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Damme M, Stroobants S, Lüdemann M, et al. Chronic enzyme replacement therapy ameliorates neuropathology in alpha-mannosidosis mice. Ann Clin Transl Neurol. 2015;2(11):987-1001doi: 10.1002/acn3.245.
Damme, M., Stroobants, S., Lüdemann, M., Rothaug, M., Lüllmann-Rauch, R., Beck, H. C., Ericsson, A., Andersson, C., Fogh, J., D'Hooge, R., Saftig, P., & Blanz, J. (2015). Chronic enzyme replacement therapy ameliorates neuropathology in alpha-mannosidosis mice. Annals of clinical and translational neurology, 2(11), 987-1001. https://doi.org/10.1002/acn3.245
Damme, Markus, et al. "Chronic enzyme replacement therapy ameliorates neuropathology in alpha-mannosidosis mice." Annals of clinical and translational neurology vol. 2,11 (2015): 987-1001. doi: https://doi.org/10.1002/acn3.245
Damme M, Stroobants S, Lüdemann M, Rothaug M, Lüllmann-Rauch R, Beck HC, Ericsson A, Andersson C, Fogh J, D'Hooge R, Saftig P, Blanz J. Chronic enzyme replacement therapy ameliorates neuropathology in alpha-mannosidosis mice. Ann Clin Transl Neurol. 2015 Sep 19;2(11):987-1001. doi: 10.1002/acn3.245. eCollection 2015 Nov. PMID: 26817023; PMCID: PMC4693626.
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Ann Clin Transl Neurol. 2015 Sep 19;2(11):987-1001. doi: 10.1002/acn3.245. eCollection 2015 Nov.

Chronic enzyme replacement therapy ameliorates neuropathology in alpha-mannosidosis mice.

Annals of clinical and translational neurology

Markus Damme, Stijn Stroobants, Meike Lüdemann, Michelle Rothaug, Renate Lüllmann-Rauch, Hans Christian Beck, Annika Ericsson, Claes Andersson, Jens Fogh, Rudi D'Hooge, Paul Saftig, Judith Blanz

Affiliations

  1. Biochemical Institute University of Kiel D-24098 Kiel Germany.
  2. Laboratory of Biological Psychology University of Leuven B-3000 Leuven Belgium.
  3. Anatomical Institute University of Kiel D-24098 Kiel Germany.
  4. Department of Biochemistry and Pharmacology Centre for Clinical Proteomics Odense University Hospital Sdr Boulevard 29 DK-5000 Odense C Denmark.
  5. Zymenex A/S Roskildevej 12C 3400 Hillerød Denmark.

PMID: 26817023 PMCID: PMC4693626 DOI: 10.1002/acn3.245

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.

INTERPRETATION: 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.

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