Heparan sulfate in cerebrospinal fluid as a biomarker to assess disease severity and for treatment monitoring in patients with Mucopolysaccharidosis Type II: a position statement.

Patients with mucopolysaccharidosis type II (MPS II) can present with a severe neuronopathic phenotype or an attenuated non-neuronopathic phenotype. In the light of the recent development of drugs that cross the blood-brain barrier for treatment of neurologic MPS II symptoms, it is critical to define biomarkers that objectively differentiate phenotypes and monitor therapeutic outcomes of advanced treatments. In December 2023, a panel of Brazilian experts discussed the potential of quantifying heparan sulfate (HS) in the cerebrospinal fluid (CSF) as a biomarker for assessing neurological impairment in patients with MPS II, as well as the potential of the molecule as an objective parameter for therapeutic monitoring. Based on scientific evidence, the experts concluded that HS in CSF is predominantly derived from the brain and reflects neurological impairment in patients with MPS II. CSF HS levels may help differentiate between neuronopathic and non-neuronopathic forms of MPS II, with preliminary observations suggesting a potential threshold around 4,000 ng/mL when HS quantification is performed using the same method described in clinical studies of pabinafusp alfa. According to the authors, monitoring HS levels in CSF can serve as an objective parameter for assessing the effectiveness of treatment with drugs that cross the blood-brain barrier. The recommended timing of HS evaluations in CSF of patients with the severe phenotype is: (i) before treatment; (ii) six months after starting treatment; and (iii) two years after starting treatment. The same monitoring scheme is recommended for patients with the attenuated MPS II phenotype, however, after two years of treatment, the physician may elect to perform regular neurocognitive evaluations instead of measuring HS in CSF. Lastly, the authors reinforced the importance of evaluating adherence to treatment, including interruptions, to provide a more meaningful assessment of the treatment's real-world impact and to determine the ideal timing of CSF collection for therapeutic monitoring.