Development of Gene Therapies for Cardiovascular and Renal Diseases by Nucleic Acid Medicines

Noboru      Fukuda

doi:10.2174/157340606775197723

Abstract

Nucleic acid medicines such as antisense DNA, antisense peptide nucleic acid (PNA), ribozyme, and decoy are expected to be novel therapeutic strategy for sever diseases which are resistant to present therapy. We have developed antisense DNA, antisense PNA and ribozyme targeting platelet-derived growth factor (PDGF) A-chain and transforming growth factor-β1 (TGF-β1) for arterial proliferative diseases such as coronary artery stenosis after angioplasty or stent implantation, hypertensive vascular diseases and atherosclerosis, and progressive renal diseases. Antisense DNA to PDGF A-chain inhibited arterial growth in spontaneously hypertensive rats without lowering blood pressure and inhibited the neointima formation of pig coronary artery after stent implantation. Ribozymes to PDGF A-chain and TGF-β1 specifically inhibited the target transcripts and prevented the neointima formation. Ribozymes to TGF-β1 improved renal damages in hypertensive rats. These nucleic acid medicines targeting PDGF A-chain and TGF-β1 will be feasible gene therapies for the arterial proliferative diseases and progressive renal diseases. Pyrrole-imidazole polyamides are novel gene scilencing compound, which bind to minor grove of double strand DNA by base-specific manner to inhibit gene expression. We developed pyrrole-imidazole polyamide to TGF-β1 and confirmed that the polyamide binds to the TGF-β1 promoter. The polyamide inhibited TGF-β1 promoter activity and decreased expression of TGF-β1 in vitro and in vivo. The polyamide markedly improved the renal injury in hypertensive rats. The pyrrole-imidazole polyamide will be a novel gene scilencing agent for cardiovascular and renal diseases.

Keywords: Pyrrole-Imidazole (Py-Im) polyamides, nephrosclerosis, vascular smooth muscle cells, heart disease, antisense DNA

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