title: Enzyme replacement reduces neuropathology in MPS IIIA dogs.
abstract: There is no treatment for the progressive neurodegenerative lysosomal storage disorder mucopolysaccharidosis type IIIA (MPS IIIA), which occurs due to a deficiency of functional N-sulfoglucosamine sulfohydrolase (SGSH), with subsequent accumulation of partially-degraded heparan sulfate and secondarily-stored compounds including GM2 and GM3 gangliosides and unesterified cholesterol. The brain is a major site of pathology and affected children exhibit progressive cognitive decline and early death. In the present study, six MPS IIIA dogs received intravenous recombinant human SGSH (rhSGSH) from birth to either 8 or 12 weeks of age (1 mg/kg, up to 5 mg), with subsequent intra-cerebrospinal fluid injection of 3 or 15 mg rhSGSH (or vehicle) on a weekly or fortnightly basis to 23 weeks of age. All dogs completed the protocol without incident, and there was no clinically-relevant cellular or humoral immune response to rhSGSH delivery. Immunohistochemistry demonstrated rhSGSH delivery to widespread regions of the brain, and tandem mass spectrometry revealed an apparent dose-dependent decrease in the relative level of a heparan sulfate-derived disaccharide, with near normalization of substrate in many brain regions at the higher dose. Secondarily-stored GM3 ganglioside and unesterified cholesterol, determined using histological methods, were also reduced in a dose-dependent manner, as was the number of activated microglia. We have demonstrated that pre-symptomatic treatment of this progressive neurodegenerative disorder via intra-cerebrospinal fluid injection of rhSGSH mediates highly significant reductions in neuropathology in this MPS IIIA model and clinical trials of this treatment approach in MPS IIIA patients are therefore indicated.
authors.affiliation: Lysosomal Diseases Research Unit, SA Pathology (Women's and Children's Hospital campus), North Adelaide, SA 5006, Australia.
authors.forename: Allison C
authors.initials: AC
authors.lastname: Crawley
authors.forename: Neil
authors.initials: N
authors.lastname: Marshall
authors.forename: Helen
authors.initials: H
authors.lastname: Beard
authors.forename: Sofia
authors.initials: S
authors.lastname: Hassiotis
authors.forename: Vicki
authors.initials: V
authors.lastname: Walsh
authors.forename: Barbara
authors.initials: B
authors.lastname: King
authors.forename: Nicola
authors.initials: N
authors.lastname: Hucker
authors.forename: Maria
authors.initials: M
authors.lastname: Fuller
authors.forename: Robert D
authors.initials: RD
authors.lastname: Jolly
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hemsley
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D056947:Enzyme Replacement Therapy / Q000379:methods*; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology* / Q000627:therapeutic use; D007276:Injections, Intraventricular; D009084:Mucopolysaccharidosis III / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D011993:Recombinant Fusion Proteins; D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase