Low-density lipoprotein receptor gene therapy using helper-dependent adenovirus produces long-term protection against atherosclerosis in a mouse model of familial hypercholesterolemia.
We tested the efficacy of low-density lipoprotein receptor (LDLR) therapy using helper-dependent adenovirus (HD-Ad), comparing it with that of very low-density lipoprotein receptor (VLDLR), an LDLR homolog. We treated high cholesterol diet fed LDLR-/- mice with a single intravenous injection of HD-Ad expressing monkey LDLR (1.5 x 10(13) or 5 x 10(12) VP/kg) or VLDLR. Throughout the 24-week experiment, plasma cholesterol of LDLR-treated mice was lower than that of VLDLR-treated mice, which was in turn lower than that of PBS-treated mice. Anti-LDLR antibodies developed in 2/10 mice treated with high-dose HD-Ad-LDLR but in none (0/14) of the other treatment groups. HD-Ad-treated mice displayed significant retardation of atherosclerotic lesion progression. We next tested the long-term efficacy of low-dose HD-Ad-LDLR injected into 12-week-old LDLR-/- mice. After 60 weeks, atherosclerosis lesions covered approximately 50% of the surface of aortas of control mice, whereas aortas of treated mice were essentially lesion-free. The lipid lowering effect of HD-Ad-LDLR lasted at least 108 weeks (>2 years) when all control mice had died. In addition to retarding lesion progression, treatment caused lesion remodeling from a vulnerable-looking to a more stable-appearing phenotype. In conclusion, HD-Ad-mediated LDLR gene therapy is effective in conferring long-term protection against atherosclerosis in a mouse model of familial hypercholesterolemia.
Department of Molecular and Cellular Biology, Baylor College of Medicine, TX 77030, USA.
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Nomura
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Merched
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Nour
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Dieker
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Oka
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Chan
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D001483:Base Sequence; D018450:Disease Progression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006938:Hyperlipoproteinemia Type II / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D008969:Molecular Sequence Data; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*
D011973:Receptors, LDL; C036053:VLDL receptor