title: Examination of intravenous and intra-CSF protein delivery for treatment of neurological disease.
abstract: Mucopolysaccharidosis type IIIA is a neurodegenerative lysosomal storage disorder characterized by progressive loss of learned skills, sleep disturbance and behavioural problems. Absent or greatly reduced activity of sulphamidase, a lysosomal protein, results in intracellular accumulation of heparan sulphate. Subsequent neuroinflammation and neurodegeneration typify this and many other lysosomal storage disorders. We propose that intra-cerebrospinal fluid protein delivery represents a potential therapeutic avenue for treatment of this and other neurodegenerative conditions; however, technical restraints restrict examination of its use prior to adulthood in mice. We have used a naturally-occurring Mucopolysaccharidosis type IIIA mouse model to determine the effectiveness of combining intravenous protein replacement (1 mg/kg) from birth to 6 weeks of age with intra-cerebrospinal fluid sulphamidase delivery (100 microg, fortnightly from 6 weeks) on behaviour, the level of heparan sulphate-oligosaccharide storage and other neuropathology. Mice receiving combination treatment exhibited similar clinical improvement and reduction in heparan sulphate storage to those only receiving intra-cerebrospinal fluid enzyme. Reductions in micro- and astrogliosis and delayed development of ubiquitin-positive lesions were seen in both groups. A third group of intravenous-only treated mice did not exhibit clinical or neuropathological improvements. Intra-cerebrospinal fluid injection of sulphamidase effectively, but dose-dependently, treats neurological pathology in Mucopolysaccharidosis type IIIA, even when treatment begins in mice with established disease.
authors.affiliation: Lysosomal Diseases Research Unit, SA Pathology at the Women's and Children's Hospital, North Adelaide, SA, Australia. Kim.Hemsley@adelaide.edu.au
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hemsley
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Luck
authors.forename: Allison C
authors.initials: AC
authors.lastname: Crawley
authors.forename: Sofia
authors.initials: S
authors.lastname: Hassiotis
authors.forename: Helen
authors.initials: H
authors.lastname: Beard
authors.forename: Barbara
authors.initials: B
authors.lastname: King
authors.forename: Tomas
authors.initials: T
authors.lastname: Rozek
authors.forename: Tina
authors.initials: T
authors.lastname: Rozaklis
authors.forename: Maria
authors.initials: M
authors.lastname: Fuller
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006497:Heparan Sulfate / Q000008:administration & dosage; D006867:Hydrolases / Q000008:administration & dosage* / Q000276:immunology; D016464:Lysosomal Storage Diseases / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009084:Mucopolysaccharidosis III / Q000235:genetics / Q000378:metabolism; D009336:Necrosis / Q000188:drug therapy / Q000209:etiology; D011506:Proteins / Q000008:administration & dosage* / Q000276:immunology; D053719:Tandem Mass Spectrometry / Q000379:methods; D013997:Time Factors
chemical_list: D000906:Antibodies; D006497:Heparan Sulfate; D006867:Hydrolases; D011506:Proteins; C018589:lysosomal proteins; C022708:N-sulfoglucosamine sulfohydrolase