Low-density lipoprotein receptor gene therapy using helper-dependent adenovirus produces long-term protection against atherosclerosis in a mouse model of familial hypercholesterolemia

Abstract

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 À/À mice with a single intravenous injection of HD-Ad expressing monkey LDLR (1.5 Â 10 13 or 5 Â 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 À/À mice. After 60 weeks, atherosclerosis lesions covered B50% 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 (42 years) when all control mice had died. In addition to retarding lesion progression, treatment caused lesion remodeling from a vulnerablelooking 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.

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

“…For example, intravenous injection of HDAd expressing the canine coagulation factor IX in hemophilia B dogs resulted in sustained phenotypic improvement of the bleeding diathesis for the duration of the experiment of over 1 year after vector administration. 3 These, as well as other recent studies, [4][5][6][7][8][9][10][11][12][13] provide compelling evidence for using HDAd to treat genetic disorders.…”

Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector

“…1 Our experience in two other mouse models of dyslipidemias 10,11 suggests that a dose in the range of 0.5-4.5 Â 10 12 vector particles (VP)/ kg may be required to reverse the phenotype. 10,11,15 We, therefore, treated APOA1 À/À mice with escalating doses of HDAd-AI, starting at 5 Â 10 11 VP/kg (HDAd-AI-L), increasing by a half-log increment to 1.5 Â 10 12 VP/kg (HDAd-AI-M) and finally using a maximum dose of 4.5 Â 10 12 VP/kg (HDAd-AI-H). An additional group of mice was treated with FGAd-AI (4.5 Â 10 12 VP/kg).…”

Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice

“…Hepatic overexpression of VLDLR induced by a helper-dependent adenoviral vector has been shown to prevent atherosclerotic lesion formation and progression of fatty streak lesions in LDLR-deficient mice. 16,33 This ability of HD-Ad-VLDLR treatment to reduce atherosclerosis is most likely due to the marked lowering of VLDL and intermediate density lipoprotein levels in mice overexpressing hepatic VLDLR. Because intermediate density lipoprotein is a precursor of LDL, LDL levels are also lowered as a result of VLDLR overexpression.…”