title: Biodistribution of Idursulfase Formulated for Intrathecal Use (Idursulfase-IT) in Cynomolgus Monkeys after Intrathecal Lumbar Administration.
abstract: Enzyme replacement therapy with intravenous idursulfase (recombinant iduronate-2-sulfatase) is approved for the treatment of Hunter syndrome. Intravenous administration does not, however, treat the neurological manifestations, due to its low central nervous system bioavailability. Using intrathecal-lumbar administration, iduronate-2-sulfatase is delivered directly to the central nervous system. This study investigates the central nervous system biodistribution of intrathecal-lumbar administered iduronate-2-sulfatase in cynomolgus monkeys. Twelve monkeys were administered iduronate-2-sulfatase in one 30 mg intrathecal-lumbar injection. Brain, spinal cord, liver, and kidneys were collected for iduronate-2-sulfatase concentration (measured by an enzyme linked immunosorbent assay) and enzyme activity measurement (via a method utilizing 4-methylumbelliferyl-α-iduronate-2-sulfate) at 1, 2, 5, 12, 24, and 48 hours following administration. The tissue enzyme linked immunosorbent assay confirmed iduronate-2-sulfatase uptake to the brain, spinal cord, kidneys, and liver in a time-dependent manner. In spinal cord and brain, iduronate-2-sulfatase appeared as early as 1 hour following administration, and peak concentrations were observed at ~2 and ~5 hours. Iduronate-2-sulfatase appeared in liver and kidneys 1 hour post intrathecal-lumbar dose with peak concentrations between 5 and 24 hours. Liver iduronate-2-sulfatase concentration was approximately 10-fold higher than kidney. The iduronate-2-sulfatase localization and enzyme activity in the central nervous system, following intrathecal administration, demonstrates that intrathecal-lumbar treatment with iduronate-2-sulfatase may be considered for further investigation as a treatment for Hunter syndrome patients with neurocognitive impairment.
authors.affiliation: Shire, Lexington, Massachusetts, United States of America.
authors.forename: Jou-Ku
authors.initials: JK
authors.lastname: Chung
authors.affiliation: Shire, Lexington, Massachusetts, United States of America.
authors.forename: Eilish
authors.initials: E
authors.lastname: Brown
authors.affiliation: Shire, Lexington, Massachusetts, United States of America.
authors.forename: Bob
authors.initials: B
authors.lastname: Crooker
authors.affiliation: Shire, Lexington, Massachusetts, United States of America.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Palmieri
authors.affiliation: Shire, Lexington, Massachusetts, United States of America.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: McCauley
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D056947:Enzyme Replacement Therapy; D005260:Female; D006801:Humans; D007066:Iduronate Sulfatase / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007278:Injections, Spinal; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008252:Macaca fascicularis; D008297:Male; D016532:Mucopolysaccharidosis II / Q000188:drug therapy*; D013116:Spinal Cord / Q000201:enzymology; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D007066:Iduronate Sulfatase; C517982:idursulfase