Key result
ApoA-I Milano gene therapy cuts aortic atherosclerosis ~65% vs. control, outperforming wild-type apoA-I.
Why the study?
Does apoA-IMilano gene therapy reduce atherosclerosis more effectively than wild-type apoA-I in hyperlipidemic mice?
Does apoA-IMilano gene therapy reduce atherosclerosis more effectively than wild-type apoA-I in hyperlipidemic mice?
Answers are grounded in this paper and cite their sources.
Macrophage-specific expression of the apoA-IMilano gene is more effective than wild-type apoA-I in reducing atherosclerosis and plaque inflammation in a hyperlipidemic mouse model.
OBJECTIVES: We tested the hypothesis that gene therapy using apolipoprotein A-I Milano (apoA-IMilano) is more effective than that using wild-type apolipoprotein A-I (apoA-I) in reducing atherosclerosis. BACKGROUND: Apolipoprotein A-I Milano is a naturally occurring mutant with established antiatherogenic activity; however, its relative antiatherogenic efficacy compared with that of wild-type apoA-I remains unclear. METHODS: We performed bone marrow transplantation in female double-knockout mice lacking both the apoE and apoA-I genes using male donor mice-derived bone marrow that had been transduced with a retroviral vector alone or retroviral vector expressing wild-type apoA-I or apoA-IMilano gene under the control of macrophage-specific scavenger receptor A promoter. Mice were fed a high-cholesterol diet and killed 24 weeks after transplantation, at which time the extent of aortic atherosclerosis was determined. RESULTS: Compared with vector control (n = 12), apoA-IMilano gene therapy (n = 15) reduced aortic atherosclerosis by 65% (p < 0.001) and plaque macrophage immunoreactivity by 58% (p < 0.0001), whereas wild-type apoA-I (n = 11) reduced atherosclerosis by 25% (p = 0.1) and plaque macrophage immunoreactivity by 23% (p < 0.05). The apoA-IMilano gene therapy was significantly more effective in reducing atherosclerosis (p < 0.05) and macrophage immunoreactivity (p < 0.001) compared with wild-type apoA-I. The circulating levels of cholesterol, lipoprotein profile, and apoA-IMilano or wild-type apoA-I were comparable among the groups. Apolipoprotein A-I Milano was more effective than wild-type apoA-I in promoting macrophage cholesterol efflux. CONCLUSIONS: Macrophage-specific expression of the apoA-IMilano gene is more effective than wild-type apoA-I in reducing atherosclerosis and plaque inflammation despite comparable circulating levels of the transgene and lipid profile.
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Wang et al. (2006) studied Atherosclerosis (n=38). Gene therapy with apolipoprotein A-I Milano vs. Wild-type apolipoprotein A-I and vector control was evaluated on Extent of aortic atherosclerosis (65% reduction vs vector control, p=<0.001). Gene therapy with apolipoprotein A-I Milano reduced aortic atherosclerosis by 65% compared with vector control (P<0.001) and was significantly more effective than wild-type apoA-I (P<0.05).
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