PMID- 27211612
OWN - NLM
STAT- MEDLINE
DCOM- 20170829
LR  - 20210202
IS  - 1096-7206 (Electronic)
IS  - 1096-7192 (Linking)
VI  - 118
IP  - 3
DP  - 2016 Jul
TI  - A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with 
      mucopolysaccharidosis IIIA.
PG  - 198-205
LID - S1096-7192(16)30064-6 [pii]
LID - 10.1016/j.ymgme.2016.05.006 [doi]
AB  - OBJECTIVE: 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). STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 
      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.
CI  - Copyright (c) 2016 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Jones, Simon A
AU  - Jones SA
AD  - Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central 
      Manchester University Hospitals NHS Foundation Trust (CMFT), University of 
      Manchester, United Kingdom.
FAU - Breen, Catherine
AU  - Breen C
AD  - Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central 
      Manchester University Hospitals NHS Foundation Trust (CMFT), University of 
      Manchester, United Kingdom.
FAU - Heap, Fiona
AU  - Heap F
AD  - Willink Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Central 
      Manchester University Hospitals NHS Foundation Trust (CMFT), University of 
      Manchester, United Kingdom.
FAU - Rust, Stewart
AU  - Rust S
AD  - Paediatric Psychosocial Department, Royal Manchester Children's Hospital, 
      Manchester, United Kingdom.
FAU - de Ruijter, Jessica
AU  - de Ruijter J
AD  - Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands.
FAU - Tump, Evelien
AU  - Tump E
AD  - Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands.
FAU - Marchal, Jan Pieter
AU  - Marchal JP
AD  - Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands.
FAU - Pan, Luying
AU  - Pan L
AD  - Shire, Lexington, MA, USA.
FAU - Qiu, Yongchang
AU  - Qiu Y
AD  - Shire, Lexington, MA, USA.
FAU - Chung, Jou-Ku
AU  - Chung JK
AD  - Shire, Lexington, MA, USA.
FAU - Nair, Nitin
AU  - Nair N
AD  - Shire, Lexington, MA, USA.
FAU - Haslett, Patrick A J
AU  - Haslett PAJ
AD  - Shire, Lexington, MA, USA.
FAU - Barbier, Ann J
AU  - Barbier AJ
AD  - Shire, Lexington, MA, USA.
FAU - Wijburg, Frits A
AU  - Wijburg FA
AD  - Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands. 
      Electronic address: f.a.wijburg@amc.uva.nl.
LA  - eng
SI  - ClinicalTrials.gov/NCT01155778
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20160510
PL  - United States
TA  - Mol Genet Metab
JT  - Molecular genetics and metabolism
JID - 9805456
RN  - 0 (Antibodies)
RN  - 9050-30-0 (Heparitin Sulfate)
RN  - EC 3.1.6.- (Sulfatases)
RN  - EC 3.1.6.- (heparan sulfate sulfatase)
SB  - IM
MH  - Adolescent
MH  - Antibodies/blood/cerebrospinal fluid
MH  - Child
MH  - Child, Preschool
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Heparitin Sulfate/*cerebrospinal fluid
MH  - Humans
MH  - Injections, Spinal/instrumentation
MH  - Male
MH  - Mucopolysaccharidosis III/cerebrospinal fluid/*drug therapy
MH  - Sulfatases/*administration & dosage/adverse effects/immunology
MH  - Treatment Outcome
MH  - Young Adult
OTO - NOTNLM
OT  - Enzyme replacement therapy
OT  - Heparan sulfate
OT  - Intrathecal drug delivery device
OT  - Lysosomal storage disease
OT  - Mucopolysaccharidosis IIIA (MPS IIIA)
OT  - Sanfilippo syndrome A
EDAT- 2016/05/24 06:00
MHDA- 2017/08/30 06:00
CRDT- 2016/05/24 06:00
PHST- 2016/05/09 00:00 [received]
PHST- 2016/05/09 00:00 [accepted]
PHST- 2016/05/24 06:00 [entrez]
PHST- 2016/05/24 06:00 [pubmed]
PHST- 2017/08/30 06:00 [medline]
AID - S1096-7192(16)30064-6 [pii]
AID - 10.1016/j.ymgme.2016.05.006 [doi]
PST - ppublish
SO  - Mol Genet Metab. 2016 Jul;118(3):198-205. doi: 10.1016/j.ymgme.2016.05.006. Epub 
      2016 May 10.