title: Glycosaminoglycan storage in neuroanatomical regions of mucopolysaccharidosis I dogs following intrathecal recombinant human iduronidase.
abstract: Intrathecal (IT) recombinant human α-l-iduronidase (rhIDU) has been shown to reduce mean brain glycosaminoglycans (GAGs) to normal levels in mucopolysaccharidosis I (MPS I) dogs. In this study, we examined storage in neuroanatomical regions of the MPS I dog brain, including frontal lobe, cerebellum, basal ganglia, thalamus, hippocampal formation, and brainstem, to determine the response of these functional regions to treatment with IT rhIDU. GAG storage in untreated MPS I dogs was significantly different from normal dogs in all examined sections. GAG levels in normal dogs varied by region: frontal lobe (mean: 2.36 ± 0.54 μg/mg protein), cerebellum (2.67 ± 0.33), basal ganglia and thalamus (3.51 ± 0.60), hippocampus (3.30 ± 0.40), and brainstem (3.73 ± 1.10). Following IT treatment, there was a reduction in GAG storage in each region in all treatment groups, except for the brainstem. Percent reduction in GAG levels from untreated to treated MPS I dogs in the deeper regions of the brain was 30% for basal ganglia and thalamus and 30% for hippocampus, and storage reduction was greater in superficial regions, with 61% reduction in the frontal lobe and 54% in the cerebellum compared with untreated MPS I dogs. Secondary lipid storage in neurons was also reduced in frontal lobe, but not in the other brain regions examined. Response to therapy appeared to be greater in more superficial regions of the brain, particularly in the frontal lobe cortex.
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90509, USA. ahchen@ucla.edu
authors.forename: Agnes
authors.initials: A
authors.lastname: Chen
authors.forename: Carole
authors.initials: C
authors.lastname: Vogler
authors.forename: Michael
authors.initials: M
authors.lastname: McEntee
authors.forename: Stephen
authors.initials: S
authors.lastname: Hanson
authors.forename: N Matthew
authors.initials: NM
authors.lastname: Ellinwood
authors.forename: Jackie
authors.initials: J
authors.lastname: Jens
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Snella
authors.forename: Merry
authors.initials: M
authors.lastname: Passage
authors.forename: Steven
authors.initials: S
authors.lastname: Le
authors.forename: Catalina
authors.initials: C
authors.lastname: Guerra
authors.forename: Patricia
authors.initials: P
authors.lastname: Dickson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism*; D006651:Histocytochemistry / Q000662:veterinary; D007068:Iduronidase / Q000008:administration & dosage*; D007278:Injections, Spinal / Q000662:veterinary; D008297:Male; D008059:Mucopolysaccharidosis I / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000662:veterinary*; D011994:Recombinant Proteins / Q000008:administration & dosage; D014018:Tissue Distribution
chemical_list: D006025:Glycosaminoglycans; D011994:Recombinant Proteins; D007068:Iduronidase