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Mucopolysaccharidosis Type I (Hurler Syndrome)

Recent research efforts aimed at curing Mucopolysaccharidosis Type I (Hurler Syndrome).

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Mucopolysaccharidosis Type I (Hurler Syndrome)

Overview

Mucopolysaccharidosis type I (MPS I) is an inherited, autosomal-recessive lysosomal storage disorder caused by harmful variants in the IDUA gene. The resulting shortage of the enzyme alpha-L-iduronidase (IDUA) prevents normal breakdown of glycosaminoglycans (GAGs), complex sugars that then build up in cells and damage many organs. Hurler syndrome, also called severe MPS I, is the most severe end of the MPS I spectrum and can affect the brain, heart, airways, bones and joints, hearing, vision, and physical growth. GeneReviews overview (ncbi.nlm.nih.gov)

Without treatment, progressive heart and lung disease typically causes death within the first decade of life in severe MPS I. Current disease-modifying care is early allogeneic hematopoietic stem-cell transplantation (HSCT, replacement of bone-marrow-forming blood stem cells from a donor) together with intravenous enzyme replacement therapy (ERT) using laronidase and extensive multidisciplinary care. HSCT can protect some brain function when performed early, but neither HSCT nor standard intravenous ERT fully prevents skeletal, eye, heart-valve, or central nervous system disease; ERT does not adequately cross the blood-brain barrier. GeneReviews treatment guidance (ncbi.nlm.nih.gov)

Scope of Recent Research (2020–present)

Research has been active and increasingly focused on supplying IDUA throughout the body and, crucially, in the brain early enough to prevent irreversible injury. The leading potentially transformative approaches are autologous blood-stem-cell gene therapy, direct central-nervous-system gene therapy, and brain-penetrating enzyme replacement; gene editing and engineered-cell platforms remain earlier-stage. There is not yet a proven cure, but the clinical evidence for durable enzyme restoration from autologous stem-cell gene therapy is substantially stronger than it was in 2020, while recent safety events have reinforced the need for long-term follow-up of viral-vector approaches. HSPC gene-therapy trial RGX-111 regulatory update (nejm.org)

Major Breakthroughs and Emerging Therapies

The most mature curative-intent strategy is autologous hematopoietic stem and progenitor cell (HSPC) gene therapy, also called OTL-203. Clinicians collect a child’s own CD34-positive blood-forming stem cells, add a working IDUA gene with a lentiviral vector outside the body, and reinfuse the corrected cells after conditioning chemotherapy. In an interim report of eight children with Hurler syndrome, treated children developed stable gene marking, detectable IDUA activity in cerebrospinal fluid, clearance of GAGs, and encouraging stabilization or improvement across cognitive, motor, imaging, growth, and joint measures over approximately 1.5 to 2.9 years of follow-up. This approach is intended to provide a lifelong source of high-level enzyme without donor-cell rejection or graft-versus-host disease, although it still requires intensive chemotherapy and long-term monitoring for insertion-related risks. HSPC gene-therapy trial (nejm.org)

A second strategy is direct brain-targeted AAV gene therapy. RGX-111 uses an adeno-associated virus type 9 (AAV9) vector carrying IDUA, administered into cerebrospinal fluid through the cisterna magna or cerebral ventricles, with the goal of making IDUA within the central nervous system. A 2026 case report described sustained neurodevelopment in a treated child who had not received HSCT, and mouse studies found that intrathecal, intravenous, or combined dosing could prevent neurological, skeletal, and cardiac manifestations at tested effective doses. However, this program cannot currently be considered established or curative: in January 2026, the U.S. Food and Drug Administration placed RGX-111 on clinical hold after an asymptomatic participant was found to have an intraventricular brain tumor; preliminary analysis detected an AAV-vector integration event associated with overexpression of PLAG1. RGX-111 first-in-human report AAV9-IDUA mouse study RGX-111 regulatory update (pubmed.ncbi.nlm.nih.gov)

Brain-penetrating enzyme replacement is a less permanent but important disease-modifying approach. Lepunafusp alfa (JR-171) fuses IDUA to an antibody fragment that binds the transferrin receptor, using that receptor as a transport route across the blood-brain barrier. In a phase I/II study, the drug was detected in cerebrospinal fluid, cerebrospinal-fluid heparan sulfate declined, and urine and serum substrate reductions were broadly comparable with conventional laronidase; no notable safety issues were reported in the published short-term study. Because it requires repeated infusions and does not correct the DNA defect, JR-171 is not a cure, but it could address a central limitation of current ERT if durable neurological benefit is demonstrated. Lepunafusp alfa phase I/II trial (pubmed.ncbi.nlm.nih.gov)

Genome editing aims to make a permanent enzyme-producing cell population. The clinical zinc-finger nuclease program SB-318 used AAV vectors to insert an IDUA sequence at the liver albumin locus. The small phase I/II study was terminated after three treated participants entered long-term follow-up; published results found no sustained enzyme activity or GAG control after ERT withdrawal, illustrating the difficulty of achieving enough edited liver cells in people. In mice, however, CRISPR-based editing has continued to generate useful proof-of-concept results, including nasal liposomal delivery targeting the ROSA26 locus and local joint injection of liposomal CRISPR/Cas9 systems that reduced GAG storage in joints. SB-318 trial record First-in-human genome-editing results Nasal CRISPR study Joint CRISPR study (clinicaltrials.gov)

Cell-based treatments remain preclinical but broaden the options for reaching difficult tissues. Engineered human memory T cells that secrete IDUA produced detectable blood enzyme for up to 22 weeks and reduced GAG storage in multiple organs and the central nervous system in immunodeficient MPS I mice. Separately, human induced-pluripotent-stem-cell-derived neural stem cells engrafted widely in neonatal MPS I mouse brains, partially restored IDUA activity, and reduced markers of lysosomal and inflammatory pathology. These studies are promising platforms, but neither has been tested as a treatment in people with MPS I. Engineered memory T-cell study Neural stem-cell study (pubmed.ncbi.nlm.nih.gov)

Clinical Trials and Experimental Approaches

The strongest clinical efficacy signal remains the investigator-sponsored phase I/II autologous HSPC lentiviral gene-therapy study at San Raffaele Hospital in Milan, Italy, which produced the encouraging eight-patient interim report. Its successor, the HURCULES phase III study of OTL-203, is registered to compare autologous gene-corrected HSPCs with standard allogeneic HSCT in children with MPS I-H. The key question is whether the higher, self-produced IDUA levels translate into superior long-term neurocognitive, skeletal, and overall functional outcomes compared with the best available transplant care. HSPC gene-therapy trial OTL-203 phase III trial (nejm.org)

REGENXBIO’s RGX-111 phase I/II trial was designed to test a one-time intracisternal or intraventricular AAV9-IDUA treatment in participants with central nervous system involvement. The registry lists the study as suspended, and the January 2026 FDA clinical hold followed the tumor finding described above; therefore, new dosing and any future development depend on resolution of the safety investigation. RGX-111 phase I/II trial RGX-111 regulatory update (clinicaltrials.gov)

JCR Pharmaceuticals’ multinational phase I/II JR-171 study is completed. It enrolled 18 participants across Japan, Brazil, and the United States and provided evidence that the fusion enzyme can reach cerebrospinal fluid and lower central and systemic substrate biomarkers, but it was small, open-label, and short in duration; it was not designed to establish long-term clinical benefit or cure. The terminated SB-318 study is an equally valuable negative result, showing that permanent editing is not enough unless the level of corrected enzyme production is sufficient to replace ERT. JR-171 trial record Lepunafusp alfa phase I/II trial SB-318 trial record (clinicaltrials.gov)

Methodologies and Scientific Approaches

Researchers use enzyme activity, urine and blood GAGs, cerebrospinal-fluid heparan sulfate and dermatan sulfate, brain and spine MRI, growth, joint movement, and age-appropriate neurodevelopmental testing to ask whether a therapy reaches both body and brain and changes disease progression. Studies must measure not merely whether IDUA becomes detectable, but whether enough enzyme reaches affected tissues for long enough to lower storage material and preserve function. HSPC gene-therapy trial RGX-111 phase I/II trial Lepunafusp alfa phase I/II trial (nejm.org)

Preclinical work combines Idua-deficient mice, larger canine models for joint delivery, patient-derived or engineered human cells, and multiple delivery systems: integrating lentiviral vectors for blood stem cells, non-integrating AAV vectors for direct gene transfer, receptor-mediated antibody-enzyme shuttles, and nonviral liposomes for CRISPR editing. Each platform is evaluated for tissue distribution, IDUA activity, GAG reduction, immune responses, off-target editing or integration, and persistence of benefit. Canine intra-articular AAV9 study Nasal CRISPR study Neural stem-cell study (pubmed.ncbi.nlm.nih.gov)

Leading Institutions and Funding

San Raffaele Telethon Institute for Gene Therapy and San Raffaele Hospital in Milan developed the autologous HSPC approach, with Fondazione Telethon support and later commercial development by Orchard Therapeutics. The early clinical study was funded by Fondazione Telethon and other supporters, while the registered OTL-203 phase III program represents the field’s principal confirmatory gene-therapy effort. HSPC gene-therapy trial OTL-203 phase III trial (nejm.org)

Children’s Hospital of Orange County and the University of California, Irvine have been central to RGX-111 clinical and neural-stem-cell research, alongside REGENXBIO. JCR Pharmaceuticals funded the JR-171 phase I/II study with academic sites in the United States, Brazil, and Japan. In Brazil, Hospital de Clínicas de Porto Alegre and Universidade Federal do Rio Grande do Sul have led nonviral editing research supported by named programs from CAPES, Brazil’s National Council for Scientific and Technological Development, FIPE/HCPA, and FAPERGS. RGX-111 first-in-human report Lepunafusp alfa phase I/II trial Nasal CRISPR study (pubmed.ncbi.nlm.nih.gov)

Strengths, Limitations, and Challenges

The major strength of MPS I research is biological: IDUA is a secreted enzyme, so corrected cells can supply enzyme to nearby uncorrected cells, a process called cross-correction. Autologous HSPC gene therapy directly builds on decades of HSCT experience while potentially supplying considerably more enzyme than a donor graft. Brain-directed AAV therapy and receptor-mediated ERT specifically tackle the central nervous system, which is the largest unmet need in Hurler syndrome. HSPC gene-therapy trial Lepunafusp alfa phase I/II trial (nejm.org)

The limitations are equally important. Conditioning chemotherapy for HSPC gene therapy has acute and long-term toxicity, lentiviral insertion requires lifelong surveillance, and early studies have involved very few children. AAV treatment may be limited by pre-existing immunity, dose-related toxicity, inability to redose easily, and—following the RGX-111 tumor finding—the possibility that rare vector integration can contribute to serious adverse events. Repeated brain-penetrating ERT may avoid permanent genomic changes but entails lifelong access, infusion burden, cost, and uncertain long-term neurocognitive efficacy. First-in-human genome-editing results RGX-111 regulatory update Lepunafusp alfa phase I/II trial (pmc.ncbi.nlm.nih.gov)

Outlook and Future Directions

As of August 8, 2026, MPS I is not curable in routine practice, but autologous HSPC gene therapy is the closest current candidate for a functional, one-time treatment that could substantially change the disease course. The milestones to watch are phase III OTL-203 comparative results, long-term neurological and skeletal outcomes from the original treated cohort, the FDA investigation and future status of RGX-111, and whether JR-171’s cerebrospinal-fluid biomarker effects translate into durable cognitive benefit. A true cure will require lasting correction in both body and brain, acceptable long-term safety, treatment early enough to prevent irreversible damage, and access beyond a small number of specialist centers. OTL-203 phase III trial RGX-111 phase I/II trial Lepunafusp alfa phase I/II trial (clinicaltrials.gov)

References

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