title: Delivery of therapeutic protein for prevention of neurodegenerative changes: comparison of different CSF-delivery methods.
abstract: Injection of lysosomal enzyme into cisternal or ventricular cerebrospinal fluid (CSF) has been carried out in 11 lysosomal storage disorder models, with each study demonstrating reductions in primary substrate and secondary neuropathological changes, and several reports of improved neurological function. Whilst acute studies in mucopolysaccharidosis (MPS) type II mice revealed that intrathecally-delivered enzyme (into thoraco-lumbar CSF) accesses the brain, the impact of longer-term treatment of affected subjects via this route is unknown. This approach is presently being utilized to treat children with MPS types I, II and III. Our aim was to determine the efficacy of repeated intrathecal injection of recombinant human sulfamidase (rhSGSH) on pathological changes in the MPS IIIA dog brain. The outcomes were compared with those in dogs treated via intra-cisternal or ventricular routes. Control dogs received buffer or no treatment. Significant reductions in primary/secondary substrate levels in brain were observed in dogs treated via all routes, although the extent of the reduction differed regionally. Treatment via all CSF access points resulted in large reductions in microgliosis in superficial cerebral cortex, but only ventricular injection enabled amelioration in deep cerebral cortex. Formation of glutamic acid decarboxylase-positive axonal spheroids in deep cerebellar nuclei was prevented by treatment delivered via any route. Anti-rhSGSH antibodies in the sera of some dogs did not reduce therapeutic efficacy. Our data indicates the capacity of intra-spinal CSF-injected rhSGSH to circulate within CSF-filled spaces, penetrate into brain and mediate a significant reduction in substrate accumulation and secondary pathology in the MPS IIIA dog brain.
authors.affiliation: Institute of Veterinary, Animal and Biomedical Science, Massey University, Palmerston North, New Zealand.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Marshall
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: Sofia
authors.initials: S
authors.lastname: Hassiotis
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: King
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: Tina
authors.initials: T
authors.lastname: Rozaklis
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Trim
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Duplock
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: Leanne K
authors.initials: LK
authors.lastname: Winner
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Beard
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: Marten F
authors.initials: MF
authors.lastname: Snel
authors.affiliation: Institute of Veterinary, Animal and Biomedical Science, Massey University, Palmerston North, New Zealand.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Jolly
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia. Electronic address: Kim.Hemsley@sahmri.com.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hemsley
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D006497:Heparan Sulfate / Q000032:analysis; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage*; D007150:Immunohistochemistry; D007278:Injections, Spinal; D013058:Mass Spectrometry; D009083:Mucopolysaccharidoses / Q000473:pathology*; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D006497:Heparan Sulfate; D006867:Hydrolases; D011994:Recombinant Proteins; C022708:N-sulfoglucosamine sulfohydrolase
keywords: Canine; Cerebrospinal fluid; Lysosomal storage disorder; Neurodegenerative disease; Recombinant protein; Treatment