title: CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder.
abstract: A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.
authors.affiliation: Shire Human Genetic Therapies, Inc., Lexington, Massachusetts, United States of America. pcalias@shire.com
authors.forename: Pericles
authors.initials: P
authors.lastname: Calias
authors.forename: Mikhail
authors.initials: M
authors.lastname: Papisov
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.forename: Nancy
authors.initials: N
authors.lastname: Savioli
authors.forename: Vasily
authors.initials: V
authors.lastname: Belov
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Jason
authors.initials: J
authors.lastname: Lotterhand
authors.forename: Mary
authors.initials: M
authors.lastname: Alessandrini
authors.forename: Nan
authors.initials: N
authors.lastname: Liu
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fischman
authors.forename: Jan L
authors.initials: JL
authors.lastname: Powell
authors.forename: Michael W
authors.initials: MW
authors.lastname: Heartlein
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D056947:Enzyme Replacement Therapy / Q000379:methods*; D006801:Humans; D007066:Iduronate Sulfatase / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007278:Injections, Spinal; D007457:Iodine Radioisotopes; D008247:Lysosomes / Q000378:metabolism; D008252:Macaca fascicularis; D051379:Mice; D018345:Mice, Knockout; D016532:Mucopolysaccharidosis II / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D013045:Species Specificity; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D007066:Iduronate Sulfatase