First-in-human intracisternal dosing of RGX-111 in severe MPS I is well tolerated and generates sustained neurodevelopment without HSCT.

Overview

Authors: Raymond Y Wang^1,2, Nina Movsesyan³, Shih-Hsin Kan³, Tammam Beydoun⁴, Mery Taylor⁵, Richard C Chang¹, Dawn Phillips⁶, Jenna Burke⁶, Michelle Gilmor⁶, Yoonjin Cho⁶, Paulo Falabella⁶, Laura Pisani⁶

ORCID iDs: Raymond Y Wang, Shih-Hsin Kan

Division of Metabolic Disorders, Children’s Hospital of Orange County Specialists, Orange, CA 92868, USA
Department of Pediatrics, University of California, Irvine, Orange, CA 92868, USA
Research Institute, Children’s Hospital of Orange County, Orange, CA 92868, USA
Orange County Pediatric Radiology Associates, Orange, CA 92868, USA
Department of Pediatric Psychology, Children’s Hospital of Orange County, Orange, CA 92868, USA
REGENXBIO Inc., Rockville, MD 20850, USA

Institutions: Children's Hospital of Orange County (United States); University of California, Irvine (United States); Regenxbio (United States) (United States)

Journal: Molecular therapy : the journal of the American Society of Gene Therapy, volume 34, issue 6, pages 3217-3223

Dates: received 10 February 2026; accepted 8 April 2026; published online 10 April 2026; in print 3 June 2026

Type: Brief report · Language: English

License: CC BY

Identifiers: DOI 10.1016/j.ymthe.2026.04.016 · PMID 41966056 · PMCID PMC13239742 · OpenAlex W7152977546

Open access: hybrid, a free copy (OpenAlex)

Status: code on request

Categories: human (organism)

Methods: Smoothing, state filtering, decompositions

Keywords: mucopolysaccharidosis, Hurler syndrome, central nervous system, gene therapy, safety, outcome, cognition, intra-cisterna magna, iduronidase, adeno-associated virus

MeSH: Genetic Therapy*, Genetic Vectors*, Iduronidase*, Mucopolysaccharidosis I*, Dependovirus, Enzyme Replacement Therapy, Gene Therapy Agents, Hematopoietic Stem Cell Transplantation, Humans, Infant, Male, Neurodevelopment, Treatment Outcome (* major topic)

Topic: Hereditary Neurological Disorders (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex

Funding: Campbell Foundation

Citations: cited by 1 paper (Europe PMC); 20 references in the paper

Abstract

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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De-identified participant data and images collected for the study will be made available for review upon reasonable request to the corresponding author with a signed data access agreement. The study protocol and informed consent are available as supplemental information.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 10 keywords, 13 MeSH terms, 1 funder, 17 references.

Cite

This paper

Wang, R. Y., Movsesyan, N., Kan, S.-H., Beydoun, T., Taylor, M., Chang, R. C., Phillips, D., Burke, J., Gilmor, M., Cho, Y., Falabella, P., & Pisani, L. (2026). First-in-human intracisternal dosing of RGX-111 in severe MPS I is well tolerated and generates sustained neurodevelopment without HSCT. Molecular therapy : the journal of the American Society of Gene Therapy, 34(6), 3217-3223. https://doi.org/10.1016/j.ymthe.2026.04.016

BibTeX

@article{wang2026first, author = {Wang, Raymond Y and Movsesyan, Nina and Kan, Shih-Hsin and Beydoun, Tammam and Taylor, Mery and Chang, Richard C and Phillips, Dawn and Burke, Jenna and Gilmor, Michelle and Cho, Yoonjin and Falabella, Paulo and Pisani, Laura}, title = {{First-in-human intracisternal dosing of RGX-111 in severe MPS I is well tolerated and generates sustained neurodevelopment without HSCT}}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, year = {2026}, month = apr, volume = {34}, number = {6}, pages = {3217--3223}, publisher = {American Society of Gene \& Cell Therapy}, issn = {1525-0016}, doi = {10.1016/j.ymthe.2026.04.016}, url = {https://doi.org/10.1016/j.ymthe.2026.04.016}, pmid = {41966056}, pmcid = {PMC13239742} }

RIS

TY - JOUR AU - Wang, Raymond Y AU - Movsesyan, Nina AU - Kan, Shih-Hsin AU - Beydoun, Tammam AU - Taylor, Mery AU - Chang, Richard C AU - Phillips, Dawn AU - Burke, Jenna AU - Gilmor, Michelle AU - Cho, Yoonjin AU - Falabella, Paulo AU - Pisani, Laura TI - First-in-human intracisternal dosing of RGX-111 in severe MPS I is well tolerated and generates sustained neurodevelopment without HSCT T2 - Molecular therapy : the journal of the American Society of Gene Therapy J2 - Mol Ther PY - 2026 DA - 2026/04/10 VL - 34 IS - 6 SP - 3217 EP - 3223 SN - 1525-0016 PB - American Society of Gene & Cell Therapy DO - 10.1016/j.ymthe.2026.04.016 UR - https://doi.org/10.1016/j.ymthe.2026.04.016 LA - en ER -

CSL-JSON

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