Du_2008_J.Lipid.Res_49_1646

Reference

Title : Wolman disease\/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice - Du_2008_J.Lipid.Res_49_1646
Author(s) : Du H , Cameron TL , Garger SJ , Pogue GP , Hamm LA , White E , Hanley KM , Grabowski GA
Ref : J Lipid Res , 49 :1646 , 2008
Abstract :

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: approximately 90 min (plasma), approximately 14 h (liver), and approximately 32 h (spleen), with return to baseline by approximately 150 h in liver and approximately 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.

PubMedSearch : Du_2008_J.Lipid.Res_49_1646
PubMedID: 18413899
Gene_locus related to this paper: mouse-1llip

Citations formats

Du H, Cameron TL, Garger SJ, Pogue GP, Hamm LA, White E, Hanley KM, Grabowski GA (2008)
Wolman disease\/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice
J Lipid Res 49 :1646

Du H, Cameron TL, Garger SJ, Pogue GP, Hamm LA, White E, Hanley KM, Grabowski GA (2008)
J Lipid Res 49 :1646