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Maxizymes and Small Hairpin-Type RNAs That Are Driven by a tRNA Promoter Specifically Cleave a Chimeric Gene Associated with Leukemia in Vitro and in Vivo¹

Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan [K. O., H. K., K. Tai.]; Gene Function Research Center, National Institute of Advanced Industrial Science and Technology, Tsukuba Science City 305-8562, Japan [H. K., K. Tai.]; Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan [Y. S., S. A.]; and Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan [K. Tan.]

Many leukemias result from chromosomal translocations that lead to the generation of chimeric oncoproteins. Chimeric gene for the promyelocytic leukemia-retinoic acid receptor (PML-RAR ) is the hallmark of acute promyelocytic leukemia. Specific gene silencing of an oncogene is desirable for the treatment of these diseases. We have previously constructed an allosterically controllable ribozyme (designated maxizyme) targeted for bcr-abl chimeric mRNA, whose cleavage activity is induced only in the presence of a specific RNA sequence of interest. It has been demonstrated recently that RNA interference induced by short hairpin-type RNAs provides a powerful method for sequence-specific gene silencing. Here we report that DNA vector-based maxizymes and short hairpin-type RNAs driven by the promoter of a human gene for tRNA^Val specifically inhibit the expression of the chimeric gene for PML-RAR both in vitro and in vivo. Our findings confirm the potential utility of maxizymes and shRNAs as therapeutic agents.

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				M. Shiota, M. Sano, M. Miyagishi, and K. Taira Ribozymes: Applications to Functional Analysis and Gene Discovery J. Biochem., August 1, 2004; 136(2): 133 - 147. [Abstract] [Full Text] [PDF]