title: Chronic enzyme replacement therapy ameliorates neuropathology in alpha-mannosidosis mice.
abstract: OBJECTIVE
  The lysosomal storage disease alpha-mannosidosis is caused by the deficiency of the lysosomal acid hydrolase alpha-mannosidase (LAMAN) leading to lysosomal accumulation of neutral mannose-linked oligosaccharides throughout the body, including the brain. Clinical findings in alpha-mannosidosis include skeletal malformations, intellectual disabilities and hearing impairment. To date, no curative treatment is available. We previously developed a beneficial enzyme replacement therapy (ERT) regimen for alpha-mannosidase knockout mice, a valid mouse model for the human disease. However, humoral immune responses against the injected recombinant human alpha-mannosidase (rhLAMAN) precluded long-term studies and chronic treatment.
  
  
  METHODS
  Here, we describe the generation of an immune-tolerant alpha-mannosidosis mouse model that allowed chronic injection of rhLAMAN by transgenic expression of a catalytically inactive variant of human LAMAN in the knockout background.
  
  
  RESULTS
  Chronic ERT of rhLAMAN revealed pronounced effects on primary substrate storage throughout the brain, normalization of lysosomal enzyme activities and morphology as well as a decrease in microglia activation. The positive effect of long-term ERT on neuronal lysosomal function was reflected by an improvement of cognitive deficits and exploratory activity. in vivo and in vitro uptake measurements indicate rapid clearance of rhLAMAN from circulation and a broad uptake into different cell types of the nervous system.
  
  
  CONCLUSIONS
  Our data contribute to the understanding of neurological disorders treatment by demonstrating that lysosomal enzymes such as rhLAMAN can penetrate into the brain and is able to ameliorate neuropathology.
authors.affiliation: Biochemical Institute University of Kiel D-24098 Kiel Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Damme
authors.affiliation: Laboratory of Biological Psychology University of Leuven B-3000 Leuven Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Biochemical Institute University of Kiel D-24098 Kiel Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Lüdemann
authors.affiliation: Biochemical Institute University of Kiel D-24098 Kiel Germany.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rothaug
authors.affiliation: Anatomical Institute University of Kiel D-24098 Kiel Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Lüllmann-Rauch
authors.affiliation: Department of Biochemistry and Pharmacology Centre for Clinical Proteomics Odense University Hospital Sdr Boulevard 29 DK-5000 Odense C Denmark.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Beck
authors.affiliation: Zymenex A/S Roskildevej 12C 3400 Hillerød Denmark.
authors.forename: Annika
authors.initials: A
authors.lastname: Ericsson
authors.affiliation: Zymenex A/S Roskildevej 12C 3400 Hillerød Denmark.
authors.forename: Claes
authors.initials: C
authors.lastname: Andersson
authors.affiliation: Zymenex A/S Roskildevej 12C 3400 Hillerød Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Fogh
authors.affiliation: Laboratory of Biological Psychology University of Leuven B-3000 Leuven Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Biochemical Institute University of Kiel D-24098 Kiel Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Biochemical Institute University of Kiel D-24098 Kiel Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Blanz
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