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Nischal H, Sun H, Wang Y, et al. Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice. Mol Ther Nucleic Acids. 2013;2:e125doi: 10.1038/mtna.2013.53.
Nischal, H., Sun, H., Wang, Y., Ford, D. A., Cao, Y., Wei, P., & Teng, B. B. (2013). Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice. Molecular therapy. Nucleic acids, 2e125. https://doi.org/10.1038/mtna.2013.53
Nischal, Hersharan, et al. "Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice." Molecular therapy. Nucleic acids vol. 2 (2013): e125. doi: https://doi.org/10.1038/mtna.2013.53
Nischal H, Sun H, Wang Y, Ford DA, Cao Y, Wei P, Teng BB. Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice. Mol Ther Nucleic Acids. 2013 Oct 01;2:e125. doi: 10.1038/mtna.2013.53. PMID: 24084845; PMCID: PMC4027429.
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Mol Ther Nucleic Acids. 2013 Oct 01;2:e125. doi: 10.1038/mtna.2013.53.

Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits Atherosclerosis in Mice.

Molecular therapy. Nucleic acids

Hersharan Nischal, Hua Sun, Yuchun Wang, David A Ford, Ying Cao, Peng Wei, Ba-Bie Teng

Affiliations

  1. Center for Human Genetics, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center, Houston, Texas, USA.

PMID: 24084845 PMCID: PMC4027429 DOI: 10.1038/mtna.2013.53

Abstract

Target substrate-specific hammerhead ribozyme cleaves the specific mRNA efficiently and results in the inhibition of gene expression. In humans, overproduction of apolipoprotein B (apoB) is positively associated with premature coronary artery diseases. The goal of this study is to demonstrate that long-term reduction of apoB gene expression using hammerhead ribozyme would result in inhibition of atherosclerosis development. We designed two hammerhead ribozymes targeted at the nucleotides of apoB mRNA GUC(2326) (designated RB1) and GUA(6679) (designated RB15), and we used self-complementary adeno-associated virus 8.2 (scAAV8.2) vector to deliver these active ribozymes of RB1, RB15, combination of RB1/RB15, and an inactive hammerhead ribozyme RB15 mutant to atherosclerosis-prone LDb mice (Ldlr(-/-)Apobec1(-/-)). LDb mice lack both low density lipoproteins (LDL) receptor (Ldlr(-/-)) and apoB mRNA editing enzyme (Apobec1(-/-)) genes and develop atherosclerosis spontaneously. After the RB1, RB15, or combination of RB1/RB15 ribozymes treatment, the LDb mice had significantly decreased plasma triglyceride and apoB levels, resulting in markedly decreased of atherosclerotic lesions, Furthermore, the active ribozymes treatment decreased the levels of diacylglycerol acyltransferase 1 (Dgat1) mRNA and the levels of multiple diacylglycerol (DAG) molecular species. These results provide the first evidence that decreased apoB levels results to reduction of Dgat1 expression and triglyceride levels (TAG), which had a significant impact on the development of atherosclerosis.Molecular Therapy-Nucleic Acids (2013) 2, e125; doi:10.1038/mtna.2013.53; published online 1 October 2013.

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