Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy

• Published in: Human molecular genetics 2005-05, Vol.14 (9), p.1139-1152
• Main Authors: Matzner, Ulrich, Herbst, Eva, Hedayati, Kerstin Khalaj, Lüllmann-Rauch, Renate, Wessig, Carsten, Schröder, Stephan, Eistrup, Carl, Möller, Christer, Fogh, Jens, Gieselmann, Volkmar
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; Biological and medical sciences; Central Nervous System - drug effects; Central Nervous System - metabolism; Central Nervous System - pathology; Cerebroside-Sulfatase - blood; Cerebroside-Sulfatase - deficiency; Cerebroside-Sulfatase - genetics; Cerebroside-Sulfatase - pharmacokinetics; Cerebroside-Sulfatase - therapeutic use; CHO Cells; Cricetinae; Cricetulus; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Endocytosis; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Half-Life; Humans; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Leukodystrophy, Metachromatic - drug therapy; Leukodystrophy, Metachromatic - etiology; Leukodystrophy, Metachromatic - metabolism; Leukodystrophy, Metachromatic - pathology; Liver - drug effects; Liver - metabolism; Liver - pathology; Medical sciences; Mice; Mice, Knockout; Molecular and cellular biology; Neurology; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi126

A deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy, which is characterized by accumulation of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide). Sphingolipid storage results in progressive demyelination and severe neurologic symptoms. The disease is lethal, and curative therapy is not available. To assess the therapeutic potential of enzyme replacement therapy (ERT), ASA knockout mice were treated by intravenous injection of recombinant human ASA. Plasma levels of ASA declined with a half-time of ∼40 min, and enzyme was detectable in tissues within minutes after injection. The uptake of injected enzyme was high into liver, moderate into peripheral nervous system (PNS) and kidney and very low into brain. The apparent half-life of endocytosed enzyme was ∼4 days. A single injection led to a time- and dose-dependent decline of the excess sulfatide in PNS and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections with 20 mg/kg body weight not only reduced storage in peripheral tissues progressively, but also were surprisingly effective in reducing sulfatide storage in brain and spinal cord. The histopathology of kidney and central nervous system was ameliorated. Improved neuromotor coordination capabilities and normalized peripheral compound motor action potential demonstrate the benefits of ERT on the nervous system function. Enzyme replacement may therefore be a promising therapeutic option in this devastating disease.