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 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.
Du
Hong
H
Division and Program in Human Genetics, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Cameron
Terri L
TL
Garger
Stephen J
SJ
Pogue
Gregory P
GP
Hamm
Lee A
LA
White
Earl
E
Hanley
Kathleen M
KM
Grabowski
Gregory A
GA
D000818:Animals; D006801:Humans; D007421:Intestine, Small / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D011994:Recombinant Proteins / Q000627:therapeutic use; D013154:Spleen / Q000473:pathology; D002787:Sterol Esterase / Q000172:deficiency / Q000276:immunology / Q000627:therapeutic use*; D014026:Nicotiana / Q000201:enzymology; D015223:Wolman Disease / Q000188:drug therapy* / Q000473:pathology
D011994:Recombinant Proteins; C503451:LIPA protein, human; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse