title: Low-dose, continual enzyme delivery ameliorates some aspects of established brain disease in a mouse model of a childhood-onset neurodegenerative disorder.
abstract: OBJECTIVE
  To determine the capacity of continual low-dose lysosomal enzyme infusion into the cerebrospinal fluid of mucopolysaccharidosis type IIIA (MPS IIIA) mice to reverse established neurodegenerative disease. The rationale behind the study is that there is only limited animal model-derived evidence supporting treatment of symptomatic patients, principally because few studies have been designed to examine disease reversibility.
  
  
  METHODS
  Twelve-week old MPS IIIA mice were implanted with indwelling unilateral intra-ventricular cannulae. These were connected to subcutaneous mini-osmotic pumps infusing recombinant human sulphamidase. Pump replacement was carried out in some mice at 16-weeks of age, enabling treatment to continue for a further month. Control affected/unaffected mice received vehicle via the same method. Behavioural, neuropathological and biochemical parameters of disease were assessed.
  
  
  RESULTS
  Improvement in some, but not all, behavioural parameters occurred. Sulphamidase infusion mediated a statistically significant reduction in primary (heparan sulphate) and secondary (gangliosides GM2, GM3) substrate accumulation in the brain, with small reductions in micro- but not astro-gliosis. There was no change in axonal spheroid number. All mice developed a humoural response, however the antibodies were non-neutralising and no adverse clinical effects were observed.
  
  
  CONCLUSIONS
  Continual infusion of replacement enzyme partially ameliorates clinical, histological and biochemical aspects of MPS IIIA mice, when treatment begins at an early symptomatic stage.
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, North Terrace, 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, North Terrace, Adelaide, SA 5001, Australia.
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Setford
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, North Terrace, 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, North Terrace, 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, North Terrace, Adelaide, SA 5001, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Duplock
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5001, Australia.
authors.forename: Justin N
authors.initials: JN
authors.lastname: Tucker
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5001, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Hattersley
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA 5001, Australia.
authors.forename: Marten F
authors.initials: MF
authors.lastname: Snel
authors.affiliation: Lysosomal Diseases Research Unit, South Australian Health and Medical Research Institute, North Terrace, 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, North Terrace, Adelaide, SA 5001, Australia. Electronic address: Kim.Hemsley@sahmri.com.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hemsley
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D016503:Drug Delivery Systems; D005260:Female; D005679:G(M3) Ganglioside / Q000378:metabolism; D020143:Gangliosidoses, GM2 / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009084:Mucopolysaccharidosis III / Q000150:complications; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D013429:Sulfatases / Q000235:genetics / Q000378:metabolism
chemical_list: D005679:G(M3) Ganglioside; D006867:Hydrolases; D013429:Sulfatases; C021346:heparan sulfate sulfatase; C022708:N-sulfoglucosamine sulfohydrolase
keywords: Cerebrospinal fluid; Enzyme replacement therapy; Lysosomal storage disorder; MPS IIIA; Mouse; Osmotic pump