title: A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA.
abstract: This was an open-label, phase 1/2 dose-escalation, safety trial of intrathecal recombinant human heparan-N-sulfatase (rhHNS) administered via intrathecal drug delivery device (IDDD) for treating mucopolysaccharidosis IIIA (NCT01155778).
  
  
  
  Twelve patients received 10, 45, or 90mg of rhHNS via IDDD once monthly for a total of 6 doses. Primary endpoints included adverse events (AEs) and anti-rhHNS antibodies. Secondary endpoints included standardized neurocognitive assessments, cortical gray matter volume, and pharmacokinetic/pharmacodynamic analyses.
  
  
  
  All patients experienced treatment-emergent AEs; most of mild-to-moderate severity. Seven patients reported a total of 10 serious AEs (SAEs), all but one due to hospitalization to revise a nonfunctioning IDDD. No SAEs were considered related to rhHNS. Anti-rhHNS antibodies were detected in the serum of 6 patients and in the cerebrospinal fluid (CSF) of 2 of these. CSF heparan sulfate levels were elevated at baseline and there were sustained declines in all tested patients following the first rhHNS dose. No impact of anti-rhHNS antibodies on any pharmacodynamic or safety parameters was evident. 4 of 12 patients showed a decline in developmental quotient, 6 were stable, and 2 patients had only a single data point. No dose group showed a clearly different response pattern.
  
  
  
  rhHNS administration via IDDD appeared generally safe and well tolerated. Treatment resulted in consistent declines in CSF heparan sulfate, suggesting in vivo activity in the relevant anatomical compartment. Results of this small study should be interpreted with caution. Future studies are required to assess the potential clinical benefits of rhHNS and to test improved IDDD models.
authors.affiliation: Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), University of Manchester, United Kingdom.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), University of Manchester, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Breen
authors.affiliation: Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust (CMFT), University of Manchester, United Kingdom.
authors.forename: Fiona
authors.initials: F
authors.lastname: Heap
authors.affiliation: Paediatric Psychosocial Department, Royal Manchester Children's Hospital, Manchester, United Kingdom.
authors.forename: Stewart
authors.initials: S
authors.lastname: Rust
authors.affiliation: Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: de Ruijter
authors.affiliation: Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Evelien
authors.initials: E
authors.lastname: Tump
authors.affiliation: Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jan Pieter
authors.initials: JP
authors.lastname: Marchal
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Luying
authors.initials: L
authors.lastname: Pan
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Jou-Ku
authors.initials: JK
authors.lastname: Chung
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Nitin
authors.initials: N
authors.lastname: Nair
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Patrick A J
authors.initials: PAJ
authors.lastname: Haslett
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Barbier
authors.affiliation: Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: f.a.wijburg@amc.uva.nl.
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
mesh_terms: D000293:Adolescent; D000906:Antibodies / Q000097:blood / Q000134:cerebrospinal fluid; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006497:Heparan Sulfate / Q000134:cerebrospinal fluid*; D006801:Humans; D007278:Injections, Spinal / Q000295:instrumentation; D008297:Male; D009084:Mucopolysaccharidosis III / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D013429:Sulfatases / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000906:Antibodies; D006497:Heparan Sulfate; D013429:Sulfatases; C021346:heparan sulfate sulfatase
keywords: Enzyme replacement therapy; Heparan sulfate; Intrathecal drug delivery device; Lysosomal storage disease; Mucopolysaccharidosis IIIA (MPS IIIA); Sanfilippo syndrome A