title: Enzyme replacement therapy in alpha-mannosidosis guinea-pigs.
abstract: alpha-Mannosidosis is a lysosomal storage disorder caused by deficient activity of lysosomal alpha-mannosidase and is characterised by massive accumulation of mannose-containing oligosaccharides in affected individuals. Patients develop behaviour and learning difficulties, skeletal abnormalities, immune deficiency and hearing impairment. Disease in alpha-mannosidosis guinea-pigs resembles the clinical, histopathological, biochemical and molecular features of the human disease. We have used the guinea-pig model to investigate efficacy of enzyme replacement therapy as a treatment for alpha-mannosidosis. Intravenous recombinant human lysosomal alpha-mannosidase, administered at a dose of 1mg/kg, was cleared from circulation with a half-life of 53 h, with significant enzyme activity (1.4x normal levels) detected in circulation one week post-injection. alpha-Mannosidase administered to alpha-mannosidosis guinea-pigs at 1mg/kg (onset at birth or approximately 30 days) and 10mg/kg (at birth) was distributed widely amongst tissues, including to capillary depleted brain. By monitoring with tandem mass spectrometry, enzyme replacement therapy was found to be effective in reducing stored substrates in peripheral tissues at both dose rates, and in brain by up to 39% at the 10mg/kg dose, compared with untreated alpha-mannosidosis controls. Reductions of up to 60% of urinary mannose containing oligosaccharides were also observed. No histological improvements were seen in the brain at either dose, however marked decreases in lysosomal vacuolation in liver, kidney, spleen and endocrine pancreas, as well as a significant reduction in trigeminal ganglion neurons were observed. Multiple injections of 1mg/kg recombinant enzyme in alpha-mannosidosis guinea-pigs induced a very rapid humoral immune response precluding long-term intravenous treatment.
authors.affiliation: Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service, 72 King William Rd., North Adelaide, South Australia 5006, Australia. allison.crawley@adelaide.edu.au <allison.crawley@adelaide.edu.au>
authors.forename: Allison C
authors.initials: AC
authors.lastname: Crawley
authors.forename: Barbara
authors.initials: B
authors.lastname: King
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D007275:Injections, Intravenous; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D013058:Mass Spectrometry; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D043323:alpha-Mannosidase / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D008363:alpha-Mannosidosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D043323:alpha-Mannosidase