Enzyme therapy for lysosomal acid lipase deficiency in the mouse

Lysosomal acid lipase (LAL) is the critical enzyme for the hydrolysis of th e triglycerides (TG) and cholesteryl esters (CE) delivered to lysosomes. It s deficiency produces two human phenotypes, Wolman disease (WD) and cholest eryl ester storage disease (CESD). A targeted disruption of the LAL locus p roduced a null (lal(-/-)) mouse model that mimics human WD/CESD. The potent ial for enzyme therapy was tested using mannose terminated human LAL expres sed in Pichia pastoris (phLAL), purified, and administered by tall vein inj ections,to lal(-/-) mice. Mannose receptor (MR)-dependent uptake and lysoso mal targeting of phLAL were evidenced ex vivo using competitive assays with MR-positive J774E cells, a murine monocyte/macrophage line, immunofluoresc ence and western blots. Following (bolus) IV injection, phLAL was detected in Kupffer cells, lung macrophages and intestinal macrophages in lal(-/-) m ice. Two-month-old lal(-/-) mice received phl-AL (1.5 U/dose) or saline inj ections once every 3 days for 30 days (10 doses). The treated lal(-/-) mice showed nearly complete resolution of hepatic yellow coloration; hepatic we ight decreased by similar to 36% compared to PBS-treated lal(-/-) mice. His tologic analyses of numerous tissues from phl-AL-treated mice showed reduct ions in macrophage lipid storage. TG and cholesterol levels decreased by si milar to 50% in liver, 69% in spleen and 50% in small intestine. These stud ies provide feasibility for LAL enzyme therapy in human WD and CESD.