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Journal of Cardiovascular Translational Research

Erschienen in:

01.02.2015

Development of Lipoprotein(a) siRNAs for Mechanism of Action Studies in Non-Human Primate Models of Atherosclerosis

verfasst von: Marija Tadin-Strapps, Michael Robinson, Lauretta Le Voci, Lori Andrews, Satya Yendluri, Stephanie Williams, Steve Bartz, Douglas G. Johns

Erschienen in: Journal of Cardiovascular Translational Research | Ausgabe 1/2015

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Abstract

Lipoprotein(a) [Lp(a)] has recently been recognized as an independent risk factor for coronary heart disease. While plasma Lp(a) levels are correlated with cardiovascular risk, the mechanism by which this particle contributes to atherosclerosis is largely unknown. Although humanized transgenic mouse model has recently been described to study Lp(a) biology, non-human primates (NHP) are the only preclinical model available that allow study of the role of Lp(a) in atherosclerosis in an innate setting. We describe targeting of LPA using lipid nanoparticle formulated short interfering RNAs (siRNAs) in lean rhesus macaque monkeys. We show >90 % LPA mRNA lowering in the liver and >95 % Lp(a) plasma reduction for over 3 weeks after a single siRNA dose. Given the potency of LPA siRNAs, siRNA approach may enable chronic reduction of Lp(a) in atherosclerotic NHP and help to unmask the role for Lp(a) in the genesis and progression of atherosclerosis in man.

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Bennet, A., Di Angelantonio, E., Erqou, S., Eiriksdottir, G., Sigurdsson, G., Woodward, M., Rumley, A., Lowe, G. D., Danesh, J., & Gudnason, V. (2008). Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Archives of Internal Medicine, 168, 598–608.CrossRefPubMed

Tsimikas, S., Clopton, P., Brilaklis, E. S., Marcovina, S. M., Khera, A., Miller, E. R., de Lemos, J. A., & Witztum, J. L. (2009). Relationship of oxidized phospholipids on apolipoprotein B-100 particles to race/ethnicity, apolipoprotein(a) isoform size and cardiovascular risk factors: results from the Dallas Heart Study. Circulation, 119, 1711–1719.CrossRefPubMedCentralPubMed

Clarke, R., Peden, J. F., Hopewell, J. C., Kyriakou, T., Goel, A., Heath, S. C., Parish, S., Barlera, S., Franzosi, M. G., Rust, S., Bennett, D., Silveira, A., Malarstig, A., Green, F. R., Lathrop, M., Gigante, B., Leander, K., de Faire, U., Seedorf, U., Hamsten, A., Collins, R., Watkins, H., Farrall, M., & PROCARDIS Consortium. (2009). Genetic variants associated with Lp(a) lipoprotein level and coronary disease. New England Journal of Medicine, 361, 2518–2528.CrossRefPubMed

McLean, J. W., Tomlinson, J. E., Kuang, W. J., Eaton, D. L., Chen, E. Y., Fless, G. M., Scanu, A. M., & Lawn, R. M. (1987). cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature, 330, 132–137.CrossRefPubMed

Lackner, C., Cohen, J. C., & Hobbs, H. H. (1993). Molecular definition of the extreme size polymorphism in apolipoprotein(a). Human Molecular Genetics, 2, 933–940.CrossRefPubMed

Marcovina, S. M., Albers, J. J., Wijsman, E., Zhang, Z. H., Chapman, N. H., & Kennedy, H. (1996). Differences in Lp(a) concentrations and apo(a) polymorphs between black and white Americans. Journal of Lipid Research, 37, 2569–2585.PubMed

Li, Y., Luke, M. M., Shiffman, D., & Devlin, J. J. (2011). Genetic variants in the apolipoprotein(a) gene and coronary heart disease. Circulation. Cardiovascular Genetics, 4, 565–573.CrossRefPubMed

Merki, E., Graham, M. J., Mullick, A. E., Miller, E. R., Crooke, R. M., Pitas, R. E., Witztum, J. L., & Tsimikas, S. (2008). Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation, 118, 743–753.CrossRefPubMed

Tomari, Y., & Zamore, P. D. (2005). Perspective: machines for RNAi. Genes and Development, 19, 517–529.CrossRefPubMed

10.

Bitko, V., Musiyenko, A., Shulyayeva, O., & Barok, S. (2005). Inhibition of respiratory viruses by nasally administered siRNA. Nature Medicine, 11, 50–55.CrossRefPubMed

11.

Querbes, W., Bogorad, R. L., Moslehi, J., Wong, J., Chan, A. Y., Bulgakova, E., Kuchimanchi, S., Akinc, A., Fitzgerald, K., Koteliansky, V., Jr., & Kaelin, W. G. (2012). Treatment of erythropoietin deficiency in mice with systemically administered siRNA. Blood, 120, 1916–1922.CrossRefPubMedCentralPubMed

12.

Ason, B., Castro-Perez, J., Tep, S., Stefanni, A., Tadin-Strapps, M., Roddy, T., Hankemeier, T., Hubbard, B., Sachs, A. B., Flanagan, W. M., Kuklin, N. A., & Mitnaul, L. J. (2011). ApoB siRNA-induced liver steatosis is resistant to clearance by the loss of fatty acid transport protein 5 (Fatp5). Lipids, 46, 991–1003.CrossRefPubMedCentralPubMed

13.

Muroi, Y., Ru, F., Chou, Y. L., Carr, M. J., Undem, B. J., & Canning, B. J. (2013). Selective inhibition of vagal afferent nerve pathways regulating cough using NaV1.7 shRNA silencing in guinea pig nodose ganglia. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 304, R1017–R1023.CrossRefPubMedCentralPubMed

14.

Mayra, A., Tomimitsu, H., Kubodera, T., Kobayashi, M., Piao, W., Sunaga, F., Hirai, Y., Shimada, T., Mizusawa, H., & Yokota, T. (2011). Intraperitoneal AAV9-shRNA inhibits target expression in neonatal skeletal and cardiac muscles. Biochemical and Biophysical Research Communications, 405, 204–209.CrossRefPubMed

15.

Novobrantseva, T. I., Borodovsky, A., Wong, J., Klebanov, B., Zafari, M., Yucius, K., Querbes, W., Ge, P., Ruda, V. M., Milstein, S., Speciner, L., Duncan, R., Barros, S., Basha, G., Cullis, P., Akinc, A., Donahoe, J. S., Narayanannair Jayaprakash, K., Jayaraman, M., Bogorad, R. L., Love, K., Whitehead, K., Levins, C., Manoharan, M., Swirski, F. K., Weissleder, R., Langer, R., Anderson, D. G., de Fougerolles, A., Nahrendorf, M., & Koteliansky, V. (2012). Systemic RNAi-mediated gene silencing in nonhuman primate and rodent myeloid cells. Molecular Theraphy Nucleic Acids, 1, e4.CrossRef

16.

Zimmermann, T. S., Lee, A. C., Akinc, A., Bramlage, B., Bumcrot, D., Fedoruk, M. N., Harborth, J., Heyes, J. A., Jeffs, L. B., John, M., Judge, A. D., Lam, K., McClintock, K., Nechev, L. V., Palmer, L. R., Racie, T., Röhl, I., Seiffert, S., Shanmugam, S., Sood, V., Soutschek, J., Toudjarska, I., Wheat, A. J., Yaworski, E., Zedalis, W., Koteliansky, V., Manoharan, M., Vornlocher, H. P., & MacLachlan, I. (2006). RNAi-mediated gene silencing in non-human primates. Nature, 441, 111–114.CrossRefPubMed

17.

Coelho, T., Adams, D., Silva, A., Lozeron, P., Hawkins, P. N., Mant, T., Perez, J., Chiesa, J., Warrington, S., Tranter, E., Munisamy, M., Falzone, R., Harrop, J., Cehelsky, J., Bettencourt, B. R., Geissler, M., Butler, J. S., Sehgal, A., Meyers, R. E., Chen, Q., Borland, T., Hutabarat, R. M., Clausen, V. A., Alvarez, R., Fitzgerald, K., Gamba-Vitalo, C., Nochur, S. V., Vaishnaw, A. K., Sah, D. W., Gollob, J. A., & Suhr, O. B. (2013). Safety and efficacy of RNAi therapy for transthyretin amyloidosis. New England Journal of Medicine, 369, 819–829.CrossRefPubMed

18.

Strapps, W. R., Pickering, V., Muiru, G. T., Rice, J., Orsborn, S., Polisky, B. A., Sachs, A., & Bartz, S. R. (2010). The siRNA sequence and guide strand overhangs are determinants of in vivo duration of silencing. Nucleic Acids Research, 38, 4788–4797.CrossRefPubMedCentralPubMed

19.

Gindy, M. E., Leone, A. M., & Cunningham, J. J. (2012). Challenges in the pharmaceutical development of lipid-based short interfering ribonucleic acid therapeutics. Expert Opinion on Drug Delivery, 9, 171–182.CrossRefPubMed

20.

Khoury, M., Louis-Plence, P., Escriou, V., Noel, D., Largeau, C., Cantos, C., Scherman, D., Jorgensen, C., & Apparailly, F. (2006). Efficient new cationic liposome formulation for systemic delivery of small interfering RNA silencing tumor necrosis factor alpha in experimental arthritis. Arthritis and Rheumatism, 54, 1867–1877.CrossRefPubMed

21.

Morrissey, D. V., Lockridge, J. A., Shaw, L., Blanchard, K., Jensen, K., Breen, W., Hartsough, K., Machemer, L., Radka, S., Jadhav, V., Vaish, N., Zinnen, S., Vargeese, C., Bowman, K., Shaffer, C. S., Jeffs, L. B., Judge, A., MacLachlan, I., & Polisky, B. (2005). Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nature Biotechnology, 23, 1002–1007.CrossRefPubMed

22.

Sonoke, S., Ueda, T., Fujiwara, K., Sato, Y., Takagaki, K., Hirabayashi, K., Ohgi, T., & Yano, J. (2008). Tumor regression in mice by delivery of Bcl-2 small interfering RNA with pegylated cationic liposomes. Cancer Research, 68, 8843–8851.CrossRefPubMed

23.

Semple, S. C., Akinc, A., Chen, J., Sandhu, A. P., Mui, B. L., Cho, C. K., Sah, D. W., Stebbing, D., Crosley, E. J., Yaworski, E., Hafez, I. M., Dorkin, J. R., Qin, J., Lam, K., Rajeev, K. G., Wong, K. F., Jeffs, L. B., Nechev, L., Eisenhardt, M. L., Jayaraman, M., Kazem, M., Maier, M. A., Srinivasulu, M., Weinstein, M. J., Chen, Q., Alvarez, R., Barros, S. A., De, S., Klimuk, S. K., Borland, T., Kosovrasti, V., Cantley, W. L., Tam, Y. K., Manoharan, M., Ciufolini, M. A., Tracy, M. A., de Fougerolles, A., MacLachlan, I., Cullis, P. R., Madden, T. D., & Hope, M. J. (2010). Rational design of cationic lipids for siRNA delivery. Nature Biotechnology, 28, 172–176.CrossRefPubMed

24.

Abrams, M. T., Koser, M. L., Seitzer, J., Williams, S., DiPietro, M., Wang, W., Shaw, A., Mao, X., Jadhav, V., Davide, J., Burke, P. A., Sachs, A., Stirdivant, S., & Sepp-Lorenzino, L. (2010). Evaluation of efficacy, Biodistribution, and inflammation for a potent siRNA nanoparticle: effect of Dexamethasone Co-treatment. Molecular Therapy, 18, 171–180.CrossRefPubMedCentralPubMed

25.

Tep, S., Mihaila, R., Freeman, A., Pickering, V., Huynh, F., Tadin-Strapps, M., Stracks, A., Hubbard, B., Caldwell, J., Flanagan, W. M., Kuklin, N. A., & Ason, B. (2012). Rescue of Mtp siRNA-induced hepatic steatosis by DGAT2 siRNA silencing. Journal of Lipid Research, 53, 859–867.CrossRefPubMedCentralPubMed

26.

Akdim, F., Visser, M. E., Tribble, D. L., Baker, B. F., Stroes, E. S., Yu, R., Flaim, J. D., Su, J., Stein, E. A., & Kastelein, J. J. (2010). Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. American Journal of Cardiology, 105, 1413–1419.CrossRefPubMed

27.

Merki, E., Graham, M., Taleb, A., Leibundgut, G., Yang, X., Miller, E. R., Fu, W., Mullick, A. E., Lee, R., Willeit, P., Crooke, R. M., Witztum, J. L., & Tsimikas, S. (2011). Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. Journal of the American College of Cardiology, 57, 1611–1621.CrossRefPubMed

28.

Graham, M. X., Riney, S. J., Kim, T.-W., Zanardi, T., Fu, W., Bell, T., Lee, R. R., Mullick, A., & Crooke, R. (2012). Antisense inhibition of apolipoprotein(a) in cynomolgus monkeys significantly reduces plasma apolipoprotein(a) levels without affecting plasminogen or other major lipid classes. Circulation, 126, A:11050.

29.

Sugiuchi, H., Irie, T., Uji, Y., Ueno, T., Chaen, T., Uekama, K., & Okabe, H. (1998). Homogeneous assay for measuring low-density lipoprotein cholesterol in serum with triblock copolymer and alpha-cyclodextrin sulfate. Clinical Chemistry, 44, 522–531.PubMed

30.

Baudhuin, L. M., Hartman, S. J., O’Brien, J. F., Meissner, I., Galen, R. S., Ward, J. N., Hogen, S. M., Branum, E. L., & McConnell, J. P. (2004). Electrophoretic measurement of lipoprotein(a) cholesterol in plasma with and without ultracentrifugation: comparison with an immunoturbidimetric lipoprotein(a) method. Clinical Biochemistry, 37, 481–488.CrossRefPubMed

31.

Seman, L. J., Jenner, J. L., McNamara, J. R., & Schaefer, E. J. (1994). Quantification of lipoprotein(a) in plasma by assaying cholesterol in lectin-bound plasma fraction. Clinical Chemistry, 40, 400–403.PubMed

32.

Tsimikas, S., Brilakis, E. S., Miller, E. R., McConnell, J. P., Lennon, R. J., Kornman, K. S., Witztum, J. L., & Berger, P. B. (2005). Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. New England Journal of Medicine, 353, 46–57.CrossRefPubMed

33.

Boring, L., Gosling, J., Cleary, M., & Charo, I. F. (1998). Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature, 394, 894–897.CrossRefPubMed

34.

Wiesner, P., Tafelmeier, M., Chittka, D., Choi, S. H., Zhang, L., Byun, Y. S., Almazan, F., Yang, X., Iqbal, N., Chowdhury, P., Maisel, A., Witztum, J. L., Handel, T. M., Tsimikas, S., & Miller, Y. I. (2013). MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma. Journal of Lipid Research, 54, 1877–1883.CrossRefPubMedCentralPubMed

35.

Rouy, D., Grailhe, P., Nigon, F., Chapman, J., & Angles-Cano, E. (1991). Lipoprotein(a) impairs generation of plasmin by fibrin-bound tissue-type plasminogen activator. In vitro studies in a plasma milieu. Arteriosclerosis and Thrombosis, 11, 629–638.CrossRefPubMed

36.

Feric, N. T., Boffa, M. B., Johnston, S. M., & Koschinsky, M. L. (2008). Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein(a)-mediated inhibition of plasminogen activation. Journal of Thrombosis and Haemostasis, 6, 2113–2120.CrossRefPubMed

37.

Nielsen, L. B. (1999). Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis, 143, 229–243.CrossRefPubMed

38.

Ogorelkova, M., Gruber, A., & Utermann, G. (1999). Molecular basis of congenital lp(a) deficiency: a frequent apo(a) 'null' mutation in Caucasians. Human Molecular Genetics, 8, 2087–2096.CrossRefPubMed

39.

Callow, M. J., Verstuyft, J., Tangirala, R., Palinski, W., & Rubin, E. M. (1995). Atherogenesis in transgenic mice with human apolipoprotein B and lipoprotein (a). Journal of Clinical Investigation, 96, 1639–1646.CrossRefPubMedCentralPubMed

40.

Mancini, F. P., Newland, D. L., Mooser, V., Murata, J., Marcovina, S., Young, S. G., Hammer, R. E., Sanan, D. A., & Hobbs, H. H. (1995). Relative contributions of apolipoprotein(a) and apolipoprotein-B to the development of fatty lesions in the proximal aorta of mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 15, 1911–1916.CrossRefPubMed

41.

Sanan, D. A., Newland, D. L., Tao, R., Marcovina, S., Wang, J., Mooser, V., Hammer, R. E., & Hobbs, H. H. (1998). Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a). Proceedings of the National Academy of Sciences of the United States of America, 95, 4544–4549.CrossRefPubMedCentralPubMed

42.

Fan, J., Shimoyamada, H., Sun, H., Marcovina, S., Honda, K., & Watanabe, T. (2001). Transgenic rabbits expressing human apolipoprotein(a) develop more extensive atherosclerotic lesions in response to a cholesterol-rich diet. Arteriosclerosis, Thrombosis, and Vascular Biology, 21, 88–94.CrossRefPubMed

43.

Fan, J., Sun, H., Unoki, H., Shiomi, M., & Watanabe, T. (2001). Enhanced atherosclerosis in Lp(a) WHHL transgenic rabbits. Annals of the New York Academy of Sciences, 947, 362–365.CrossRefPubMed

Titel: Development of Lipoprotein(a) siRNAs for Mechanism of Action Studies in Non-Human Primate Models of Atherosclerosis
verfasst von: Marija Tadin-Strapps
Michael Robinson
Lauretta Le Voci
Lori Andrews
Satya Yendluri
Stephanie Williams
Steve Bartz
Douglas G. Johns
Publikationsdatum: 01.02.2015
Verlag: Springer US
Erschienen in: Journal of Cardiovascular Translational Research / Ausgabe 1/2015
Print ISSN: 1937-5387
Elektronische ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-014-9605-1

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Development of Lipoprotein(a) siRNAs for Mechanism of Action Studies in Non-Human Primate Models of Atherosclerosis

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