PMID- 22704978
OWN - NLM
STAT- MEDLINE
DCOM- 20130129
LR  - 20211021
IS  - 1096-7206 (Electronic)
IS  - 1096-7192 (Print)
IS  - 1096-7192 (Linking)
VI  - 107
IP  - 1-2
DP  - 2012 Sep
TI  - Intravenous high-dose enzyme replacement therapy with recombinant 
      palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly 
      prolongs survival in a preclinical mouse model of infantile neuronal ceroid 
      lipofuscinosis.
PG  - 213-21
LID - S1096-7192(12)00198-9 [pii]
LID - 10.1016/j.ymgme.2012.05.009 [doi]
AB  - PPT1-related neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder 
      caused by deficiency in a soluble lysosomal enzyme, palmitoyl-protein 
      thioesterase-1 (PPT1). Enzyme replacement therapy (ERT) has not been previously 
      examined in a preclinical animal model. Homozygous PPT1 knockout mice reproduce 
      the known features of the disease, developing signs of motor dysfunction at 5 
      months of age and death by around 8 months. In the current study, PPT1 knockout 
      mice were treated with purified recombinant PPT1 (0.3 mg, corresponding to 12 
      mg/kg or 180 U/kg for a 25 g mouse) administered intravenously weekly either 1) 
      from birth; or 2) beginning at 8 weeks of age. The treatment was surprisingly 
      well tolerated and neither anaphylaxis nor antibody formation was observed. In 
      mice treated from birth, survival increased from 236 to 271 days (p<0.001) and 
      the onset of motor deterioration was similarly delayed. In mice treated beginning 
      at 8 weeks, no increases in survival or motor performance were seen. An 
      improvement in neuropathology in the thalamus was seen at 3 months in mice 
      treated from birth, and although this improvement persisted it was attenuated by 
      7 months. Outside the central nervous system, substantial clearance of 
      autofluorescent storage material in many tissues was observed. Macrophages in 
      spleen, liver and intestine were especially markedly improved, as were acinar 
      cells of the pancreas and tubular cells of the kidney. These findings suggest 
      that ERT may be an option for addressing visceral storage as part of a 
      comprehensive approach to PPT1-related NCL, but more effective delivery methods 
      to target the brain are needed.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Hu, Jie
AU  - Hu J
AD  - Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern 
      Medical Center, Dallas, TX 75390-8593, USA.
FAU - Lu, Jui-Yun
AU  - Lu JY
FAU - Wong, Andrew M S
AU  - Wong AM
FAU - Hynan, Linda S
AU  - Hynan LS
FAU - Birnbaum, Shari G
AU  - Birnbaum SG
FAU - Yilmaz, Denis S
AU  - Yilmaz DS
FAU - Streit, Barbara M
AU  - Streit BM
FAU - Lenartowicz, Ewelina M
AU  - Lenartowicz EM
FAU - Thompson, Thomas C M
AU  - Thompson TC
FAU - Cooper, Jonathan D
AU  - Cooper JD
FAU - Hofmann, Sandra L
AU  - Hofmann SL
LA  - eng
GR  - R01 NS036867/NS/NINDS NIH HHS/United States
GR  - R37 NS036867/NS/NINDS NIH HHS/United States
GR  - NS036867/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120522
PL  - United States
TA  - Mol Genet Metab
JT  - Molecular genetics and metabolism
JID - 9805456
RN  - 0 (Recombinant Proteins)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Animals
MH  - Brain/metabolism/pathology
MH  - Disease Models, Animal
MH  - *Enzyme Replacement Therapy
MH  - Female
MH  - Humans
MH  - Lysosomes/drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Motor Activity/drug effects
MH  - Neuronal Ceroid-Lipofuscinoses/*drug therapy/*mortality
MH  - Recombinant Proteins/*administration & dosage
MH  - Rotarod Performance Test
MH  - Thiolester Hydrolases/*administration & dosage/adverse effects
MH  - Viscera/drug effects/metabolism/pathology
PMC - PMC3444630
MID - NIHMS379947
EDAT- 2012/06/19 06:00
MHDA- 2013/01/30 06:00
PMCR- 2013/09/01
CRDT- 2012/06/19 06:00
PHST- 2012/05/01 00:00 [received]
PHST- 2012/05/16 00:00 [revised]
PHST- 2012/05/16 00:00 [accepted]
PHST- 2012/06/19 06:00 [entrez]
PHST- 2012/06/19 06:00 [pubmed]
PHST- 2013/01/30 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - S1096-7192(12)00198-9 [pii]
AID - 10.1016/j.ymgme.2012.05.009 [doi]
PST - ppublish
SO  - Mol Genet Metab. 2012 Sep;107(1-2):213-21. doi: 10.1016/j.ymgme.2012.05.009. Epub 
      2012 May 22.