AUSTRALIAN FRONTIERS OF SCIENCE, 2003
Canberra, 31 July to 1 August 2003
DNA-based catalytic
agents as potential inhibitors of vascular disorders
by Associate Professor Levon Khachigian
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Levon Khachigian is an NHMRC Principal Research Fellow and Head of the Signalling and Transcription Laboratory at the Centre for Vascular Research at the University of New South Wales, where he is Associate Professor of Pathology. His research has dramatically increased our understanding of the fundamental transcriptional mechanisms that lead to the inappropriate expression of harmful genes in cells of the artery wall. It has led to his generation of novel DNA-based drugs that block arterial renarrowing after balloon angioplasty and, more recently, the process of tumour growth by inhibiting angiogenesis. He has published extensively in scientific journals of high impact, including Science, Nature Medicine, Journal of Clinical Investigation and EMBO Journal. |
DNA enzymes (DNAzymes) are RNA-cleaving phosphodiester-linked DNA-based enzymes that seek out and cleave their target mRNA in a gene-specific fashion. DNAzymes targeting the immediate-early gene product, early growth response-1 (Egr-1), for example, inhibit intimal thickening in rat carotid arteries following balloon angioplasty, permanent ligation, and in-stent restenosis in pigs after coronary stenting. Similarly, DNAzymes targeting c-Jun, a prototypic member of the basic region-leucine zipper family of nuclear proteins inhibit inducible c-Jun expression in vascular smooth muscle cells, block smooth muscle cell proliferation and attenuate intimal thickening in injured rat carotid arteries. We have also recently demonstrated that DNAzymes are capable of inhibiting target genes in microvascular endothelial cells. These agents block microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth. DNAzymes, therefore, are versatile gene targeting tools with important therapeutic implications.
