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, Gregory A. Grabowski

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1646-1657
Number of pages12
JournalJournal of Lipid Research
Volume49
Issue number8
DOIs
StatePublished - Aug 1 2008
Externally publishedYes

Fingerprint

Cholesterol Ester Storage Disease
Wolman Disease
Cholesterol Esters
Sterol Esterase
Liver
Spleen
Triglycerides
Macrophages
Plasmas
Lysosomal Storage Diseases
Enzyme Therapy
Enzymes
human LIPA protein
Feasibility Studies
Lysosomes
Intraperitoneal Injections
Tobacco
Cholesterol
Cells
Color

Keywords

  • Cholesteryl esters
  • Enzyme therapy
  • Macrophage
  • Pharmacodynamics
  • Pharmacokinetics
  • Plantproduced human enzyme
  • Triglyceride

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Wolman disease/cholesteryl ester storage disease : Efficacy of plant-produced human lysosomal acid lipase in mice. / Du, Hong; Cameron, Terri L.; Garger, Stephen J.; Pogue, Gregory P.; Hamm, Lee A.; White, Earl; Hanley, Kathleen M.; Grabowski, Gregory A.

In: Journal of Lipid Research, Vol. 49, No. 8, 01.08.2008, p. 1646-1657.

Research output: Contribution to journalArticle

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', Journal of Lipid Research, vol. 49, no. 8, pp. 1646-1657. https://doi.org/10.1194/jlr.M700482-JLR200
Du, Hong ; Cameron, Terri L. ; Garger, Stephen J. ; Pogue, Gregory P. ; Hamm, Lee A. ; White, Earl ; Hanley, Kathleen M. ; Grabowski, Gregory A. / Wolman disease/cholesteryl ester storage disease : Efficacy of plant-produced human lysosomal acid lipase in mice. In: Journal of Lipid Research. 2008 ; Vol. 49, No. 8. pp. 1646-1657.
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AU - Garger, Stephen J.

AU - Pogue, Gregory P.

AU - Hamm, Lee A.

AU - White, Earl

AU - Hanley, Kathleen M.

AU - Grabowski, Gregory A.

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AB - 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.

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