Hammerhead Ribozyme as a Therapeutic Agent for Hyperlipidemia: Production of Truncated Apolipoprotein B and Hypolipidemic Effects in a Dyslipidemia Murine Model

作者: Munechika Enjoji , Fang Wang , Makoto Nakamuta , Lawrence Chan , Ba-Bie Teng

DOI: 10.1089/104303400750038516

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摘要: In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. To reduce the levels apoB mRNA, we used adenovirus-mediated vector to target hammerhead ribozyme at GUA6679 ↓ mRNA (designated AvRB15) in liver a dyslipidemic mouse model that deficient editing enzyme and overexpresses human apoB100. this study, delivered ~4 × 1011 virus particles AvRB15 (active ribozyme) or AvRB15-mutant (inactive animals. Using Southern blot analysis, readily detected RB15 DNA as long day 35 after injection. This result was correlated RNA expression by RNase protection assay. reverse ligation-mediated polymerase chain reaction, 3′ cleavage product detected, exact site confirmed sequencing. Importantly, decreased ~80% transduction. There marked decrease plasma...

参考文章(69)
L Liaw, D E Birk, C B Ballas, J S Whitsitt, J M Davidson, B L Hogan, Dual mechanisms for the low plasma levels of truncated apolipoprotein B proteins in familial hypobetalipoproteinemia. Analysis of a new mouse model with a nonsense mutation in the Apob gene. Journal of Clinical Investigation. ,vol. 101, pp. 1468- 1477 ,(1998) , 10.1172/JCI1122
Henry N. Ginsberg, Martijn B. Katan, Nutrition and therapeutics: where we are and where we should be going. Current Opinion in Lipidology. ,vol. 6, pp. 1- 2 ,(1995) , 10.1097/00041433-199502000-00001
L.-Q. Sun, W. L. Gerlach, G. Symonds, The Use of Ribozymes to Inhibit HIV Replication Springer, Berlin, Heidelberg. pp. 329- 342 ,(1996) , 10.1007/978-3-642-61202-2_19
R J Pease, R W Milne, W K Jessup, A Law, P Provost, J C Fruchart, R T Dean, Y L Marcel, J Scott, Use of bacterial expression cloning to localize the epitopes for a series of monoclonal antibodies against apolipoprotein B100. Journal of Biological Chemistry. ,vol. 265, pp. 553- 568 ,(1990) , 10.1016/S0021-9258(19)40266-4
M. Cotten, M.L. Birnstiel, Ribozyme mediated destruction of RNA in vivo. The EMBO Journal. ,vol. 8, pp. 3861- 3866 ,(1989) , 10.1002/J.1460-2075.1989.TB08564.X
Z Yao, R S McLeod, K Tran, Intracellular degradation of newly synthesized apolipoprotein B. Journal of Lipid Research. ,vol. 38, pp. 1937- 1953 ,(1997) , 10.1016/S0022-2275(20)37125-X
C R Pullinger, J D North, B B Teng, V A Rifici, A E Ronhild de Brito, J Scott, The apolipoprotein B gene is constitutively expressed in HepG2 cells: regulation of secretion by oleic acid, albumin, and insulin, and measurement of the mRNA half-life. Journal of Lipid Research. ,vol. 30, pp. 1065- 1077 ,(1989) , 10.1016/S0022-2275(20)38287-0