Enzyme therapy for lysosomal acid lipase deficiency in the mouse

Du, Hong; Schiavi, Susan C.; Levine, Mark; Mishra, Jaya; Heur, Martin; Grabowski, Gregory A.

doi:10.1093/hmg/10.16.1639

Cited by 90 publications

(72 citation statements)

References 28 publications

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“…13,[35][36][37][38] Deficiency of LAL via targeted gene disruption leads to a multisystemic disease that includes the phenotype of human Wolman disease, aberrant cholesterol and TG metabolism, and macrophage proliferation. 39 These diverse effects support the important and central role of LAL in the control of cholesterol and fat metabolism and macrophage proliferation, as well as a potential role in the treatment of atherosclerosis. Expression of the human LAL (hLAL) in Pichia pastoris (phLAL) systems produced active hLAL that was targeted to macrophage lysosomes.…”

Section: Conclusion-thesementioning

confidence: 73%

“…The majority of the enzyme was localized to the liver macrophages, Kupffer cells, by immunohistochemical staining after intravenous injection. 39 Biological activity of phLAL was assessed previously in lal Ϫ/Ϫ mice. 39 Such in vivo activity also was evident from the reductions in tissue CEs and TGs in lal Ϫ/Ϫ and HFCD-fed ldlr Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

“…39 Intravenous injections of phLAL into LAL-deficient mice (lal Ϫ/Ϫ ) corrected the lipid storage phenotype in multiple tissues. 39 Here, phLAL was administered to the mouse model of atherosclerosis, the LDLreceptor knockout (ldlr Ϫ/Ϫ ) mice on a high fat/high cholesterol diet (HFCD). Repeated doses of phLAL resulted in almost complete elimination of early stage lesions and significant improvement in the quality and quantity of advanced lesions.…”

Section: Conclusion-thesementioning

confidence: 99%

“…Plasma from group B mice was pooled (200 L) and subjected to fast protein liquid chromatography by using 2 Superose 6 HR columns (Pharmacia Biotech Inc.). 39,40 Cholesterol concentrations were determined in each fraction (0.5 mL; cholesterol/HP kits). Total lipids were extracted from liver and spleen by the Folch method.…”

Section: Plasma Lipids Lipoprotein Profile and Tissue Lipidsmentioning

confidence: 99%

“…3,41 TG concentrations were estimated as described. 39,42,43 Total tissue cholesterol concentrations were estimated using O-phthalaldehyde. 39,43,44 …”

Section: Plasma Lipids Lipoprotein Profile and Tissue Lipidsmentioning

confidence: 99%

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Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation

Du¹,

Schiavi²,

Wan³

et al. 2004

ATVB

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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. ␣-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. A therosclerosis is the number 1 cause of mortality and morbidity in the developed countries. A number of interventions or preventions delay the consequences of atherosclerosis, eg, low cholesterol diet and exercise, HMG-CoA reductase inhibitors, and coronary artery bypass. However, they are not suitable for all patients, and few have been shown to promote regression of lesions. Therefore, new approaches are needed for the treatment and prevention of atherosclerosis. Several stages characterize the progression of atherosclerotic lesions. 1,2 The earliest lesion is the "fatty streak," an aggregation of lipid-rich macrophages and T-lymphocytes within the intimae layer of an artery. The fatty streaks evolve into intermediate lesions that have a layer of foamy macrophages and smooth muscle cells. This develops into complex and occlusive lesions, as well as fibrous plaques. These plaques have a dense cap of connective tissue, with embedded smooth muscle cells overlaying a core of lipid and necrotic debris. Macrophages are present at all lesional stages with excessive cholesterol and cholesteryl esters in lysosomes. Continuing development of atherosclerotic plaques requires progressive macrophage processing of cholesteryl esters in and through the lysosomes. Perpetuation and maturation of the plaques depends on additional complex inflammatory and scarring processes. Lysosomal acid lipase (LAL) is the only hydrolase for cleavage of cholesteryl esters delivered to the lysosomes. 3 The receptors that mediate cholesteryl ester uptake into macrophage include those for LDL and oxidized LDL (oxLDL), ie, LDL receptor (LDL-R), the scavenger receptors type AI and AII (SR-AI and SR-AII), 4 -6 the scavenger receptor type B1 (SR-BI), 7-9 CD36, 10 and the LDL receptor related protein (LRP). 11 All of these, except SR-BI, direct associated lipids to the lysosome. 12-15 Furthermore, modification of LDL by oxidation, aggregation, and glycation occurs in the atherosclerotic lesions by histochemical and biochemical studies. 16 -20 The delivery of oxidized LDL to lysosomes of macropha...

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Section: Conclusion-thesementioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Conclusion-thesementioning

confidence: 99%

Section: Plasma Lipids Lipoprotein Profile and Tissue Lipidsmentioning

confidence: 99%

“…3,41 TG concentrations were estimated as described. 39,42,43 Total tissue cholesterol concentrations were estimated using O-phthalaldehyde. 39,43,44 …”

Section: Plasma Lipids Lipoprotein Profile and Tissue Lipidsmentioning

confidence: 99%

See 3 more Smart Citations