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Journal of Lipid Research, Vol. 49, 1646-1657, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice^*

Hong Du^*, Terri L. Cameron^,, Stephen J. Garger^,**, Gregory P. Pogue^,, Lee A. Hamm^,, Earl White^,***, Kathleen M. Hanley^, and Gregory A. Grabowski^1,*

^* Division and Program in Human Genetics, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229
Large Scale Biology Corporation, Vacaville, CA 95688
Genentech, Vacaville, CA 95688
^** Bayer HealthCare Pharmaceuticals, Berkeley, CA 94701
Office of Technology Commercialization, University of Texas, Austin, TX 78759
Alta Analytical Laboratory, El Dorado Hills, CA 95762
^*** Integrated Biomolecule Corporation, Tucson, AZ 95755
CBR International Corp, Boulder, CO 80301

^* This work was partially supported by National Institutes of Health Grant DK-36729 (G.A.G.) and a grant from the Large Scale Biology Corp (G.A.G).

Published, JLR Papers in Press, April 15, 2008.

¹To whom correspondence should be addressed. e-mail: greg.grabowski{at}cchmc.org

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 t_1/2 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.

Supplementary key words cholesteryl esters • triglyceride • plant-produced human enzyme • macrophage • pharmacokinetics • pharmacodynamics • enzyme therapy

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