Rady Children’s Health Orange County has become a preeminent center for investigating gene therapy to treat Hurler syndrome, the most severe form of mucopolysaccharidosis type I (MPS I).
Hurler syndrome, an inherited lysosomal storage disorder, results from a deficiency of the alpha-l-iduronidase enzyme, which is responsible for breaking down glycosaminoglycans (GAGs). Accumulation of these sugar molecules leads to neurodegeneration, organ enlargement and other complications. Without treatment, patients typically die before age 10.
Current treatments feature significant limitations, according to Dr. Raymond Wang, Campbell Foundation director of the Multidisciplinary Lysosomal Disorder Program in the Division of Metabolic Disorders at Rady Children’s Health Orange County.
Enzyme replacement therapy can stop symptoms from worsening, but it can’t treat neurodegeneration. A hematopoietic stem cell transplant can stabilize cognitive function but has to be performed before age 2 and runs the risk of failing or causing complications, such as graft-versus-host disease. Gene therapy may offer a new way forward for patients with Hurler syndrome.
“Gene therapy holds hope for something better because it equips the child’s brain cells with copies of a functional alpha-l-iduronidase gene,” Dr. Wang says. “So, that way, the brain cells make their own alpha-l-iduronidase without having to go through something as drastic as a stem cell transplant, or something that’s ineffective at treating the brain, not to mention impermanent, like enzyme replacement therapy.”
Breaking new ground
In the late 2010s, Dr. Wang was working with a family seeking treatment for Hurler syndrome in their infant. Three of their older children had had the condition, and two had died from transplant-related complications. The family did not wish to pursue a transplant for their youngest child, so Dr. Wang suggested another option.
“I knew there was a clinical trial ongoing for the gene therapy RGX-111 by REGENXBIO Inc., and at the time, the study was mandated by the FDA to treat children age 6 and older,” he says. “That trial wasn’t getting any patients enrolled because by the time children with Hurler syndrome reach age 6, they’re in terrible shape neurologically and in terms of overall health.”
The FDA granted Dr. Wang permission to administer the gene therapy to the 20-month-old child under a single-patient investigational new drug application. In 2019, Dr. Wang administered RGX-111, which uses a modified adeno-associated virus serotype 9 to deliver the genetic material, into the patient’s central nervous system through a cervical puncture. It was the first successful gene therapy dosing for Hurler syndrome performed anywhere in the world.
Encouraging results
The safety data that emerged from that case led the FDA to grant the trial sponsor permission to lower the dosing age for RGX-111 to 4 months. Rady Children’s Health Orange County went on to enroll four more children in the clinical trial, the most worldwide of any center involved. The trial is now paused, but five of its participants are enrolled in a long-term observational study at Rady Children’s Health Orange County. This study allows researchers to monitor the patients’ health, track developmental and cognitive status, and collect safety data.
In 2026, Dr. Wang and his collaborators published more than five years of outcomes from the patient who received the first gene therapy dosing seven years earlier. In Molecular Therapy, the authors reported that the patient tolerated the procedure well, experienced only mild adverse events, had normal brain imaging results and continued to build his developmental abilities. They wrote: “His neurodevelopment is significantly above the natural history of untransplanted Hurler syndrome patients.”
According to the authors, the study suggested that RGX-111 resulted in faster expression of the alpha-l-iduronidase enzyme and clearance of GAGs in the brain than an allogeneic hematopoietic stem cell transplant.
Extraordinary case
The cognitive progress of the patients Dr. Wang and his collaborators are following makes him optimistic for the future of gene therapy for Hurler syndrome, but also clear-eyed about the challenges ahead.
“We are realistic in realizing that gene therapy cannot treat the systemic manifestations of MPS I, and our patients still need weekly enzyme replacement therapy,” Dr. Wang says. “We are also very much aware that one of our patients developed a brain tumor that was found to be a direct effect of the gene therapy. Although it appears to be a very rare event, it is a risk that families must balance with consideration of the risks of a stem cell transplant, or the risks of not pursuing treatment.”
In early 2026, the FDA placed a hold on the clinical trial when that participant developed a neuroepithelial tumor four years after receiving RGX-111. In a rare occurrence, the viral vector integrated into the patient’s genome, leading to tumor formation. The tumor was resected, and the patient showed advanced age-based cognition, suggesting the treatment diminished the effects of MPS I. The report from Dr. Wang and collaborators appeared in The New England Journal of Medicine.
‘A lot of promise’
Dr. Wang and his colleagues continue to follow the handful of patients in the long-term observational study, and he says they’ll be ready to resume the original trial once the clinical hold is lifted.
“We are at the very beginning, the frontier, of genomic therapies for inherited or even acquired disorders,” Dr. Wang says. “It is a very exciting time, with a lot of promise. There will probably be setbacks along the way, but the potential rewards are infinitely worth those setbacks as we learn from them and keep moving forward. I am tremendously hopeful for the future of treatment for these disorders.”
Learn more about Rady Children’s Health Orange County’s MPS Multidisciplinary Center, where experts collaborate to offer comprehensive care for children with Hurler syndrome and other forms of MPS.
