Reduction of atherosclerotic plaques by lysosomal acid lipase supplementation.
OBJECTIVE
Proof of principle is presented for targeted enzyme supplementation by using lysosomal acid lipase to decrease aortic and coronary wall lipid accumulation in a mouse model of atherosclerosis.


RESULTS
Mice with LDL receptor deficiency were placed on an atherogenic diet and developed predictable aortic and coronary atheroma. alpha-Mannosyl-terminated human lysosomal acid lipase (phLAL) was produced in Pichia pastoris, purified, and administered intravenously to such mice with either early or late lesions. phLAL injections reduced plasma, hepatic, and splenic cholesteryl esters and triglycerides in affected mice. phLAL was detected in hepatic Kupffer cells and in atheromatous foam cells. Repeated enzyme injections were well tolerated, with no obvious adverse effects. In addition, the coronary and aortic atheromatous lesions were (1) eliminated in their early stages and (2) quantitatively and qualitatively reduced in their advanced stages.


CONCLUSIONS
These results support the potential utility of lysosomal acid lipase supplementation for the treatment of atherosclerosis, a leading cause of mortality and morbidity in Westernized nations.
Du
Hong
H
Division and Program in Human Genetics, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Schiavi
Susan
S
Wan
Nick
N
Levine
Mark
M
Witte
David P
DP
Grabowski
Gregory A
GA
D000818:Animals; D001018:Aortic Diseases / Q000188:drug therapy / Q000473:pathology; D001021:Aortic Valve / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology; D002788:Cholesterol Esters / Q000378:metabolism; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000473:pathology; D004036:Diet, Atherogenic; D007421:Intestine, Small / Q000378:metabolism; D008049:Lipase / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology; D008264:Macrophages / Q000201:enzymology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000627:therapeutic use; D013154:Spleen / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D002788:Cholesterol Esters; D011994:Recombinant Proteins; D014280:Triglycerides; D008049:Lipase