title: Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients.
abstract: BACKGROUND
  We retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT.
  
  
  METHODS
  Seventeen GD1 patients were included (n = 6 eliglustat, (two switched from ERT), n = 9 miglustat (seven switchers), n = 4 ERT (median dose 60U/kg/m). Plasma protein markers reflecting disease burden (chitotriosidase, CCL18) and lipids reflecting substrate accumulation (glucosylsphingosine, glucosylceramide) were determined. Also, liver and spleen volumes, hemoglobin, platelets, and fat fraction were measured.
  
  
  RESULTS
  In patients naïve to treatment, chitotriosidase, CCL18 and glucosylsphingosine decreased comparably upon eliglustat and ERT treatment, while the response to miglustat was less. After 2 years, median decrease of chitotriosidase was 89% (range 77-98), 88% (78-92) and 37% (29-46) for eliglustat, ERT and miglustat naïve patients respectively; decrease of CCL18 was 73% (63-78), 54% (43-86), and 10% (3-18); decrease of glucosylsphingosine was 86% (78-93), 78% (65-91), 48% (46-50). Plasma glucosylceramide in eliglustat treated patients (n = 4) reached values below the normal range (n = 20 healthy controls). Biochemical markers decreased or stabilized in switchers from ERT to eliglustat (n = 2), but less in miglustat switchers (n = 7). Clinical parameters responded comparably upon eliglustat and ERT treatment.
  
  
  CONCLUSIONS
  Our explorative study provides evidence that biochemical markers respond comparably in patients receiving eliglustat treatment and ERT, while the corresponding response to miglustat treatment is less.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Bouwien E
authors.initials: BE
authors.lastname: Smid
authors.affiliation: Department of Medical Biochemistry, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ferraz
authors.affiliation: Department of Biochemistry, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Marri
authors.initials: M
authors.lastname: Verhoek
authors.affiliation: Department of Medical Biochemistry, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Mina
authors.initials: M
authors.lastname: Mirzaian
authors.affiliation: Department of Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wisse
authors.affiliation: Department of Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Carla E
authors.initials: CE
authors.lastname: Hollak
authors.affiliation: Department of Biochemistry, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands. j.m.f.g.aerts@lic.leidenuniv.nl.|Leiden Institute of Chemistry, Gorlaeus Laboratory, room number 0.3.15, Einsteinweg 55, 2300 RA, Leiden, The Netherlands. j.m.f.g.aerts@lic.leidenuniv.nl.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D056947:Enzyme Replacement Therapy / Q000379:methods*; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy* / Q000201:enzymology*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005963:Glucosylceramides / Q000378:metabolism; D006801:Humans; D008297:Male; D011759:Pyrrolidines / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D011759:Pyrrolidines; D017485:1-Deoxynojirimycin; C059896:miglustat; C522917:eliglustat; D005962:Glucosylceramidase
keywords: Chitotriosidase; Eliglustat; Enzyme replacement therapy; Gaucher disease; Glucosylceramide; Glucosylsphingosine; Miglustat