title: Enzyme replacement therapy of a novel humanized mouse model of globoid cell leukodystrophy.
abstract: An inherited deficiency of β-galactosylceramidase (GALC) causes the lysosomal storage disease globoid cell leukodystrophy (GLD). The disease is characterized by the accumulation of the cytotoxic metabolite psychosine (galactosylsphingosine), causing rapid degeneration of myelinating cells. Most patients suffer from the infantile form of GLD with onset of disease between 3 and 6 months after birth and death by 2 years of age. The most widely used animal model of GLD, the twitcher mouse, presents with an even more rapid course of disease and death around 40 days of age. We have generated a novel "humanized" mouse model of GLD by inserting a human GALC cDNA containing an adult-onset patient mutation into the murine GALC gene. Humanized GALC mice exhibit pathological hallmarks of GLD including psychosine accumulation, neuroinflammation, CNS infiltration of macrophages, astrogliosis and demyelination. Residual GALC activities in mouse tissues are low and the mice display a median lifespan of 46 days. Due to the expression of the human transgene, the mice do not develop an immune response against rhGALC, rendering the animal model suitable for therapies based on human enzyme. Intravenously injected rhGALC was able to surmount the blood-brain barrier and was targeted to lysosomes of brain macrophages, astrocytes and neurons. High-dose enzyme replacement therapy started at postnatal day 21 reduced the elevated psychosine levels in the peripheral and central nervous system by 14-16%, but did not ameliorate neuroinflammation, demyelination and lifespan. These results may indicate that treatment must be started earlier before pathology occurs.
authors.affiliation: Rheinische Friedrich-Wilhelms University, Institute of Biochemistry and Molecular Biology, Nussallee 11, D-53115 Bonn, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Matthes
authors.affiliation: Zymenex A/S, Dalénum 13, S-18170 Lidingö, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Andersson
authors.affiliation: Rheinische Friedrich-Wilhelms University, Institute of Biochemistry and Molecular Biology, Nussallee 11, D-53115 Bonn, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Stein
authors.affiliation: Zymenex A/S, Roskildevej 12C, DK-3400 Hillerød, Denmark.
authors.forename: Carl
authors.initials: C
authors.lastname: Eistrup
authors.affiliation: Zymenex A/S, Roskildevej 12C, DK-3400 Hillerød, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Fogh
authors.affiliation: Rheinische Friedrich-Wilhelms University, Institute of Biochemistry and Molecular Biology, Nussallee 11, D-53115 Bonn, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.affiliation: Department of Neurology, Jefferson Medical College, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wenger
authors.affiliation: Rheinische Friedrich-Wilhelms University, Institute of Biochemistry and Molecular Biology, Nussallee 11, D-53115 Bonn, Germany. Electronic address: matzner@ibmb.uni-bonn.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matzner
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000235:genetics; D002490:Central Nervous System / Q000201:enzymology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy / Q000379:methods*; D005260:Female; D005698:Galactosylceramidase / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011609:Psychosine / Q000378:metabolism
chemical_list: D016207:Cytokines; D009419:Nerve Tissue Proteins; D011609:Psychosine; D005698:Galactosylceramidase
keywords: Enzyme replacement therapy; Galactosylceramidase; Globoid cell leukodystrophy; Humanized mouse model; Lysosomal storage disease; Psychosine