title: Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study.
abstract: BACKGROUND
  Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment.
  
  
  METHODS
  This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7-17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF.
  
  
  RESULTS
  Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6% (CI -92.0 -85.2, p < 0.001), 54.1% (CI -69.5- -38.7, p < 0,001), and 25.7% (CI -44.3- -7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15%, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI -8.9 -51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI -0.2-0.8, NS).
  
  
  CONCLUSIONS
  These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.
authors.affiliation: Department of Clinical Genetics, Centre for Inherited Metabolic Disorders, Copenhagen University hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark, line.gutte.borgwardt@rh.regionh.dk.
authors.forename: L
authors.initials: L
authors.lastname: Borgwardt
authors.forename: C I
authors.initials: CI
authors.lastname: Dali
authors.forename: J
authors.initials: J
authors.lastname: Fogh
authors.forename: J E
authors.initials: JE
authors.lastname: Månsson
authors.forename: K J
authors.initials: KJ
authors.lastname: Olsen
authors.forename: H C
authors.initials: HC
authors.lastname: Beck
authors.forename: K G
authors.initials: KG
authors.lastname: Nielsen
authors.forename: L H
authors.initials: LH
authors.lastname: Nielsen
authors.forename: S O E
authors.initials: SO
authors.lastname: Olsen
authors.forename: H M F
authors.initials: HM
authors.lastname: Riise Stensland
authors.forename: O
authors.initials: O
authors.lastname: Nilssen
authors.forename: F
authors.initials: F
authors.lastname: Wibrand
authors.forename: A M
authors.initials: AM
authors.lastname: Thuesen
authors.forename: T
authors.initials: T
authors.lastname: Pearl
authors.forename: U
authors.initials: U
authors.lastname: Haugsted
authors.forename: P
authors.initials: P
authors.lastname: Saftig
authors.forename: J
authors.initials: J
authors.lastname: Blanz
authors.forename: S A
authors.initials: SA
authors.lastname: Jones
authors.forename: A
authors.initials: A
authors.lastname: Tylki-Szymanska
authors.forename: N
authors.initials: N
authors.lastname: Guffon-Fouiloux
authors.forename: M
authors.initials: M
authors.lastname: Beck
authors.forename: A M
authors.initials: AM
authors.lastname: Lund
mesh_terms: D000293:Adolescent; D002648:Child; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy / Q000009:adverse effects / Q000379:methods; D005080:Exercise Test; D005500:Follow-Up Studies; D006801:Humans; D011597:Psychomotor Performance / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D016896:Treatment Outcome; D043323:alpha-Mannosidase / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D008363:alpha-Mannosidosis / Q000188:drug therapy*
chemical_list: D011994:Recombinant Proteins; D043323:alpha-Mannosidase