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. METHODS AND 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.
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. METHODS AND RESULTS:Mice with LDL receptor deficiency were placed on an atherogenic diet and developed predictable aortic and coronary atheroma. alpha-Mannosyl-terminated humanlysosomal 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.
Authors: Kristin L Bowden; Joshua A Dubland; Teddy Chan; You-Hai Xu; Gregory A Grabowski; Hong Du; Gordon A Francis Journal: Arterioscler Thromb Vasc Biol Date: 2018-03-29 Impact factor: 8.311
Authors: Sylvia T Nurnberg; Hanrui Zhang; Nicholas J Hand; Robert C Bauer; Danish Saleheen; Muredach P Reilly; Daniel J Rader Journal: Circ Res Date: 2016-02-19 Impact factor: 17.367