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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 lysosomal storage disorder caused by harmful variants in the IDUA gene. The resulting shortage of the enzyme alpha-L-iduronidase (IDUA) allows long sugar chains called glycosaminoglycans (GAGs) to build up in cells and tissues. Hurler syndrome, also called severe MPS I or MPS I-H, is the most severe end of the MPS I spectrum and usually begins in infancy, affecting the brain, skeleton, heart, airways, hearing, vision, liver, and other organs. Without disease-modifying treatment, death—often from heart or lung complications—typically occurs within the first decade of life. GeneReviews: Mucopolysaccharidosis Type I (ncbi.nlm.nih.gov)

The current standard of care is early allogeneic hematopoietic stem-cell transplantation (HSCT), ideally before age two, often with intravenous laronidase enzyme-replacement therapy (ERT) before and around transplantation plus extensive specialist care. HSCT can supply enzyme-producing donor-derived blood and immune cells and is the only established treatment that changes the course of central-nervous-system disease, but it does not fully prevent skeletal, eye, heart-valve, hearing, or cognitive complications. Intravenous laronidase improves several body-wide manifestations but does not adequately reach the brain. GeneReviews: Mucopolysaccharidosis Type I (ncbi.nlm.nih.gov)

Scope of Recent Research (2020–present)

Research since 2020 has been active and increasingly focused on providing lifelong, higher-than-normal IDUA production early enough to protect both the brain and the body. The leading clinical strategy is autologous blood stem-cell gene therapy, while brain-directed adeno-associated virus (AAV) gene therapy, genome editing, and nonviral RNA delivery are being investigated to overcome the residual disease left by HSCT. No therapy has yet demonstrated that it can safely and permanently cure Hurler syndrome across all affected organs, but the field has moved from animal proof-of-concept to comparative late-stage testing of one gene-therapy approach. HSPC gene therapy for Hurler syndrome HURCULES trial (nejm.org)

Major Breakthroughs and Emerging Therapies

The strongest clinical advance is ex vivo hematopoietic stem-and-progenitor-cell gene therapy. In this approach, a child’s own CD34-positive blood stem cells are collected, modified outside the body with a lentiviral vector carrying a working IDUA gene, and returned after chemotherapy conditioning. This avoids donor matching and graft-versus-host disease while aiming to generate much higher enzyme levels than conventional donor transplantation. In the initial eight-patient study of OTL-203, participants had sustained engraftment, very high blood IDUA activity, normalization of urinary GAGs, and early evidence of stable cognitive and motor development; later reports described favorable skeletal, hearing, corneal, cardiac, and carpal-tunnel outcomes through up to four years, although the sample remains small and nonrandomized. HSPC gene therapy for Hurler syndrome Early skeletal outcomes after HSPC gene therapy Four-year multisystem outcomes (nejm.org)

A second approach is in vivo AAV gene replacement, in which a modified, non-disease-causing virus delivers a functional IDUA gene directly to cells. RGX-111 was designed to deliver the gene into the central nervous system by injection into cerebrospinal fluid near the base of the skull, with the goal of treating the neurological disease that intravenous ERT cannot reach. A published first-in-human case described continued developmental skill acquisition more than five years after treatment without HSCT, but the child continued weekly enzyme replacement and a single case cannot establish efficacy. Five-year RGX-111 case report (pmc.ncbi.nlm.nih.gov)

However, AAV gene therapy has also delivered a major safety warning. In January 2026, the FDA placed the RGX-111 program on partial clinical hold after preliminary analysis of an intraventricular central-nervous-system tumor in one Phase I/II participant; the company reported that analysis identified AAV vector-genome integration associated with overexpression of a proto-oncogene. This does not prove that every AAV approach causes cancer, but it makes long-term tumor surveillance and a clearer understanding of vector integration essential before brain-directed AAV treatment can be considered curative. REGENXBIO regulatory update Five-year RGX-111 case report (regenxbio.gcs-web.com)

Genome editing and RNA-based treatments remain preclinical but could eventually avoid permanent viral gene delivery or enable repeat dosing. Liver-directed CRISPR editing has corrected metabolic and neurological abnormalities in MPS I mice by inserting IDUA into the highly active albumin gene locus. More recently, lipid nanoparticles carrying adenine base-editor messenger RNA and a guide RNA partially corrected an MPS I-H mutation in neonatal mouse brain, restoring 7–11% of normal IDUA activity in tested regions and lowering GAG storage. A separate neonatal-mouse study reported that liver-targeted lipid nanoparticles carrying IDUA messenger RNA fused to a blood-brain-barrier-penetrating peptide improved biochemical, cardiac, skeletal, and cognitive measures with repeated dosing. These are promising animal results, not human therapies. CRISPR editing in MPS I mice Lipid-nanoparticle base editing Lipid-nanoparticle mRNA therapy (pmc.ncbi.nlm.nih.gov)

Clinical Trials and Experimental Approaches

OTL-203 is the most advanced MPS I-H gene-therapy program. Its Phase I/II study, sponsored by Orchard Therapeutics and conducted with the San Raffaele Telethon Institute for Gene Therapy, treated eight children with autologous lentiviral IDUA-modified stem cells. The follow-on randomized Phase III HURCULES study, NCT06149403, compares OTL-203 directly with standard allogeneic HSCT and is designed to determine whether the gene therapy offers a clinically meaningful advantage rather than merely showing favorable results against historical comparisons. Orchard reported that the final patient was treated in July 2025; patients require years of follow-up for efficacy and delayed safety outcomes. Phase I/II OTL-203 study HURCULES trial Last patient treated in HURCULES (nejm.org)

RGX-111, REGENXBIO’s intracisternal AAV9-IDUA therapy, was studied in the Phase I/II CAMPSIITE trial, NCT03580083. Although early clinical observations suggested possible neurological benefit, the program’s January 2026 FDA clinical hold means that new conclusions about efficacy or routine clinical use must await resolution of the tumor investigation and regulatory review. Earlier in vivo genome editing was tested with Sangamo’s SB-318, which used AAV-delivered zinc-finger nucleases to insert IDUA into liver cells; the Phase I/II study enrolled three adults with attenuated MPS I and was terminated after completion, with results showing low or undetectable editing at clinically relevant levels rather than a compelling therapeutic effect. RGX-111 trial REGENXBIO regulatory update SB-318 trial results First-in-human ZFN editing (clinicaltrials.gov)

Methodologies and Scientific Approaches

Researchers use MPS I mouse models, patient cells, human tissue samples, large-animal studies, and clinical natural-history cohorts to test whether a treatment restores IDUA activity and lowers GAG storage in blood, urine, cerebrospinal fluid, brain, bone, heart, and other organs. Key measures include enzyme activity, urinary and cerebrospinal-fluid GAG fragments, magnetic-resonance imaging, skeletal imaging, hearing and eye examinations, heart-valve assessments, growth, developmental testing, and long-term vector-integration or cancer surveillance. HSPC gene therapy for Hurler syndrome Lipid-nanoparticle base editing (nejm.org)

The central delivery problem is reaching the brain while also correcting body-wide disease. Stem-cell therapies rely on enzyme secretion and “cross-correction,” in which enzyme made by corrected cells is taken up by nearby deficient cells. AAV programs attempt direct delivery to the central nervous system or liver, whereas lipid nanoparticles aim to carry transient messenger RNA or gene-editing machinery without using a viral vector. Each platform must balance sufficient tissue exposure with immune reactions, off-target editing, manufacturing consistency, and long-term safety. HSPC gene therapy for Hurler syndrome Lipid-nanoparticle base editing (nejm.org)

Leading Institutions and Funding

The clinical stem-cell gene-therapy program was developed by the San Raffaele Telethon Institute for Gene Therapy and IRCCS San Raffaele Scientific Institute in Milan, supported initially by Fondazione Telethon and subsequently advanced by Orchard Therapeutics, now a Kyowa Kirin company. REGENXBIO and Nippon Shinyaku have driven the AAV9 RGX-111 program, although its status is constrained by the FDA hold. HSPC gene therapy for Hurler syndrome REGENXBIO regulatory update (nejm.org)

In the United States, Children’s Hospital of Philadelphia and the University of Pennsylvania received a five-year, $26 million NIH award in 2023 to develop CRISPR-based therapies for three newborn genetic diseases, including MPS I. NIH also supports canine MPS I combination-gene-therapy work at Children’s Hospital of Orange County through award R01HD106916; the fiscal-year 2026 continuation was $593,114, within a project period extending through February 2028. CHOP and Penn NIH award NIH award R01HD106916 (chop.edu)

Strengths, Limitations, and Challenges

Autologous stem-cell gene therapy has a particularly strong rationale because it can provide durable enzyme production without a donor and may improve disease features that remain problematic after standard HSCT. Its most important evidence gap is whether the encouraging results in eight early participants translate into superior long-term neurocognitive, skeletal, cardiac, eye, and quality-of-life outcomes in a randomized comparison with transplantation. It also still requires stem-cell collection, intensive chemotherapy conditioning, specialized centers, and long-term monitoring for lentiviral insertion-related risks. HSPC gene therapy for Hurler syndrome Four-year multisystem outcomes HURCULES trial (nejm.org)

AAV, editing, and RNA platforms may be less dependent on transplantation and could potentially be administered earlier, but they face formidable barriers. Direct brain delivery is invasive, high-dose systemic AAV can provoke immune toxicity, pre-existing antibodies can exclude some patients, and the RGX-111 tumor case illustrates the need to evaluate rare but serious long-term risks. Genome editing must demonstrate accurate delivery to enough cells throughout the brain and body, very low off-target changes, and durable benefit; messenger-RNA approaches may require repeated dosing and have not yet entered MPS I clinical trials. REGENXBIO regulatory update Lipid-nanoparticle base editing Lipid-nanoparticle mRNA therapy (regenxbio.gcs-web.com)

Outlook and Future Directions

As of October 24, 2026, a true cure for Hurler syndrome is not available. The most consequential near-term milestone is long-term, comparative evidence from the Phase III HURCULES trial of OTL-203: durable high IDUA activity, preservation of development, and clearly better skeletal and multisystem outcomes than optimized HSCT would make it the leading candidate for a functional one-time treatment. For AAV therapies, the immediate milestone is transparent resolution of the RGX-111 safety investigation; for editing and RNA approaches, it is reproducible whole-body and brain correction in larger animal models with long-term safety data. HURCULES trial REGENXBIO regulatory update Lipid-nanoparticle base editing (clinicaltrials.gov)

References

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