Intrathecal delivery of recombinant human iduronate-2-sulfatase (idursulfase-IT)

Background: Idursulfase has limited passage through the bloodbrain barrier when administered intravenously. Objectives: We have undertaken a program to develop an intrathecal (IT) formulation of idursulfase to target CNS manifestations of MPS II. Methods: In a safety study, single bolus injections of idursulfase-IT 3 mg (n=12), 30 mg (n=6), or 100 mg (n=12) were administered via implanted drug delivery device (IDDD) once every 4 weeks to cynomolgus monkeys for 6 months. Weekly IV injections of 0.5 mg/ kg idursulfase were administered concomitantly. Device implant controls (n=6) were administered IV saline and IT PBS; vehicle controls (n=12) were administered IV and IT vehicle. In an efficacy study, idursulfase-IT was administered intrathecally to idursulfase knockout mice (n=3) once weekly for 3 weeks. Results: In monkeys, the combination of IV and IT idursulfase was not associated with any significant adverse toxicologic events compared with controls. Immunohistochemical (IHC) staining detected idursulfase-IT protein in all brain areas in the 100 mg dose group, with a deposition gradient from the cerebral cortex to the ventricular white matter. Colocalization staining revealed idursulfase-IT associated with neurons and oligodendrocytes. Additionally, idursulfase-IT appeared to be associated with axonal structures, suggestive of anterograde axonal transport. In the efficacy study in mice, morphological improvements were seen in all brain areas. A marked reduction in CNS cellular vacuolization was seen via both light and electron microscopy. IHC staining revealed a reduction in LAMP-1 (lysosomal associated membrane protein 1). Conclusions: Idursulfase-IT safely reaches relevant CNS tissues in monkeys and is efficacious in MPS II mice.