title: Efficacy of enzyme replacement therapy in an aggravated mouse model of metachromatic leukodystrophy declines with age.
abstract: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency of arylsulfatase A (ASA). Previous studies in ASA-knockout mice suggested enzyme replacement therapy (ERT) to be a promising treatment option. The mild phenotype of ASA-knockout mice did, however, not allow to examine therapeutic responses of the severe neurological symptoms that dominate MLD. We, therefore, generated an aggravated MLD mouse model displaying progressive demyelination and reduced nerve conduction velocity (NCV) and treated it by weekly intravenous injections of 20 mg/kg recombinant human ASA for 16 weeks. To analyze the stage-dependent therapeutic effects, ERT was initiated in a presymptomatic, early and progressed disease stage, at age 4, 8 and 12 months, respectively. Brain sulfatide storage, NCV and behavioral alterations were improved only in early, but not in late, treated mice showing a clear age-dependent efficacy of treatment. Hematopoietic stem cell transplantation (HSCT) for late-onset variants is the only therapeutic option for MLD to date. ERT resembles a part of the HSCT rationale, which is based on ASA supply by donor cells. Beyond ERT, our results, therefore, corroborate the clinical observation that HSCT is only effective when performed in early stages of disease.
authors.affiliation: Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms University, Bonn D-53115, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Matthes
authors.forename: Stijn
authors.initials: S
authors.lastname: Stroobants
authors.forename: Debora
authors.initials: D
authors.lastname: Gerlach
authors.forename: Claudia
authors.initials: C
authors.lastname: Wohlenberg
authors.forename: Carsten
authors.initials: C
authors.lastname: Wessig
authors.forename: Jens
authors.initials: J
authors.lastname: Fogh
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Eckhardt
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matzner
mesh_terms: D000818:Animals; D016466:CHO Cells; D002553:Cerebroside-Sulfatase / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D015316:Genetic Therapy; D007966:Leukodystrophy, Metachromatic / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D002553:Cerebroside-Sulfatase