Hurler Syndrome Glycosaminoglycans Decrease in Cerebrospinal Fluid without Brain-Targeted Therapy

Abstract

Novel therapies for Hurler syndrome aim to cross the blood-brain barrier (BBB) to target neurodegeneration by degrading glycosaminoglycans (GAG). BBB penetration has been assumed with decreased cerebrospinal fluid (CSF) GAG, yet little is known about CSF GAG without brain-targeting therapies. We compared pre-transplant CSF GAG in patients who were treatment naïve (n = 19) versus receiving standard non-BBB penetrating enzyme replacement therapy (ERT, n = 12). In the ERT versus treatment naïve groups, CSF GAG was significantly lower across all content assayed, raising questions about using CSF GAG decrements to show BBB penetration. Future studies should compare GAG reduction in standard versus novel therapies. ANN NEUROL 2023;94:1182-1186.

FIGURE 1

Changes in cerebrospinal fluid (CSF) glycosaminoglycans (GAGs) in enzyme replacement therapy (ERT) naïve MPS IH patients and those on intravenous (IV) ERT. (A) CSF NRE I0S0, I0S6, and HS levels determined at initial evaluation. (B) CSF NRE I0S0, I0S6, and HS determined for infants <6 months of age and >6 months of age at initial evaluation pre‐HSCT. Normal control CSF I0S0 and I0S6 are not detectable (per ARUP). HS in unaffected CSF controls is <120 ng/mL. No patients in the naïve group and three patients in the ERT treated group had HS < 120 ng/mL. All patients had a measurable value for I0S0 or I0S6. Shown are means ± SD and p‐values derived from a Student's t‐test.