title: Effects of enzyme replacement therapy started late in a murine model of mucopolysaccharidosis type I.
abstract: Mucopolysaccharidosis type I (MPS I) is a progressive disorder caused by deficiency of α-L-iduronidase (IDUA), which leads to storage of heparan and dermatan sulphate. It is suggested that early enzyme replacement therapy (ERT) leads to better outcomes, although many patients are diagnosed late and don't receive immediate treatment. This study aims to evaluate the effects of late onset ERT in a MPS I murine model. MPS I mice received treatment from 6 to 8 months of age (ERT 6-8mo) with 1.2mg laronidase/kg every 2 weeks and were compared to 8 months-old wild-type (Normal) and untreated animals (MPS I). ERT was effective in reducing urinary and visceral GAG to normal levels. Heart GAG levels and left ventricular (LV) shortening fraction were normalized but cardiac function was not completely improved. While no significant improvements were found on aortic wall width, treatment was able to significantly reduce heart valves thickening. High variability was found in behavior tests, with treated animals presenting intermediate results between normal and affected mice, without correlation with cerebral cortex GAG levels. Cathepsin D activity in cerebral cortex also did not correlate with behavior heterogeneity. All treated animals developed anti-laronidase antibodies but no correlation was found with any parameters analyzed. However, intermediary results from locomotion parameters analyzed are in accordance with intermediary levels of heart function, cathepsin D, activated glia and reduction of TNF-α expression in the cerebral cortex. In conclusion, even if started late, ERT can have beneficial effects on many aspects of the disease and should be considered whenever possible.
authors: Post-Graduation Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors: Gabriela
authors: G
authors: Pasqualim
authors: Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Department of Physiology, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors: Guilherme
authors: G
authors: Baldo
authors: Post-Graduation Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors: Talita Giacomet
authors: TG
authors: de Carvalho
authors: Health Science Department, Uniritter-Laureate International Universities, Porto Alegre, Brazil.
authors: Angela Maria Vicente
authors: AM
authors: Tavares
authors: Post-Graduation Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; INAGEMP, Porto Alegre, Porto Alegre, Brazil; Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors: Roberto
authors: R
authors: Giugliani
authors: Post-Graduation Program in Genetics and Molecular Biology (PPGBM), Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; INAGEMP, Porto Alegre, Porto Alegre, Brazil; Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors: Ursula
authors: U
authors: Matte
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001921:Brain / Q000473:pathology; D002402:Cathepsin D / Q000378:metabolism; D056947:Enzyme Replacement Therapy / Q000379:methods*; D005260:Female; D006025:Glycosaminoglycans / Q000032:analysis / Q000652:urine; D006321:Heart / Q000503:physiopathology; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008059:Mucopolysaccharidosis I / Q000097:blood / Q000503:physiopathology / Q000628:therapy* / Q000652:urine; D009206:Myocardium / Q000473:pathology
chemical_list: D006025:Glycosaminoglycans; D007074:Immunoglobulin G; D002402:Cathepsin D
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