Development of gene therapies for cardiovascular and renal diseases by nucleic acid medicines.
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-beta1 (TGF-beta1) 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-beta1 specifically inhibited the target transcripts and prevented the neointima formation. Ribozymes to TGF-beta1 improved renal damages in hypertensive rats. These nucleic acid medicines targeting PDGF A-chain and TGF-beta1 will be feasible gene therapies for the arterial proliferative diseases and progressive renal diseases. Pyrrole-imidazole polyamides are novel gene silencing 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-beta1 and confirmed that the polyamide binds to the TGF-beta1 promoter. The polyamide inhibited TGF-beta1 promoter activity and decreased expression of TGF-beta1 in vitro and in vivo. The polyamide markedly improved the renal injury in hypertensive rats. The pyrrole-imidazole polyamide will be a novel gene silencing agent for cardiovascular and renal diseases.
Fukuda
Noboru
N
Advanced Research Institute of the Science and Humanities, Nihon University, Ooyaguchi-kami 30-1, Itabashi-ku, Tokyo 173-8610, Japan. fukudan@med.nihon-u.ac.jp
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002318:Cardiovascular Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016373:DNA, Antisense / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects*; D015316:Genetic Therapy; D006978:Hypertension, Renovascular / Q000628:therapy; D007093:Imidazoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000494:pharmacology; D016337:RNA, Catalytic / Q000494:pharmacology; D051381:Rats; D013552:Swine; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics; D053773:Transforming Growth Factor beta1; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism
D000577:Amides; D016373:DNA, Antisense; D007093:Imidazoles; D016376:Oligonucleotides, Antisense; D010982:Platelet-Derived Growth Factor; D011758:Pyrroles; D016337:RNA, Catalytic; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1