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

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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−/− mice with a single intravenous injection of HD-Ad expressing monkey LDLR (1.5 × 1013 or 5 × 1012 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 ∼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.

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Acknowledgements

This work was supported by HL59314 and HL073144. We thank C Arden-Riley, M Merched-Sauvage, S Billah, and R Montgomery for their assistance in the study; L Pastore and A Beaudet for valuable discussion; S Kochanek and G Shiedner for providing 293Cre66 cells; M Krieger for CHO-ldlA7 cells; DP Via for providing I125-LDL; F Graham for providing helper virus; Merck & Co. for providing reagents developed by F Graham.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, TX, USA

    S Nomura, A Merched, E Nour, C Dieker, K Oka & L Chan

  2. Department of Medicine, Baylor College of Medicine, TX, USA

    K Oka & L Chan

  3. Department of Neurology, Baylor College of Medicine, TX, USA

    K Oka

  4. St Luke's Episcopal Hospital, Houston, TX, USA

    L Chan

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  1. S Nomura
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  2. A Merched
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  3. E Nour
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  4. C Dieker
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  5. K Oka
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  6. L Chan
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Nomura, S., Merched, A., Nour, E. et al. Low-density lipoprotein receptor gene therapy using helper-dependent adenovirus produces long-term protection against atherosclerosis in a mouse model of familial hypercholesterolemia. Gene Ther 11, 1540–1548 (2004). https://doi.org/10.1038/sj.gt.3302310

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  • DOI: https://doi.org/10.1038/sj.gt.3302310

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