Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy.
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 approximately 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 approximately 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.
Matzner
Ulrich
U
Institut Für Physiologische Chemi, Rheinische Friedrich-Wilhelms Universität, Nussallee 11, 53115 Bonn, Germany. matzner@institut.physiochem.uni-bonn.de
Herbst
Eva
E
Hedayati
Kerstin Khalaj
KK
Lüllmann-Rauch
Renate
R
Wessig
Carsten
C
Schröder
Stephan
S
Eistrup
Carl
C
Möller
Christer
C
Fogh
Jens
J
Gieselmann
Volkmar
V
D000818:Animals; D019540:Area Under Curve; D016466:CHO Cells; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D002553:Cerebroside-Sulfatase / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004705:Endocytosis; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007966:Leukodystrophy, Metachromatic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use
D011994:Recombinant Proteins; D002553:Cerebroside-Sulfatase