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:
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.
2026-04-12 | 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
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.
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.
2026-04-12 | 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
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.
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
1 orphan drug designation for Hurler syndrome.
1 orphan drug designation for Hurler syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adult adherent bone marrow-derived multipotent stem cells | cell therapies | FDA | 2012-07-06 | — | Athersys, Inc. |
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