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Lipoproteins and Cardiovascular Disease pp 309–324Cite as

Modulation of Lipoprotein Metabolism by Antisense Technology: Preclinical Drug Discovery Methodology

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 1027))

Abstract

Antisense oligonucleotides (ASOs) are a new class of specific therapeutic agents that alter the intermediary metabolism of mRNA, resulting in the suppression of disease-associated gene products. ASOs exert their pharmacological effects after hybridizing, via Watson-Crick base pairing, to a specific target RNA. If appropriately designed, this event results in the recruitment of RNase H, the degradation of targeted mRNA or pre-mRNA, and subsequent inhibition of the synthesis of a specific protein. A key advantage of the technology is the ability to selectively inhibit targets that cannot be modulated by traditional therapeutics such as structural proteins, transcription factors, and, of topical interest, lipoproteins. In this chapter, we will first provide an overview of antisense technology, then more specifically describe the status of lipoprotein-related genes that have been studied using the antisense platform, and finally, outline the general methodology required to design and evaluate the in vitro and in vivo efficacy of those drugs.

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Acknowledgments

The authors would like to thank Drs. Stanley T. Crooke and Sue Freier for their careful review of the manuscript, Tracy Reigle for her excellent help with figure production, and finally, Pamela Black for her expertise in producing the final document.

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Authors and Affiliations

  1. Cardiovascular Disease Research, Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA, USA

    Rosanne M. Crooke

  2. Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA, USA

    Mark J. Graham

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  1. Pulmonary & Vascular Medicine Branch, National Institutes of Health (NIH) National Heart, Lung & Blood Institute, Bethesda, Maryland, USA

    Lita A. Freeman

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Crooke, R.M., Graham, M.J. (2013). Modulation of Lipoprotein Metabolism by Antisense Technology: Preclinical Drug Discovery Methodology. In: Freeman, L. (eds) Lipoproteins and Cardiovascular Disease. Methods in Molecular Biology, vol 1027. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-369-5_14

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  • DOI: https://doi.org/10.1007/978-1-60327-369-5_14

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