Human Molecular Genetics, 2001, Vol. 10, No. 16 1639-1648
© 2001 Oxford University Press
Enzyme therapy for lysosomal acid lipase deficiency in the mouse
The Children’s Hospital Research Foundation, Division of Human Genetics, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA and 1Genzyme Corporation, Cambridge, MA, USA
Lysosomal acid lipase (LAL) is the critical enzyme for the hydrolysis of the triglycerides (TG) and cholesteryl esters (CE) delivered to lysosomes. Its deficiency produces two human phenotypes, Wolman disease (WD) and cholesteryl ester storage disease (CESD). A targeted disruption of the LAL locus produced a null (lal –/–) mouse model that mimics human WD/CESD. The potential for enzyme therapy was tested using mannose terminated human LAL expressed in Pichia pastoris (phLAL), purified, and administered by tail vein injections to lal –/– mice. Mannose receptor (MR)-dependent uptake and lysosomal targeting of phLAL were evidenced ex vivo using competitive assays with MR-positive J774E cells, a murine monocyte/macrophage line, immunofluorescence and western blots. Following (bolus) IV injection, phLAL was detected in Kupffer cells, lung macrophages and intestinal macrophages in lal –/– mice. Two-month-old lal –/– mice received phLAL (1.5 U/dose) or saline injections once every 3 days for 30 days (10 doses). The treated lal –/– mice showed nearly complete resolution of hepatic yellow coloration; hepatic weight decreased by 
36% compared to PBS-treated lal –/– mice. Histologic analyses of numerous tissues from phLAL-treated mice showed reductions in macrophage lipid storage. TG and cholesterol levels decreased by 50% in liver, 69% in spleen and 50% in small intestine. These studies provide feasibility for LAL enzyme therapy in human WD and CESD.
+ To whom correspondence should be addressed. Tel: +1 513 636 7290; Fax: +1 513 636 2261; Email: grabg0@chmcc.org
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