May 2026 Research Update

This month added a clearer picture of how different treatments relate to sugar-storage levels in the fluid around the brain and spinal cord (CSF). In a cohort of people with Hurler syndrome, IV enzyme replacement therapy (ERT) lowered these CSF markers before transplant, and the largest further drop happened after hematopoietic cell transplantation (HCT). The same report found that continuing IV ERT for a long time after HCT did not reduce the CSF markers beyond what was seen with HCT alone, even though some other body markers differed. [1]

The study focused on CSF glycosaminoglycan (GAG) non-reducing ends, which are lab signals of stored material in MPS I, and compared groups based on IV ERT exposure before HCT and IV ERT use after HCT. People who received IV ERT before HCT had lower CSF markers than those who were IV ERT-naive, and levels fell further after HCT, reaching their lowest around 1 year post-transplant. After HCT, CSF marker levels were similar whether IV ERT was used for a short or long time, while urine GAG levels were lower in the long-term IV ERT group at 1 and 2 years. [1]

The same report noted that blood enzyme activity measures did not line up strongly with CSF marker levels across the cohort. In plain language, this means a blood enzyme number may not reliably reflect how much stored material is present in CSF in this dataset. The study did not report direct links between these CSF marker changes and day-to-day neurological outcomes, so the clinical meaning of reaching a certain CSF level remains uncertain. [1]

For families, this mainly helps clarify what current lab markers show about treatment timing: IV ERT appeared to reduce CSF storage markers before HCT, and HCT was associated with the biggest additional reduction in CSF markers. The finding that extended IV ERT after HCT did not further lower CSF markers suggests that, at least for these CSF measurements, the transplant effect was the main driver in this cohort. This is observational research and does not by itself show how these marker changes translate into learning, behavior, or daily function. [1]

This month, several reports converged on one message: getting the genetics right in MPS I can require both broader testing and clearer rules for interpreting variants. Two individual patient reports described situations where initial testing did not fully explain a person's symptoms until more comprehensive genetic work and enzyme testing were done. Separately, an expert group reported progress on IDUA-specific rules for classifying variants, aiming to make genetic reports more consistent. [2] [3] [4]

In one person with attenuated MPS I (Scheie syndrome) and major bone and spine problems, genome sequencing found two IDUA variants after exome sequencing did not provide the diagnosis. After this genetic clarification, the report described starting laronidase (IV enzyme replacement therapy) and additional bone-focused treatments, with a substantial rise in bone density over 1 year but persistent nonunion of the fusion. This case illustrates how the choice of genetic test can matter when common tests miss certain types of DNA changes. [2]

Another case involved a person with lifelong color vision differences and later retinitis pigmentosa, plus heart valve disease, where whole exome sequencing identified a homozygous IDUA variant and also found a separate deletion affecting opsin genes that could explain the color vision finding. Enzyme testing showed very low iduronidase activity and urine testing showed elevated GAGs, supporting attenuated MPS I alongside the eye-related genetic change. This helps explain how more than one genetic finding can contribute to a person's symptoms, and why enzyme testing can help interpret what a DNA result means in the body. [3]

To support more consistent genetic answers for families, the ClinGen Lysosomal Diseases group reported building IDUA-specific criteria for classifying variants and has already classified 131 IDUA variants submitted to public databases. The paper also noted ongoing challenges and plans for further work, but did not provide detailed performance data in the summary provided. In practical terms, this is infrastructure work that aims to reduce uncertainty in genetic reports over time. [4]

For patients and caregivers, this set of papers mainly matters for diagnosis and understanding results rather than changing treatment right now. The case reports show that if testing is incomplete, some IDUA changes (including larger deletions) may be missed until broader sequencing is used, and that enzyme and urine tests can help confirm what genetic results mean. The variant-classification project is not a treatment study, but it may reduce confusion in the future by making it easier for different labs to agree on whether an IDUA change is disease-causing. [2] [3] [4]

This month included early, research-stage work aiming to raise the missing enzyme (IDUA) in new ways, alongside a safety-relevant case after gene therapy delivered to the fluid around the brain. The preclinical study reported that an RNA-based approach could temporarily increase IDUA levels in mice and showed supportive signals in retrospective human samples. Separately, one patient case described a tumor found years after AAV9 gene therapy, with molecular testing suggesting the vector integrated into a specific gene within the tumor cells. [5] [6]

The RNA activation study tested MTL-CEBPA, designed to turn on a regulator (CEBPA) that increases IDUA expression. In mice, two IV doses led to about a 2-fold rise in IDUA mRNA and circulating enzyme activity lasting up to 4 weeks, and repeated dosing in a humanized MPS I-H mouse model also raised circulating IDUA activity by about 2-fold over 3 weeks. The paper also reported that about half of evaluable cancer trial participants showed increased plasma IDUA after MTL-CEBPA, but these were retrospective observations and not Hurler syndrome outcomes. [5]

In the gene therapy case, a child with Hurler syndrome developed a neuroepithelial tumor 4 years after intracisternal magna delivery of an AAV9 vector. After tumor removal, molecular analysis found clonal integration of rearranged AAV vector elements into the gene PLAG1 and expression of an AAV-PLAG1 transcript in the tumor. The report also noted the child maintained advanced cognitive function for age, consistent with mitigation of MPS I in this individual, but the case cannot show how often this complication may occur. [6]

For families, these findings are mostly about where research may be heading and what questions remain. The RNA activation work is not yet evidence of clinical benefit in Hurler syndrome, but it supports the idea that IDUA levels might be increased in an adjustable, non-integrating way that could be studied further. The AAV9 case highlights that rare but serious events can occur in gene therapy development, and that long-term follow-up and careful reporting are part of understanding these risks; one case cannot predict an individual patient's risk. [5] [6]