High-dose enzyme replacement therapy attenuates cerebroventriculomegaly in a mouse model of mucopolysaccharidosis type II

The natural progression of the severe form of mucopolysaccharidosis II in children is a rapid decline of neurodevelopmental function with hydrocephalus. Recombinant human iduronate-2-sulfatase enzyme replacement therapy (ERT) under a standard regimen seems to have limited effect. Therefore, we determined whether early, high-dose ERT attenuated ventriculomegaly and histologic abnormalities in the brains of IdS-knockout mice. IdS-knockout mice received saline or recombinant human IdS (0.5/1.0/2.0 mg kg -1) intravenously once weekly, starting at 4 weeks of age and continuing until 20 weeks. ERT with 2.0 mg kg -1, but not 0.5 or 1.0 mg kg -1, significantly attenuated enlarged ventricles, as confirmed by in vivo 7-teslar brain magnetic reasonance image (MRI) at 20 weeks. However, neuronal cytoplasmic vacuolization and morphological alteration in the purkinje cells on brain histology and glycosaminoglycan (GAG) levels in brain homogenates were reduced in mice receiving ERT at lower dose than 2.0 mg kg -1. Additionally, GAG levels significantly correlated with the percent volume ratio of ventricle to whole brain. These results suggested that high-dose systemic ERT started early in life could be a promising therapeutic modality for improving neurologic dysfunction including ventriculomegaly in children with severe Hunter syndrome.