Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice*
Lysosomal acid lipase (LAL) is an essential enzyme that hydrolyzes triglycerides (TGs) and cholesteryl esters (CEs) in lysosomes. Genetic LAL mutations lead to Wolman disease (WD) and cholesteryl ester storage disease (CESD). An LAL-null (lal−/−) mouse model resembles human WD/CESD with storage of C...
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doaj-b29ac79e31b941a8aab0bc10a5eb74922021-04-28T05:58:32ZengElsevierJournal of Lipid Research0022-22752008-08-0149816461657Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice*Hong Du0Terri L. Cameron1Stephen J. Garger2Gregory P. Pogue3Lee A. Hamm4Earl White5Kathleen M. Hanley6Gregory A. Grabowski7Division and Program in Human Genetics, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229Large Scale Biology Corporation, Vacaville, CA 95688; Genentech, Vacaville, CA 95688Large Scale Biology Corporation, Vacaville, CA 95688; Bayer HealthCare Pharmaceuticals, Berkeley, CA 94701Large Scale Biology Corporation, Vacaville, CA 95688; Office of Technology Commercialization, University of Texas, Austin, TX 78759Large Scale Biology Corporation, Vacaville, CA 95688; Alta Analytical Laboratory, El Dorado Hills, CA 95762Large Scale Biology Corporation, Vacaville, CA 95688; Integrated Biomolecule Corporation, Tucson, AZ 95755Large Scale Biology Corporation, Vacaville, CA 95688; CBR International Corp, Boulder, CO 80301Division and Program in Human Genetics, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229Lysosomal acid lipase (LAL) is an essential enzyme that hydrolyzes triglycerides (TGs) and cholesteryl esters (CEs) in lysosomes. Genetic LAL mutations lead to Wolman disease (WD) and cholesteryl ester storage disease (CESD). An LAL-null (lal−/−) mouse model resembles human WD/CESD with storage of CEs and TGs in multiple organs. Human LAL (hLAL) was expressed in Nicotiana benthamiana using the GENEWARE® expression system (G-hLAL). Purified G-hLAL showed mannose receptor-dependent uptake into macrophage cell lines (J774E). Intraperitoneal injection of G-hLAL produced peak activities in plasma at 60 min and in the liver and spleen at 240 min. The t1/2 values were: ∼90 min (plasma), ∼14 h (liver), and ∼32 h (spleen), with return to baseline by ∼150 h in liver and ∼200 h in spleen. Ten injections of G-hLAL (every 3 days) into lal−/− mice produced normalization of hepatic color, decreases in hepatic cholesterol and TG contents, and diminished foamy macrophages in liver, spleen, and intestinal villi. All injected lal−/− mice developed anti-hLAL protein antibodies, but suffered no adverse events. These studies demonstrate the feasibility of using plant-expressed, recombinant hLAL for the enzyme therapy of human WD/CESD with general implications for other lysosomal storage diseases.http://www.sciencedirect.com/science/article/pii/S0022227520346824cholesteryl esterstriglycerideplant-produced human enzymemacrophagepharmacokineticspharmacodynamics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hong Du Terri L. Cameron Stephen J. Garger Gregory P. Pogue Lee A. Hamm Earl White Kathleen M. Hanley Gregory A. Grabowski |
spellingShingle |
Hong Du Terri L. Cameron Stephen J. Garger Gregory P. Pogue Lee A. Hamm Earl White Kathleen M. Hanley Gregory A. Grabowski Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice* Journal of Lipid Research cholesteryl esters triglyceride plant-produced human enzyme macrophage pharmacokinetics pharmacodynamics |
author_facet |
Hong Du Terri L. Cameron Stephen J. Garger Gregory P. Pogue Lee A. Hamm Earl White Kathleen M. Hanley Gregory A. Grabowski |
author_sort |
Hong Du |
title |
Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice* |
title_short |
Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice* |
title_full |
Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice* |
title_fullStr |
Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice* |
title_full_unstemmed |
Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice* |
title_sort |
wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice* |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2008-08-01 |
description |
Lysosomal acid lipase (LAL) is an essential enzyme that hydrolyzes triglycerides (TGs) and cholesteryl esters (CEs) in lysosomes. Genetic LAL mutations lead to Wolman disease (WD) and cholesteryl ester storage disease (CESD). An LAL-null (lal−/−) mouse model resembles human WD/CESD with storage of CEs and TGs in multiple organs. Human LAL (hLAL) was expressed in Nicotiana benthamiana using the GENEWARE® expression system (G-hLAL). Purified G-hLAL showed mannose receptor-dependent uptake into macrophage cell lines (J774E). Intraperitoneal injection of G-hLAL produced peak activities in plasma at 60 min and in the liver and spleen at 240 min. The t1/2 values were: ∼90 min (plasma), ∼14 h (liver), and ∼32 h (spleen), with return to baseline by ∼150 h in liver and ∼200 h in spleen. Ten injections of G-hLAL (every 3 days) into lal−/− mice produced normalization of hepatic color, decreases in hepatic cholesterol and TG contents, and diminished foamy macrophages in liver, spleen, and intestinal villi. All injected lal−/− mice developed anti-hLAL protein antibodies, but suffered no adverse events. These studies demonstrate the feasibility of using plant-expressed, recombinant hLAL for the enzyme therapy of human WD/CESD with general implications for other lysosomal storage diseases. |
topic |
cholesteryl esters triglyceride plant-produced human enzyme macrophage pharmacokinetics pharmacodynamics |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520346824 |
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