PMID- 29580682
OWN - NLM
STAT- MEDLINE
DCOM- 20190423
LR  - 20210109
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 26
IP  - 4
DP  - 2018 Apr 4
TI  - Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by 
      ZFN-Mediated In Vivo Genome Editing.
PG  - 1127-1136
LID - S1525-0016(18)30110-2 [pii]
LID - 10.1016/j.ymthe.2018.03.002 [doi]
AB  - Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal 
      disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to 
      accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, 
      progressive disease, and shortened lifespan. Currently available enzyme 
      replacement therapy (ERT) requires lifelong infusions and does not provide 
      neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to 
      mediate genome editing for insertion of the human IDS (hIDS) coding sequence into 
      a "safe harbor" site, intron 1 of the albumin locus in hepatocytes of an MPS II 
      mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of 
      ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. 
      Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in 
      the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents 
      were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, 
      we also demonstrate that ZFN-mediated genome editing prevented the development of 
      neurocognitive deficit in young MPS II mice (6-9 weeks old) treated at high 
      vector dose levels. We conclude that this ZFN-based platform for expression of 
      therapeutic proteins from the albumin locus is a promising approach for treatment 
      of MPS II and other lysosomal diseases.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Laoharawee, Kanut
AU  - Laoharawee K
AD  - Center for Genome Engineering, Department of Genetics Cell Biology and 
      Development, University of Minnesota, Minneapolis, MN, USA.
FAU - DeKelver, Russell C
AU  - DeKelver RC
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Podetz-Pedersen, Kelly M
AU  - Podetz-Pedersen KM
AD  - Center for Genome Engineering, Department of Genetics Cell Biology and 
      Development, University of Minnesota, Minneapolis, MN, USA.
FAU - Rohde, Michelle
AU  - Rohde M
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Sproul, Scott
AU  - Sproul S
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Nguyen, Hoang-Oanh
AU  - Nguyen HO
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Nguyen, Tam
AU  - Nguyen T
AD  - Center for Genome Engineering, Department of Genetics Cell Biology and 
      Development, University of Minnesota, Minneapolis, MN, USA.
FAU - St Martin, Susan J
AU  - St Martin SJ
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Ou, Li
AU  - Ou L
AD  - Gene Therapy Center, Department of Pediatrics, University of Minnesota, 
      Minneapolis, MN, USA.
FAU - Tom, Susan
AU  - Tom S
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Radeke, Robert
AU  - Radeke R
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Meyer, Kathleen E
AU  - Meyer KE
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Holmes, Michael C
AU  - Holmes MC
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - Whitley, Chester B
AU  - Whitley CB
AD  - Gene Therapy Center, Department of Pediatrics, University of Minnesota, 
      Minneapolis, MN, USA.
FAU - Wechsler, Thomas
AU  - Wechsler T
AD  - Sangamo Therapeutics, Inc., 501 Canal Boulevard, Richmond, CA, USA.
FAU - McIvor, R Scott
AU  - McIvor RS
AD  - Center for Genome Engineering, Department of Genetics Cell Biology and 
      Development, University of Minnesota, Minneapolis, MN, USA. Electronic address: 
      mcivo001@umn.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180310
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Biomarkers)
RN  - EC 3.1.- (Endonucleases)
RN  - EC 3.1.6.13 (Iduronate Sulfatase)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Disease Models, Animal
MH  - Endonucleases/genetics/metabolism
MH  - *Energy Metabolism
MH  - Enzyme Activation
MH  - *Gene Dosage
MH  - *Gene Editing
MH  - Gene Transfer Techniques
MH  - Hepatocytes/metabolism
MH  - Iduronate Sulfatase/*genetics
MH  - Introns
MH  - Mice
MH  - Mucopolysaccharidosis II/*genetics/*metabolism/pathology/physiopathology
MH  - *Phenotype
MH  - Zinc Fingers/genetics
PMC - PMC6080131
OTO - NOTNLM
OT  - Hunter syndrome
OT  - MPS II
OT  - albumin locus
OT  - gene therapy
OT  - iduronate 2-sulfatase
OT  - in vivo genome editing
OT  - lysosomal disease
OT  - zinc finger nuclease
EDAT- 2018/03/28 06:00
MHDA- 2019/04/24 06:00
PMCR- 2019/04/04
CRDT- 2018/03/28 06:00
PHST- 2017/10/24 00:00 [received]
PHST- 2018/01/31 00:00 [accepted]
PHST- 2018/03/28 06:00 [pubmed]
PHST- 2019/04/24 06:00 [medline]
PHST- 2018/03/28 06:00 [entrez]
PHST- 2019/04/04 00:00 [pmc-release]
AID - S1525-0016(18)30110-2 [pii]
AID - 10.1016/j.ymthe.2018.03.002 [doi]
PST - ppublish
SO  - Mol Ther. 2018 Apr 4;26(4):1127-1136. doi: 10.1016/j.ymthe.2018.03.002. Epub 2018 
      Mar 10.