PMID- 20036592 OWN - NLM STAT- MEDLINE DCOM- 20100712 LR - 20211020 IS - 1096-7206 (Electronic) IS - 1096-7192 (Print) IS - 1096-7192 (Linking) VI - 99 IP - 4 DP - 2010 Apr TI - Human recombinant palmitoyl-protein thioesterase-1 (PPT1) for preclinical evaluation of enzyme replacement therapy for infantile neuronal ceroid lipofuscinosis. PG - 374-8 LID - 10.1016/j.ymgme.2009.12.002 [doi] AB - Infantile neuronal ceroid lipofuscinosis (INCL, also known as Haltia-Santavuori disease) is a lysosomal storage disorder of infants and children characterized by blindness, seizures and a progressive neurodegenerative course. Recent clinical trials have involved neural stem cells and gene therapy directed to the central nervous system; however, enzyme replacement therapy has never been addressed. In the current paper, we describe the production of human recombinant PPT1 (the defective enzyme in INCL) by standard methods in Chinese Hamster Ovary (CHO) cells. The enzyme is largely mannose 6-phosphorylated as assessed by mannose 6-phosphate receptor binding (80% bound) and taken up rapidly by immortalized patient lymphoblasts, where clearance of PPT substrates was demonstrated (EC(50) of 0.25 nM after overnight incubation). When injected intravenously into PPT1-deficient mice, the clearance of recombinant human PPT1 from plasma was rapid, with a half-life of 10 min. Most of the injected dose was distributed to the kidney and liver and potentially corrective levels were also observed in heart, lung and spleen. Brain uptake was minimal, as expected based on experience with other intravenously administered lysosomal enzymes. The enzyme may be useful as an adjunct to central nervous system-directed therapies and could be used as a starting point for modifications designed to improve brain delivery. CI - Copyright 2009 Elsevier Inc. All rights reserved. FAU - Lu, Jui-Yun AU - Lu JY AD - Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA. FAU - Hu, Jie AU - Hu J 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 - R37 NS036867-13/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 - 20091205 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/enzymology MH - CHO Cells MH - Cricetinae MH - Cricetulus MH - Drug Evaluation, Preclinical MH - Humans MH - Male MH - Mice MH - Mice, Knockout MH - Neuronal Ceroid-Lipofuscinoses/*therapy MH - Recombinant Proteins/administration & dosage/metabolism MH - Thiolester Hydrolases/*administration & dosage/chemistry/metabolism MH - Tissue Distribution PMC - PMC2839016 MID - NIHMS164520 OTO - NOTNLM OT - Batten disease OT - enzyme replacement therapy OT - infantile neuronal ceroid lipofuscinosis OT - lysosomal storage disorder EDAT- 2009/12/29 06:00 MHDA- 2010/07/14 06:00 PMCR- 2011/04/01 CRDT- 2009/12/29 06:00 PHST- 2009/11/13 00:00 [received] PHST- 2009/12/01 00:00 [revised] PHST- 2009/12/02 00:00 [accepted] PHST- 2009/12/29 06:00 [entrez] PHST- 2009/12/29 06:00 [pubmed] PHST- 2010/07/14 06:00 [medline] PHST- 2011/04/01 00:00 [pmc-release] AID - S1096-7192(09)00523-X [pii] AID - 10.1016/j.ymgme.2009.12.002 [doi] PST - ppublish SO - Mol Genet Metab. 2010 Apr;99(4):374-8. doi: 10.1016/j.ymgme.2009.12.002. Epub 2009 Dec 5.