enzyme replacement therapy (ERT) is the prevailing treatment, but its limitations (including high cost, time requirements, inefficiency in treatment of central nervous system (CNS), and immunogenicity) necessitate exploration of alternative therapeutic strategies. This research propose a novel approach leveraging the synergistic effects of ERT and resveratrol-induced autophagy. Resveratrol, with its immunomodulatory and GAG degradation-stimulating properties, holds a promise in mitigating immune responses triggered by ERT. Moreover, its ability to penetrate the blood-brain barrier presents a potential solution for addressing CNS manifestations. This study employed cells from MPS I patients to investigate the combined effects of resveratrol and the enzyme. Evaluation of the therapeutic impact involved assessing GAG accumulation, enzyme testing, and examining lysosome functionality and the autophagy process through fluorescence microscopy and Western blotting. The combined therapy stimulated the lysosomal mannose-6-phosphate receptor (M6PR) and lysosome biogenesis through the transcription factor EB (TFEB). Additionally, initial block of autophagy in autophagosome formation was relieved after the combined therapy and resveratrol alone. Together with increased enzyme activity through stimulation of the receptor, this synergistic therapy can be considered a new potential treatment for MPS I patients, improving their overall quality of life.
2024-07-02 | Anaesthetic Challenge in a Child with Hurler’s Syndrome: Encouraging Experience with Neuraxial Blockade
Mucopolysaccharidoses are uncommon genetic diseases with multisystem involvement. The potential for airway difficulties and varying success rate of neuraxial blockade demands considerable expertise in the anesthetic management in these patients. Airway management has evolved significantly in such syndromic patients with the increasing use of video laryngoscopes and Supraglottic airway devices. However, airway catastrophes are not uncommon. This calls for better utilization of neuraxial and peripheral nerve blocks along with the use of newer agents for sedation having a favorable pharmacological profile. Here, we present a case of child having Hurler disease with an inguinal hernia successfully operated under subarachnoid blockade.
proteins
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].
2026-05-15 | CSF GAG non-reducing ends in MPS IH after peripheral and brain-penetrating therapies: A model comparing IV non-targeted ERT and HCT.
Mucopolysaccharidosis type IH (MPS IH) is a lysosomal disease caused by insufficient L-iduronidase (IDUA), resulting in progressive accumulation of glycosaminoglycans (GAGs) in the central nervous system (CNS). Hematopoietic cell transplantation (HCT) replaces IDUA through cellular cross-correction, stabilizing the CNS. Intravenous (i.v.) enzyme replacement therapy (ERT) is also effective at reducing GAG accumulation; however, it is thought to inefficiently cross the blood-brain barrier. To compare the effect of i.v. ERT on GAG degradation in the CNS with the effect of brain-penetrant therapy, i.e., HCT, we measured cerebrospinal fluid (CSF) GAG non-reducing ends in patients with MPS IH who were ERT-naive (n = 33), received i.v. ERT prior to HCT (n = 34), or underwent HCT (n = 26). We found that CSF GAGs (cGAGs) were 33%-65% lower in patients exposed to i.v. ERT. One year after HCT, cGAGs declined to their lowest levels. There was no difference in cGAG levels between patients treated with i.v. ERT for 52 weeks after HCT and those treated for only 8 weeks after HCT. In summary, i.v. ERT can lead to a significant decrease in cGAGs prior to HCT, indicating that i.v. ERT may affect CNS biomarkers, which reach their lowest levels with a brain-penetrant therapy.
2026-01-22 | Features of the course of the early period of primary tuberculosis infection in a patient with Hurler syndrome: tactics of managing a comorbid patient
A clinical case of a child with comorbid pathology demonstrates the high importance of alertness of specialists of various profiles of the pediatric network. Doctors of the pediatric phthisiology network are of no small importance, since in children with genetic diseases, tuberculosis can proceed under the «masks» of other pathologies. Mucopolysaccharidosis type I (MPS I) is a rare genetic disease caused by a mutation of the IDUA gene, which encodes the enzyme alpha-L-iduronidase. Hurler syndrome, which is the most severe form of MPS I, requires special attention to prevent the development of severe complications, which often lead to death.
2025-12-07 | Clinical outcomes of exclusive enzyme therapy (laronidase) in a cohort of patients with mucopolysaccharidosis type I.
Mucopolysaccharidosis type I (MPS I), is an autosomal recessive disorder caused by a deficiency in the enzyme α-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans (GAGs) in tissues. Early diagnosis and treatment [i.e., bone marrow transplantation and/or enzyme replacement therapy (ERT) with laronidase] are essential to prevent irreversible damage. The long-term effectiveness of exclusive ERT has been primarily described in attenuated phenotypes, while only a few cases have been reported in severe phenotypes. This study is a retrospective analysis summarising the collective experience of disease progression in 48 patients with severe and attenuated MPS I who were treated exclusively with laronidase over a median of 10 years at the Lyon Reference Centre for Hereditary Metabolic Diseases in France. Patients were categorised by genotype and further stratified by age at treatment initiation. The study assessed the evolution of urinary excretion of GAGs, pulmonary function, cardiac involvement and evolution, height, cognitive impairment, functional status, orthopaedic and ear-nose-throat (ENT) procedures, sleep apnoea, and carpal tunnel syndrome. Descriptive statistical analysis methods were used. ERT reduced the GAGus levels by 88% in severe MPS I and by 71% in attenuated MPS I, of which 47% and 65% patients, respectively achieved normal age-related GAG levels at the last follow-up. ERT provided stable or consistent improvement in forced vital capacity, slowed progression of adverse cardiac course and improved auditory transmission in majority of the severe and attenuated patients. At the last follow-up, 84% attenuated patients had normal cognitive development. In alive Hurler patients, cognitive development was very heterogenous; however, 73% patients had a developmental quotient (DQ) ≥ 70. Laronidase was effective in improving statural growth of attenuated patients treated before 9 years of age. Early ERT and regular multidisciplinary management are effective in slowing disease progression in severe and attenuated patients with MPS I and helping to maintain autonomy in patients with attenuated MPS I, ensuring a better quality of life.
2025-11-22 | Long-term safety outcomes and patient preferences for home-based intravenous enzyme replacement therapy (ERT) in Pompe disease and Mucopolysaccharidosis Type I (MPS-I): final results of two-year observation.
BACKGROUND: Pompe disease and Mucopolysaccharidoses Type I (MPS-I) are lysosomal disorders caused by a deficiency of α-glucosidase and alpha-L-iduronidase, respectively. The mainstay of treatment is enzyme replacement therapy (ERT), a life-long treatment that requires regular I.V. infusions. Hospital-based therapy can, however, negatively impact quality of life over time. The purpose of the HomERT study (Home infusions of ERT) was to evaluate the safety, treatment compliance, and treatment satisfaction related to home therapy of Pompe disease patients with Myozyme® (alglucosidase alfa) and MPS-I patients with Aldurazyme® (laronidase). The final results are presented in this paper. RESULTS: The HomERT study was a multicenter, non-interventional, minimum 12-month prospective observational, double-cohort study that analyzed 56 patients from 14 sites in Italy from October 2021 to February 2024: cohort A (Pompe disease − 47 patients) and cohort B (MPS-I − 9 patients: 6 Hurler/Scheie, 3 Scheie). During the observation period, the mean (SD) number of missed infusions was 5.8 (3.92) in cohort A and 3.0 (3.52) in cohort B, corresponding to a mean (SD) of missed infusions of 19.8 (32.7)% and 4.1 (4.2)%, respectively, versus the number of planned infusions. Only 2 patients in cohort A returned to the hospital setting due to “adverse event” and “other” reasons. A total of 13 Adverse Drug Reactions (ADR) were reported during the home-care setting before and after enrollment. The average number of ADRs per patient was 0.2 (1.46) in cohort A and 0.2 (0.67) in group B, and the rate of ADRs/year was 0.15 (95% CI: 0.06; 0.34) in cohort A and 0.06 (95% CI: 0.01; 0.38) in cohort B. The majority of patients preferred home-based infusions (cohort A: 93.6%; cohort B: 88.9%), and the main reason was attributed to treatment convenience (cohort A: 93.6%; cohort B: 100%). Despite the underlying conditions, most patients self-evaluated their health as “Fair” in cohort A (36.2%) and “Good” in cohort B (44.5%). CONCLUSION: The use of ERT with α-glucosidase and alpha-L-iduronidase alfa remains a strong candidate for home therapy, with favorable safety profile, improved treatment ERT compliance, and patient satisfaction. NCT05073783.
cell therapies
2024-10-05 | Engineering memory T cells as a platform for long-term enzyme replacement therapy in lysosomal storage disorders.
Enzymopathy disorders are the result of missing or defective enzymes. Among these enzymopathies, mucopolysaccharidosis type I is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), which ultimately causes toxic buildup of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T (Tm) cells migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm cells as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm cells leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm cells take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS, although only minimal improved cognition was observed. Our study indicates that genetically engineered Tm cells hold great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.
2024-03-08 | Modeling skeletal dysplasia in Hurler syndrome using patient-derived bone marrow osteoprogenitor cells
Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet–based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders.
2021-12-28 | Articular Syndrome Characteristics in Children with Mucopolysaccharidosis Type I
Background . Mucopolysaccharidosis type I is disease from the group of lysosomal storage disease developing due to mutations in the IDUA gene. It leads to the accumulation of glycosaminoglycans (GAGs) in organs and tissues. Joints damage in this disease is systemic and progressive. Objective . The aim of the study. Nowadays, relevant issue is to investigate the effects of various types of pathogenetic therapy on the state of the osteoarticular system in patients with severe and mild phenotypes of MPS I to prevent further progression of joint pathology. Methods. The study included 46 patients diagnosed with “mucopolysaccharidosis type I”. 35 children had severe phenotype (Hurler syndrome) and 11 — with mild phenotypes (Hurler-Scheie and Scheie syndromes). The onset age of clinical manifestations in osteoarticular system, the state of large and small joints, and the presence of cervical stenosis according to the therapy were evaluated in these patients. Results. The osteoarticular system pathology can be usually revealed in all patients with MPS I, in both mild and severe phenotypes. The contractures of shoulder, ulnar, wrist, and small hand joints have been revealed in most patients with Hurler syndrome, regardless of the administered therapy. Hip joints pathology was observed in children who was administered with: enzyme replacement therapy (ERT) — in 46.7% of cases, hematopoietic stem cell transplantation (HSCT) in combination with ERT — in 34.4% of cases. Patients with Hurler syndrome administered with HSCT in combination with ERT had cervical stenosis statistically significantly more rarely (p = 0.018) compared to patients treated with ERT only. Patients with Hurler syndrome who were on ERT had statistically significantly lower growth rates than patients after HSCT in combination with ERT. Lesions in ulnar, wrist, knee and small hand joints were the most common in children with mild phenotypes (in 90% of cases). Conclusion . Combined therapy (HSCT and ERT) in patients with Hurler syndrome reduces severe manifestations in osteoarticular system, including children with a pathogenic nucleotide variant c.208C>T in a homozygous state.
2021-05-14 | Hurdles in treating Hurler disease: potential routes to achieve a "real" cure.
Mucopolysaccharidoses (MPSs) are multiorgan devastating diseases for which hematopoietic cell transplantation (HCT) and, to a lesser extent, enzyme replacement therapy have substantially altered the course of the disease. Furthermore, they have resulted in increased overall survival, especially for Hurler disease (MPS-1). However, despite the identification of clinical predictors and harmonized transplantation protocols, disease progression still poses a significant burden to patients, although at a slower pace. To design better therapies, we need to understand why and where current therapies fail. In this review, we discuss important aspects of the underlying disease and the disease progression. We note that the majority of progressive symptoms that occur in "hard-to-treat" tissues are actually tissues that are difficult to reach, such as avascular connective tissue or tissues isolated from the circulation by a specific barrier (eg, blood-brain barrier, blood-retina barrier). Although easily reached tissues are effectively cured by HCT, disease progression is observed in these "hard-to-reach" tissues. We used these insights to critically appraise ongoing experimental endeavors with regard to their potential to overcome the encountered hurdles and improve long-term clinical outcomes in MPS patients treated with HCT.
2021-01-13 | Obstructive sleep apnea and craniofacial appearance in MPS type I-Hurler children after hematopoietic stem cell transplantation.
Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder characterized by severe multi-systemic organ manifestations including obstructive sleep apnea syndrome (OSAS). Hematopoietic stem cell transplantation (HSCT) is the treatment of choice in severe MPS I (MPS IH, Hurler syndrome). However, the effect of HSCT on OSAS in MPS IH still remains unclear. The purpose of this study was to analyze respiratory patterns during sleep following HSCT in MPS IH children and to relate these findings to craniofacial abnormalities. Overnight polysomnographies of nine MPS IH children (mean age: 8.2 years) previously treated with HSCT were retrospectively analyzed. Magnetic resonance images of the head were assessed with regard to soft and hard tissue abnormalities of the upper respiratory tract. The mean apnea hypopnea index (AHI) was 5.3 events/h (range, 0.3-12.2), and the majority of apnea/hypopneas were obstructive. Whereas two patients had severe OSAS (AHI > 10) and two moderate OSAS (5 > AHI < 10), five patients had no evidence of OSAS (AHI < 2.0). Donor cell chimerism was significantly lower in MPS IH patients with OSAS as compared to patients without OSAS (p < 0.001). The upper airway space and the maxilla were significantly smaller and the adenoids larger in MPS IH patients with OSAS as compared to those of non-OSAS patients. OSAS was only observed in MPS IH patients with graft failure or low donor cell chimerism. Conversely, successful HSCT seems to ameliorate adenoid hyperplasia and maxillary constriction in MPS IH patients and thereby minimizes the risk of OSAS at least at younger ages.
gene therapies
2026-04-12 | First-in-human intracisternal dosing of RGX-111 in severe MPS I is well tolerated and generates sustained neurodevelopment without HSCT.
Mucopolysaccharidosis type I (MPS I), caused by α-L-iduronidase enzyme (IDUA) deficiency, manifests multisystemic symptoms from tissue accumulation of undegraded glycosaminoglycans. Severe MPS I (Hurler syndrome) is associated with developmental delay and loss of neurocognition. Although IDUA enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation (HSCT) are standard therapies for Hurler syndrome, gene therapy represents potential alternative treatment of neurodevelopmental disease. We report more than 5 years of clinical, biochemical, and neurocognitive outcomes following a first-in-human, open-label, single-patient, single administration of intra-cisterna magna (ICM) RGX-111 (AAV9.CB7.hIDUA, 1E-10 vector genomes/g brain mass) in a 20-month-old boy with Hurler syndrome with two older affected siblings deceased from HSCT-related complications. The ICM procedure was safe and well tolerated; treatment-emergent adverse events were mild and self-limiting. Crucially, serial brain imaging has been normal. He has never received an HSCT and continues with weekly IDUA infusions. Neurocognitive testing demonstrates ongoing acquisition of developmental abilities, with cognitive, speech, and motor age equivalents measuring one to two standard deviations below the normative mean. His neurodevelopment is significantly above the natural history of untransplanted Hurler syndrome patients. This single-patient experience of central nervous system-directed gene therapy demonstrates therapeutic potential for severe MPS I and other genetic neurodegenerative diseases.
2026-04-08 | Prime Editing Explained: A Comprehensive Guide to the Next Generation of Precision Genome Engineering
Prime editing represents a paradigm shift in precision genome engineering, offering a highly versatile search-and-replace mechanism that bypasses the limitations of traditional CRISPR-Cas9 systems. Unlike conventional methods that rely on double-strand DNA breaks (DSBs) and error-prone cellular repair, prime editing utilizes a fusion protein comprising a Cas9 nickase (H840A) and an engineered reverse transcriptase. This complex is directed by a prime editing guide RNA (pegRNA) that not only targets a specific genomic locus but also encodes the desired genetic edit. This unique architecture enables the precise installation of all twelve possible base substitutions, as well as targeted insertions and deletions, without requiring external donor DNA. Since its introduction, prime editing has evolved rapidly through multiple generations. Early iterations like PE1 and PE2 established the foundational mechanism and optimized the reverse transcriptase. Subsequent systems addressed critical efficiency barriers: PE3 introduced a dual-nicking strategy to bias cellular repair, while PE4 and PE5 incorporated dominant-negative MLH1 to transiently inhibit the mismatch repair (MMR) pathway, which otherwise antagonizes editing outcomes. Recent advancements, such as PEmax and PE7, focus on improved nuclear localization, compact enzyme variants for better delivery, and the use of engineered pegRNAs (epegRNAs) with structural motifs to protect against exonuclease degradation. The therapeutic applications of prime editing are expanding rapidly. A notable breakthrough is the Prime Editing-mediated Readthrough of Premature Termination Codons (PERT) strategy, a disease-agnostic approach that installs a universal suppressor tRNA to treat diverse genetic disorders caused by nonsense mutations, demonstrating efficacy in models of Hurler syndrome and Batten disease. Furthermore, the technology has entered the clinic, with PM359 representing the first human trial for treating chronic granulomatous disease (CGD) using ex vivo edited hematopoietic stem cells. Despite its immense potential, challenges remain regarding the delivery of large editor complexes and the optimization of pegRNA designs. Researchers are actively exploring split prime editors, compact reverse transcriptase domains, and lipid nanoparticles to overcome adeno-associated virus (AAV) packaging constraints. By offering a safer and more precise alternative to DSB-dependent editing and restricted base editors, prime editing is positioned to become a cornerstone technology in functional genomics and the development of next-generation genetic therapies. Source: https://www.geneeditsci.com/posts/prime-editing-explained-a-comprehensive-guide-to-the-next-generation-of-precision-genome-engineering
2025-12-02 | From trial to transformation: insights into hematopoietic stem cell-gene therapy for Hurler syndrome
1. Mucopolysaccharidosis type I (MPSI) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the enzyme α-L-iduronidase (IDUA), essential for the degradation of gly...
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.
2025-11-19 | Prime editing-installed suppressor tRNAs for disease-agnostic genome editing
Abstract Precise genome-editing technologies such as base editing 1,2 and prime editing 3 can correct most pathogenic gene variants, but their widespread clinical application is impeded by the need to develop new therapeutic agents for each mutation. For diseases that are caused by premature stop codons, suppressor tRNAs (sup-tRNAs) offer a more general strategy. Existing approaches to use sup-tRNAs therapeutically, however, require lifelong administration 4,5 or show modest potency, necessitating potentially toxic overexpression. Here we present prime editing-mediated readthrough of premature termination codons (PERT), a strategy to rescue nonsense mutations in a disease-agnostic manner by using prime editing to permanently convert a dispensable endogenous tRNA into an optimized sup-tRNA. Iterative screening of thousands of variants of all 418 human tRNAs identified tRNAs with the strongest sup-tRNA potential. We optimized prime editing agents to install an engineered sup-tRNA at a single genomic locus without overexpression and observed efficient readthrough of premature termination codons and protein rescue in human cell models of Batten disease, Tay–Sachs disease and cystic fibrosis. In vivo delivery of a single prime editor that converts an endogenous mouse tRNA into a sup-tRNA extensively rescued disease pathology in a model of Hurler syndrome. PERT did not induce detected readthrough of natural stop codons or cause significant transcriptomic or proteomic changes. Our findings suggest the potential of disease-agnostic therapeutic genome-editing approaches that require only a single composition of matter to treat diverse genetic diseases.
other
2026-03-26 | Lipid Nanoparticle-Delivered mRNA Therapy Corrects Neonatal Murine MPS I-H.
Mucopolysaccharidosis type I-Hurler (MPS I-H) is a severe lysosomal storage disorder caused by α-L-iduronidase (IDUA) deficiency, leading to glycosaminoglycan (GAG) accumulation and progressive multisystem dysfunction, including the central nervous system (CNS). Early hematopoietic stem cell transplantation remains the primary disease-modifying intervention for MPS I-H despite its clinical challenges. Conventional enzyme replacement therapy (ERT), which has limited CNS efficacy due to blood-brain barrier (BBB) restrictions, is being addressed by the development of novel BBB-penetrating ERT platforms. Recently, mRNA therapy has become a promising treatment option for rare genetic diseases by enabling the in vivo supplementation of defective or deficient proteins to ameliorate the disease phenotype. To evaluate mRNA therapy for MPS I-H, we screened ionizable lipids to develop lipid nanoparticle systems optimized for hepatic delivery, which were subsequently used to encapsulate mRNA encoding human IDUA (hIDUA) fused to a validated BBB-penetrating melanotransferrin peptide (MTfp). This formulation was intravenously administered to neonatal MPS I-H mice at a dose of 1.0 mg/kg every 2 weeks for 4 months. The treatment significantly increased IDUA enzyme activity in both the serum and liver. Concurrently, it reduced GAG accumulation in the urine, peripheral tissues, and partial CNS regions (olfactory bulbs, hippocampus, and cerebellum). Furthermore, the treatment significantly improved cardiac and skeletal development, as assessed by echocardiography and micro-computed tomography, respectively. Notably, it also enhanced cognitive function, as evidenced by the improved performance in the Delayed-Matching-to-Place dry maze test. Our findings demonstrate that LNP-MTfp-hIDUA treatment effectively ameliorates key pathological features and promotes neurodevelopment in MPS I-H, establishing a promising and safe therapeutic strategy for this disorder.
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.
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.
2024-02-18 | Evaluation of tendon and ligament microstructure and mechanical properties in a canine model of mucopolysaccharidosis I
Mucopolysaccharidosis (MPS) I is a lysosomal storage disorder characterized by deficient alpha-l-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a strong clinical need for improved treatment approaches that specifically target joint tissues; however, their development is hampered by poor understanding of underlying disease pathophysiology, including how pathological changes to component tissues contribute to overall joint dysfunction. Ligaments and tendons, in particular, have received very little attention, despite the critical roles of these tissues in joint stability and biomechanical function. The goal of this study was to leverage the naturally canine model to undertake functional and structural assessments of the anterior (cranial) cruciate ligament (CCL) and Achilles tendon in MPS I. Tissues were obtained postmortem from 12-month-old MPS I and control dogs and tested to failure in uniaxial tension. Both CCLs and Achilles tendons from MPS I animals exhibited significantly lower stiffness and failure properties compared to those from healthy controls. Histological examination revealed multiple pathological abnormalities, including collagen fiber disorganization, increased cellularity and vascularity, and elevated GAG content in both tissues. Clinically, animals exhibited mobility deficits, including abnormal gait, which was associated with hyperextensibility of the stifle and hock joints. These findings demonstrate that pathological changes to both ligaments and tendons contribute to abnormal joint function in MPS I, and suggest that effective clinical management of joint disease in patients should incorporate treatments targeting these tissues.
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.
small molecules
2025-11-19 | 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.
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.
2025-06-13 | 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.
2024-08-08 | Synergistic effects of resveratrol and enzyme replacement therapy in the Mucopolysaccharidosis type I.
Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder caused by mutations in the IDUA gene, leading to alpha-L-iduronidase enzyme deficiency and resulting in the accumulation of glycosaminoglycans (GAG; heparan and dermatan sulfate) in lysosomes. The consequent GAG accumulation within cells leads to organ dysfunction and a range of debilitating symptoms. Enzyme replacement therapy (ERT) is the prevailing treatment, but its limitations (including high cost, time requirements, inefficiency in treatment of central nervous system (CNS), and immunogenicity) necessitate exploration of alternative therapeutic strategies. This research propose a novel approach leveraging the synergistic effects of ERT and resveratrol-induced autophagy. Resveratrol, with its immunomodulatory and GAG degradation-stimulating properties, holds a promise in mitigating immune responses triggered by ERT. Moreover, its ability to penetrate the blood-brain barrier presents a potential solution for addressing CNS manifestations. This study employed cells from MPS I patients to investigate the combined effects of resveratrol and the enzyme. Evaluation of the therapeutic impact involved assessing GAG accumulation, enzyme testing, and examining lysosome functionality and the autophagy process through fluorescence microscopy and Western blotting. The combined therapy stimulated the lysosomal mannose-6-phosphate receptor (M6PR) and lysosome biogenesis through the transcription factor EB (TFEB). Additionally, initial block of autophagy in autophagosome formation was relieved after the combined therapy and resveratrol alone. Together with increased enzyme activity through stimulation of the receptor, this synergistic therapy can be considered a new potential treatment for MPS I patients, improving their overall quality of life.
2024-07-02 | Anaesthetic Challenge in a Child with Hurler’s Syndrome: Encouraging Experience with Neuraxial Blockade
Mucopolysaccharidoses are uncommon genetic diseases with multisystem involvement. The potential for airway difficulties and varying success rate of neuraxial blockade demands considerable expertise in the anesthetic management in these patients. Airway management has evolved significantly in such syndromic patients with the increasing use of video laryngoscopes and Supraglottic airway devices. However, airway catastrophes are not uncommon. This calls for better utilization of neuraxial and peripheral nerve blocks along with the use of newer agents for sedation having a favorable pharmacological profile. Here, we present a case of child having Hurler disease with an inguinal hernia successfully operated under subarachnoid blockade.
proteins
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].
2026-05-15 | CSF GAG non-reducing ends in MPS IH after peripheral and brain-penetrating therapies: A model comparing IV non-targeted ERT and HCT.
Mucopolysaccharidosis type IH (MPS IH) is a lysosomal disease caused by insufficient L-iduronidase (IDUA), resulting in progressive accumulation of glycosaminoglycans (GAGs) in the central nervous system (CNS). Hematopoietic cell transplantation (HCT) replaces IDUA through cellular cross-correction, stabilizing the CNS. Intravenous (i.v.) enzyme replacement therapy (ERT) is also effective at reducing GAG accumulation; however, it is thought to inefficiently cross the blood-brain barrier. To compare the effect of i.v. ERT on GAG degradation in the CNS with the effect of brain-penetrant therapy, i.e., HCT, we measured cerebrospinal fluid (CSF) GAG non-reducing ends in patients with MPS IH who were ERT-naive (n = 33), received i.v. ERT prior to HCT (n = 34), or underwent HCT (n = 26). We found that CSF GAGs (cGAGs) were 33%-65% lower in patients exposed to i.v. ERT. One year after HCT, cGAGs declined to their lowest levels. There was no difference in cGAG levels between patients treated with i.v. ERT for 52 weeks after HCT and those treated for only 8 weeks after HCT. In summary, i.v. ERT can lead to a significant decrease in cGAGs prior to HCT, indicating that i.v. ERT may affect CNS biomarkers, which reach their lowest levels with a brain-penetrant therapy.
2026-01-22 | Features of the course of the early period of primary tuberculosis infection in a patient with Hurler syndrome: tactics of managing a comorbid patient
A clinical case of a child with comorbid pathology demonstrates the high importance of alertness of specialists of various profiles of the pediatric network. Doctors of the pediatric phthisiology network are of no small importance, since in children with genetic diseases, tuberculosis can proceed under the «masks» of other pathologies. Mucopolysaccharidosis type I (MPS I) is a rare genetic disease caused by a mutation of the IDUA gene, which encodes the enzyme alpha-L-iduronidase. Hurler syndrome, which is the most severe form of MPS I, requires special attention to prevent the development of severe complications, which often lead to death.
2025-12-07 | Clinical outcomes of exclusive enzyme therapy (laronidase) in a cohort of patients with mucopolysaccharidosis type I.
Mucopolysaccharidosis type I (MPS I), is an autosomal recessive disorder caused by a deficiency in the enzyme α-L-iduronidase (IDUA), leading to the accumulation of glycosaminoglycans (GAGs) in tissues. Early diagnosis and treatment [i.e., bone marrow transplantation and/or enzyme replacement therapy (ERT) with laronidase] are essential to prevent irreversible damage. The long-term effectiveness of exclusive ERT has been primarily described in attenuated phenotypes, while only a few cases have been reported in severe phenotypes. This study is a retrospective analysis summarising the collective experience of disease progression in 48 patients with severe and attenuated MPS I who were treated exclusively with laronidase over a median of 10 years at the Lyon Reference Centre for Hereditary Metabolic Diseases in France. Patients were categorised by genotype and further stratified by age at treatment initiation. The study assessed the evolution of urinary excretion of GAGs, pulmonary function, cardiac involvement and evolution, height, cognitive impairment, functional status, orthopaedic and ear-nose-throat (ENT) procedures, sleep apnoea, and carpal tunnel syndrome. Descriptive statistical analysis methods were used. ERT reduced the GAGus levels by 88% in severe MPS I and by 71% in attenuated MPS I, of which 47% and 65% patients, respectively achieved normal age-related GAG levels at the last follow-up. ERT provided stable or consistent improvement in forced vital capacity, slowed progression of adverse cardiac course and improved auditory transmission in majority of the severe and attenuated patients. At the last follow-up, 84% attenuated patients had normal cognitive development. In alive Hurler patients, cognitive development was very heterogenous; however, 73% patients had a developmental quotient (DQ) ≥ 70. Laronidase was effective in improving statural growth of attenuated patients treated before 9 years of age. Early ERT and regular multidisciplinary management are effective in slowing disease progression in severe and attenuated patients with MPS I and helping to maintain autonomy in patients with attenuated MPS I, ensuring a better quality of life.
2025-11-22 | Long-term safety outcomes and patient preferences for home-based intravenous enzyme replacement therapy (ERT) in Pompe disease and Mucopolysaccharidosis Type I (MPS-I): final results of two-year observation.
BACKGROUND: Pompe disease and Mucopolysaccharidoses Type I (MPS-I) are lysosomal disorders caused by a deficiency of α-glucosidase and alpha-L-iduronidase, respectively. The mainstay of treatment is enzyme replacement therapy (ERT), a life-long treatment that requires regular I.V. infusions. Hospital-based therapy can, however, negatively impact quality of life over time. The purpose of the HomERT study (Home infusions of ERT) was to evaluate the safety, treatment compliance, and treatment satisfaction related to home therapy of Pompe disease patients with Myozyme® (alglucosidase alfa) and MPS-I patients with Aldurazyme® (laronidase). The final results are presented in this paper. RESULTS: The HomERT study was a multicenter, non-interventional, minimum 12-month prospective observational, double-cohort study that analyzed 56 patients from 14 sites in Italy from October 2021 to February 2024: cohort A (Pompe disease − 47 patients) and cohort B (MPS-I − 9 patients: 6 Hurler/Scheie, 3 Scheie). During the observation period, the mean (SD) number of missed infusions was 5.8 (3.92) in cohort A and 3.0 (3.52) in cohort B, corresponding to a mean (SD) of missed infusions of 19.8 (32.7)% and 4.1 (4.2)%, respectively, versus the number of planned infusions. Only 2 patients in cohort A returned to the hospital setting due to “adverse event” and “other” reasons. A total of 13 Adverse Drug Reactions (ADR) were reported during the home-care setting before and after enrollment. The average number of ADRs per patient was 0.2 (1.46) in cohort A and 0.2 (0.67) in group B, and the rate of ADRs/year was 0.15 (95% CI: 0.06; 0.34) in cohort A and 0.06 (95% CI: 0.01; 0.38) in cohort B. The majority of patients preferred home-based infusions (cohort A: 93.6%; cohort B: 88.9%), and the main reason was attributed to treatment convenience (cohort A: 93.6%; cohort B: 100%). Despite the underlying conditions, most patients self-evaluated their health as “Fair” in cohort A (36.2%) and “Good” in cohort B (44.5%). CONCLUSION: The use of ERT with α-glucosidase and alpha-L-iduronidase alfa remains a strong candidate for home therapy, with favorable safety profile, improved treatment ERT compliance, and patient satisfaction. NCT05073783.
cell therapies
2024-10-05 | Engineering memory T cells as a platform for long-term enzyme replacement therapy in lysosomal storage disorders.
Enzymopathy disorders are the result of missing or defective enzymes. Among these enzymopathies, mucopolysaccharidosis type I is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), which ultimately causes toxic buildup of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T (Tm) cells migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm cells as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm cells leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm cells take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS, although only minimal improved cognition was observed. Our study indicates that genetically engineered Tm cells hold great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.
2024-03-08 | Modeling skeletal dysplasia in Hurler syndrome using patient-derived bone marrow osteoprogenitor cells
Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet–based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders.
2021-12-28 | Articular Syndrome Characteristics in Children with Mucopolysaccharidosis Type I
Background . Mucopolysaccharidosis type I is disease from the group of lysosomal storage disease developing due to mutations in the IDUA gene. It leads to the accumulation of glycosaminoglycans (GAGs) in organs and tissues. Joints damage in this disease is systemic and progressive. Objective . The aim of the study. Nowadays, relevant issue is to investigate the effects of various types of pathogenetic therapy on the state of the osteoarticular system in patients with severe and mild phenotypes of MPS I to prevent further progression of joint pathology. Methods. The study included 46 patients diagnosed with “mucopolysaccharidosis type I”. 35 children had severe phenotype (Hurler syndrome) and 11 — with mild phenotypes (Hurler-Scheie and Scheie syndromes). The onset age of clinical manifestations in osteoarticular system, the state of large and small joints, and the presence of cervical stenosis according to the therapy were evaluated in these patients. Results. The osteoarticular system pathology can be usually revealed in all patients with MPS I, in both mild and severe phenotypes. The contractures of shoulder, ulnar, wrist, and small hand joints have been revealed in most patients with Hurler syndrome, regardless of the administered therapy. Hip joints pathology was observed in children who was administered with: enzyme replacement therapy (ERT) — in 46.7% of cases, hematopoietic stem cell transplantation (HSCT) in combination with ERT — in 34.4% of cases. Patients with Hurler syndrome administered with HSCT in combination with ERT had cervical stenosis statistically significantly more rarely (p = 0.018) compared to patients treated with ERT only. Patients with Hurler syndrome who were on ERT had statistically significantly lower growth rates than patients after HSCT in combination with ERT. Lesions in ulnar, wrist, knee and small hand joints were the most common in children with mild phenotypes (in 90% of cases). Conclusion . Combined therapy (HSCT and ERT) in patients with Hurler syndrome reduces severe manifestations in osteoarticular system, including children with a pathogenic nucleotide variant c.208C>T in a homozygous state.
2021-05-14 | Hurdles in treating Hurler disease: potential routes to achieve a "real" cure.
Mucopolysaccharidoses (MPSs) are multiorgan devastating diseases for which hematopoietic cell transplantation (HCT) and, to a lesser extent, enzyme replacement therapy have substantially altered the course of the disease. Furthermore, they have resulted in increased overall survival, especially for Hurler disease (MPS-1). However, despite the identification of clinical predictors and harmonized transplantation protocols, disease progression still poses a significant burden to patients, although at a slower pace. To design better therapies, we need to understand why and where current therapies fail. In this review, we discuss important aspects of the underlying disease and the disease progression. We note that the majority of progressive symptoms that occur in "hard-to-treat" tissues are actually tissues that are difficult to reach, such as avascular connective tissue or tissues isolated from the circulation by a specific barrier (eg, blood-brain barrier, blood-retina barrier). Although easily reached tissues are effectively cured by HCT, disease progression is observed in these "hard-to-reach" tissues. We used these insights to critically appraise ongoing experimental endeavors with regard to their potential to overcome the encountered hurdles and improve long-term clinical outcomes in MPS patients treated with HCT.
2021-01-13 | Obstructive sleep apnea and craniofacial appearance in MPS type I-Hurler children after hematopoietic stem cell transplantation.
Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disorder characterized by severe multi-systemic organ manifestations including obstructive sleep apnea syndrome (OSAS). Hematopoietic stem cell transplantation (HSCT) is the treatment of choice in severe MPS I (MPS IH, Hurler syndrome). However, the effect of HSCT on OSAS in MPS IH still remains unclear. The purpose of this study was to analyze respiratory patterns during sleep following HSCT in MPS IH children and to relate these findings to craniofacial abnormalities. Overnight polysomnographies of nine MPS IH children (mean age: 8.2 years) previously treated with HSCT were retrospectively analyzed. Magnetic resonance images of the head were assessed with regard to soft and hard tissue abnormalities of the upper respiratory tract. The mean apnea hypopnea index (AHI) was 5.3 events/h (range, 0.3-12.2), and the majority of apnea/hypopneas were obstructive. Whereas two patients had severe OSAS (AHI > 10) and two moderate OSAS (5 > AHI < 10), five patients had no evidence of OSAS (AHI < 2.0). Donor cell chimerism was significantly lower in MPS IH patients with OSAS as compared to patients without OSAS (p < 0.001). The upper airway space and the maxilla were significantly smaller and the adenoids larger in MPS IH patients with OSAS as compared to those of non-OSAS patients. OSAS was only observed in MPS IH patients with graft failure or low donor cell chimerism. Conversely, successful HSCT seems to ameliorate adenoid hyperplasia and maxillary constriction in MPS IH patients and thereby minimizes the risk of OSAS at least at younger ages.
gene therapies
2026-04-12 | First-in-human intracisternal dosing of RGX-111 in severe MPS I is well tolerated and generates sustained neurodevelopment without HSCT.
Mucopolysaccharidosis type I (MPS I), caused by α-L-iduronidase enzyme (IDUA) deficiency, manifests multisystemic symptoms from tissue accumulation of undegraded glycosaminoglycans. Severe MPS I (Hurler syndrome) is associated with developmental delay and loss of neurocognition. Although IDUA enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation (HSCT) are standard therapies for Hurler syndrome, gene therapy represents potential alternative treatment of neurodevelopmental disease. We report more than 5 years of clinical, biochemical, and neurocognitive outcomes following a first-in-human, open-label, single-patient, single administration of intra-cisterna magna (ICM) RGX-111 (AAV9.CB7.hIDUA, 1E-10 vector genomes/g brain mass) in a 20-month-old boy with Hurler syndrome with two older affected siblings deceased from HSCT-related complications. The ICM procedure was safe and well tolerated; treatment-emergent adverse events were mild and self-limiting. Crucially, serial brain imaging has been normal. He has never received an HSCT and continues with weekly IDUA infusions. Neurocognitive testing demonstrates ongoing acquisition of developmental abilities, with cognitive, speech, and motor age equivalents measuring one to two standard deviations below the normative mean. His neurodevelopment is significantly above the natural history of untransplanted Hurler syndrome patients. This single-patient experience of central nervous system-directed gene therapy demonstrates therapeutic potential for severe MPS I and other genetic neurodegenerative diseases.
2026-04-08 | Prime Editing Explained: A Comprehensive Guide to the Next Generation of Precision Genome Engineering
Prime editing represents a paradigm shift in precision genome engineering, offering a highly versatile search-and-replace mechanism that bypasses the limitations of traditional CRISPR-Cas9 systems. Unlike conventional methods that rely on double-strand DNA breaks (DSBs) and error-prone cellular repair, prime editing utilizes a fusion protein comprising a Cas9 nickase (H840A) and an engineered reverse transcriptase. This complex is directed by a prime editing guide RNA (pegRNA) that not only targets a specific genomic locus but also encodes the desired genetic edit. This unique architecture enables the precise installation of all twelve possible base substitutions, as well as targeted insertions and deletions, without requiring external donor DNA. Since its introduction, prime editing has evolved rapidly through multiple generations. Early iterations like PE1 and PE2 established the foundational mechanism and optimized the reverse transcriptase. Subsequent systems addressed critical efficiency barriers: PE3 introduced a dual-nicking strategy to bias cellular repair, while PE4 and PE5 incorporated dominant-negative MLH1 to transiently inhibit the mismatch repair (MMR) pathway, which otherwise antagonizes editing outcomes. Recent advancements, such as PEmax and PE7, focus on improved nuclear localization, compact enzyme variants for better delivery, and the use of engineered pegRNAs (epegRNAs) with structural motifs to protect against exonuclease degradation. The therapeutic applications of prime editing are expanding rapidly. A notable breakthrough is the Prime Editing-mediated Readthrough of Premature Termination Codons (PERT) strategy, a disease-agnostic approach that installs a universal suppressor tRNA to treat diverse genetic disorders caused by nonsense mutations, demonstrating efficacy in models of Hurler syndrome and Batten disease. Furthermore, the technology has entered the clinic, with PM359 representing the first human trial for treating chronic granulomatous disease (CGD) using ex vivo edited hematopoietic stem cells. Despite its immense potential, challenges remain regarding the delivery of large editor complexes and the optimization of pegRNA designs. Researchers are actively exploring split prime editors, compact reverse transcriptase domains, and lipid nanoparticles to overcome adeno-associated virus (AAV) packaging constraints. By offering a safer and more precise alternative to DSB-dependent editing and restricted base editors, prime editing is positioned to become a cornerstone technology in functional genomics and the development of next-generation genetic therapies. Source: https://www.geneeditsci.com/posts/prime-editing-explained-a-comprehensive-guide-to-the-next-generation-of-precision-genome-engineering
2025-12-02 | From trial to transformation: insights into hematopoietic stem cell-gene therapy for Hurler syndrome
1. Mucopolysaccharidosis type I (MPSI) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the enzyme α-L-iduronidase (IDUA), essential for the degradation of gly...
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.
2025-11-19 | Prime editing-installed suppressor tRNAs for disease-agnostic genome editing
Abstract Precise genome-editing technologies such as base editing 1,2 and prime editing 3 can correct most pathogenic gene variants, but their widespread clinical application is impeded by the need to develop new therapeutic agents for each mutation. For diseases that are caused by premature stop codons, suppressor tRNAs (sup-tRNAs) offer a more general strategy. Existing approaches to use sup-tRNAs therapeutically, however, require lifelong administration 4,5 or show modest potency, necessitating potentially toxic overexpression. Here we present prime editing-mediated readthrough of premature termination codons (PERT), a strategy to rescue nonsense mutations in a disease-agnostic manner by using prime editing to permanently convert a dispensable endogenous tRNA into an optimized sup-tRNA. Iterative screening of thousands of variants of all 418 human tRNAs identified tRNAs with the strongest sup-tRNA potential. We optimized prime editing agents to install an engineered sup-tRNA at a single genomic locus without overexpression and observed efficient readthrough of premature termination codons and protein rescue in human cell models of Batten disease, Tay–Sachs disease and cystic fibrosis. In vivo delivery of a single prime editor that converts an endogenous mouse tRNA into a sup-tRNA extensively rescued disease pathology in a model of Hurler syndrome. PERT did not induce detected readthrough of natural stop codons or cause significant transcriptomic or proteomic changes. Our findings suggest the potential of disease-agnostic therapeutic genome-editing approaches that require only a single composition of matter to treat diverse genetic diseases.
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2026-03-26 | Lipid Nanoparticle-Delivered mRNA Therapy Corrects Neonatal Murine MPS I-H.
Mucopolysaccharidosis type I-Hurler (MPS I-H) is a severe lysosomal storage disorder caused by α-L-iduronidase (IDUA) deficiency, leading to glycosaminoglycan (GAG) accumulation and progressive multisystem dysfunction, including the central nervous system (CNS). Early hematopoietic stem cell transplantation remains the primary disease-modifying intervention for MPS I-H despite its clinical challenges. Conventional enzyme replacement therapy (ERT), which has limited CNS efficacy due to blood-brain barrier (BBB) restrictions, is being addressed by the development of novel BBB-penetrating ERT platforms. Recently, mRNA therapy has become a promising treatment option for rare genetic diseases by enabling the in vivo supplementation of defective or deficient proteins to ameliorate the disease phenotype. To evaluate mRNA therapy for MPS I-H, we screened ionizable lipids to develop lipid nanoparticle systems optimized for hepatic delivery, which were subsequently used to encapsulate mRNA encoding human IDUA (hIDUA) fused to a validated BBB-penetrating melanotransferrin peptide (MTfp). This formulation was intravenously administered to neonatal MPS I-H mice at a dose of 1.0 mg/kg every 2 weeks for 4 months. The treatment significantly increased IDUA enzyme activity in both the serum and liver. Concurrently, it reduced GAG accumulation in the urine, peripheral tissues, and partial CNS regions (olfactory bulbs, hippocampus, and cerebellum). Furthermore, the treatment significantly improved cardiac and skeletal development, as assessed by echocardiography and micro-computed tomography, respectively. Notably, it also enhanced cognitive function, as evidenced by the improved performance in the Delayed-Matching-to-Place dry maze test. Our findings demonstrate that LNP-MTfp-hIDUA treatment effectively ameliorates key pathological features and promotes neurodevelopment in MPS I-H, establishing a promising and safe therapeutic strategy for this disorder.
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.
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.
2024-02-18 | Evaluation of tendon and ligament microstructure and mechanical properties in a canine model of mucopolysaccharidosis I
Mucopolysaccharidosis (MPS) I is a lysosomal storage disorder characterized by deficient alpha-l-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a strong clinical need for improved treatment approaches that specifically target joint tissues; however, their development is hampered by poor understanding of underlying disease pathophysiology, including how pathological changes to component tissues contribute to overall joint dysfunction. Ligaments and tendons, in particular, have received very little attention, despite the critical roles of these tissues in joint stability and biomechanical function. The goal of this study was to leverage the naturally canine model to undertake functional and structural assessments of the anterior (cranial) cruciate ligament (CCL) and Achilles tendon in MPS I. Tissues were obtained postmortem from 12-month-old MPS I and control dogs and tested to failure in uniaxial tension. Both CCLs and Achilles tendons from MPS I animals exhibited significantly lower stiffness and failure properties compared to those from healthy controls. Histological examination revealed multiple pathological abnormalities, including collagen fiber disorganization, increased cellularity and vascularity, and elevated GAG content in both tissues. Clinically, animals exhibited mobility deficits, including abnormal gait, which was associated with hyperextensibility of the stifle and hock joints. These findings demonstrate that pathological changes to both ligaments and tendons contribute to abnormal joint function in MPS I, and suggest that effective clinical management of joint disease in patients should incorporate treatments targeting these tissues.
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.
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Drug Discovery Landscape
1 orphan drug designation for Hurler syndrome.
1 orphan drug designation for Hurler syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
adult adherent bone marrow-derived multipotent stem cells | cell therapies | FDA | — | Athersys, Inc. |
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