Successful prevention and stabilization of cognitive decline in Japanese patients with neuronopathic mucopolysaccharidosis type II treated by intracerebroventricular enzyme replacement therapy: Results of the Phase clinical trial for two years

Mucopolysaccharidosis type II (MPS II) is caused by congenital deficiency of iduronate 2-sulfatase. >70% of the patients show cognitive decline, which cannot be treated by current intravenous enzyme replacement therapy. To solve this problem, we have explored intracerebroventricular (ICV) enzyme replacement therapy. We performed an open-labelled clinical trial for two years. Six Japanese patients have been enrolled. The average age of the patients at the first injection is 3 years 5 months old (1:11–5:5). IDS-β (produced by GC pharma, Korea: 30 mg) was administered every 28 days using cerebrospinal fluid (CSF)-reservoir. We carried out 26 injections in 100 weeks. Primary and secondary endpoints are reduction of heparan sulfate (HS) concentration in CSF and changing of developmental age evaluated by Kyoto scale of psychological development, respectively. No serious adverse event was observed. Significant reduction (50–80%) of HS concentration in CSF was observed in all patients. We analyzed the increase of the developmental age in five enrolled patients whose developmental tests were carried out appropriately. The average increase of the developmental age during the study interval was 7.6 months. The increase of the developmental age of each patient is +5, +16, +14, +4 and −1 months. We then compared the increase of the developmental age with that of the age-matched historical control group, consisted of 13 patients treated only by intravenous ERT. The average increase of the developmental age of the control group is 0.3 months. The increase of the developmental age in each patients of the age-matched control group is −2, +10, −1, +1, and −4 months. These results indicate that the increase of the developmental age by 7.3 months was obtained by ICV-ERT. Based on the results, we conclude that ICV-ERT is tolerable and effective therapy to prevent and stabilize cognitive decline in neuronopathic MPS II.