Cerebrospinal fluid heparan sulfate as a biomarker for neuronopathic mucopolysaccharidoses: Rationale and regulatory challenges

Mucopolysaccharidoses (MPS) are a group of rare genetic disorders in which a deficiency of specific lysosomal enzymes results in abnormal glycosaminoglycans (GAG) catabolism. The biochemistry of MPS is well understood, and the primary event is a defect in GAG metabolism, leading to intralysosomal substrate accumulation and secondary lysosomal dysfunction. The MPS are heterogeneous disorders with physical and/or neurologic involvement with unmet medical needs. The severe or neuronopathic forms of MPS I (Hurler syndrome), MPS II (Hunter syndrome), MPS VII (Sly syndrome), and all classical forms of MPS III (Sanfilippo syndrome A-D) will develop cognitive impairment. Individuals with MPS I, MPS II, and MPS VII have elevated dermatan sulfate (DS) and heparan sulfate (HS) in their urine, while individuals with MPS III only have elevated HS. The predominant GAG observed in cerebrospinal fluid (CSF) in all individuals with neuronopathic MPS (nMPS) is HS. CSF HS correlates with brain tissue HS in MPS animal models. Therefore, the reduction of CSF HS reflects a decrease in brain tissue HS. CSF HS disaccharides can be reliably measured using mass spectrometry. However, regulatory challenges persist in accepting HS as a biomarker. Traditional trial designs with randomization are not feasible given the heterogeneity of nMPS and are unethical in a progressive neurodegenerative disease. Many countries have approval pathways using biomarkers, but they are underutilized. In summary, this review provides evidence supporting the use of CSF HS as a biomarker of treatment efficacy for the brain disease in individuals with nMPS.