Summary: Treatment of the neurological manifestations of lysosomal storage diseases remains an unmet medical need. BMN 250 is being developed as an enzyme replacement therapy administered directly into the brain ventricles via the intracerebroventricular (ICV) route for treating Sanfilippo type B. Patients with this rare neurological disease have deficient lysosomal alpha-N-acetylglucosaminidase (NAGLU) enzyme activity. Unlike the ICV route that readily provides biodistribution of therapy to target cells, we show in wild-type and disease animal models that intravenously-administered enzyme does not reach the target neuronal cells. The limited pharmacological response following intravenous administration is likely attributed to the clearance of substrate in endothelial cells that restrict biodistribution to target cells in the brain. Representative staining from superficial medulla oblongata from cynomolgus monkey received BMN 250 via the IV route shows that all NAGLU staining is co-localized with CD31-positive endothelial cells, indicating that IV administered NAGLU does not reach the target neurons. In contrast, NAGLU co-localizes with the neurons following ICV administration.
