title: A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II.
abstract: OBJECTIVE
  Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid.
  
  
  METHODS
  Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly.
  
  
  RESULTS
  No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months.
  
  
  CONCLUSIONS
  These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81.
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Muenzer
authors.affiliation: Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hendriksz
authors.affiliation: Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Suresh
authors.initials: S
authors.lastname: Vijayaraghavan
authors.affiliation: Department of Neurosurgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Perry
authors.affiliation: Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Saikat
authors.initials: S
authors.lastname: Santra
authors.affiliation: Department of Paediatric Neurosurgery, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Guirish A
authors.identifier: http://orcid.org/0000-0003-4394-010X
authors.initials: GA
authors.lastname: Solanki
authors.affiliation: Shire, Lexington, Massachusetts, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Mascelli
authors.affiliation: Shire, Lexington, Massachusetts, USA.
authors.forename: Luying
authors.identifier: http://orcid.org/0000-0001-9288-6176
authors.initials: L
authors.lastname: Pan
authors.affiliation: Shire, Lexington, Massachusetts, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Shire, Lexington, Massachusetts, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Sciarappa
authors.affiliation: Shire, Lexington, Massachusetts, USA.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Barbier
mesh_terms: D002648:Child; D002675:Child, Preschool; D056947:Enzyme Replacement Therapy; D005260:Female; D006025:Glycosaminoglycans / Q000134:cerebrospinal fluid; D006801:Humans; D007066:Iduronate Sulfatase / Q000008:administration & dosage* / Q000009:adverse effects / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D007278:Injections, Spinal; D008297:Male; D016532:Mucopolysaccharidosis II / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D006025:Glycosaminoglycans; D007066:Iduronate Sulfatase; C517982:idursulfase
references.citation: Arch Dis Child. 1995 Jul;73(1):77-81
references.pmid: 7639557
references.citation: J Neurol Sci. 1994 Apr;122(2):189-203
references.pmid: 8021703
references.citation: Pediatrics. 2009 Dec;124(6):e1228-39
references.pmid: 19901005
references.citation: J Med Genet. 1982 Dec;19(6):408-11
references.pmid: 6818348
references.citation: Control Clin Trials. 1988 Dec;9(4):327-44
references.pmid: 3203524
references.citation: Mol Pharm. 2013 May 6;10(5):1522-32
references.pmid: 23316936
references.citation: Mol Genet Metab. 2013 Nov;110(3):303-10
references.pmid: 23988379
references.citation: Genet Med. 2006 Aug;8(8):465-73
references.pmid: 16912578
references.citation: Biochem J. 1990 Oct 1;271(1):75-86
references.pmid: 2222422
references.citation: PLoS One. 2012;7(1):e30341
references.pmid: 22279584
references.citation: Pediatrics. 2008 Feb;121(2):e377-86
references.pmid: 18245410
references.citation: Eur J Pediatr. 2012 Jan;171(1):181-8
references.pmid: 22037758
references.citation: J Pediatr. 2011 Aug;159(2):320-6.e2
references.pmid: 21530981
references.citation: Genet Med. 2011 Feb;13(2):95-101
references.pmid: 21150784
references.citation: Proc Natl Acad Sci U S A. 1973 Jul;70(7):2134-8
references.pmid: 4269173