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 Blood, 15 July 2004, Vol. 104, No. 2, pp. 356-363.
Prepublished online as a Blood First Edition Paper on March 23, 2004; DOI 10.1182/blood-2003-06-1948.

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GENE THERAPY

A novel maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome–positive acute lymphoblastic leukemia

Yasushi Soda, Kenzaburo Tani, Yuansong Bai, Minoru Saiki, Minghan Chen, Kiyoko Izawa, Seiichiro Kobayashi, Satoshi Takahashi, Kaoru Uchimaru, Tomoko Kuwabara, Masaaki Warashina, Tsuyoshi Tanabe, Hiroyuki Miyoshi, Kanji Sugita, Shinpei Nakazawa, Arinobu Tojo, Kazunari Taira, and Shigetaka Asano

From the Division of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Department of Advanced Molecular and Cell Therapy, Medical Institute of Bioregulation, Kyushu University, Fukuoka-shi, Japan; Department of Internal Medicine Division 1, Nihon University School of Medicine, Tokyo, Japan; Gene Function Research Center and Age Dimension Research Center, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan; Subteam for Manipulation of Cell Fate, BioResource Center, Tsukuba Institute, Institute of Physical and Chemical Research (RIKEN), Tsukuba, Japan; Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Tamaho, Yamanashi, Japan; and Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.

Patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) generally have a poor prognosis and would benefit from the development of new therapeutic approaches. We previously demonstrated that an allosterically controllable ribozyme, maxizyme (Mz), can induce apoptosis in chronic myelogenous leukemia (CML) cells. Ph+ ALL cells harbor a bcrabl fusion gene (e1a2) encoding a 190-kDa fusion protein (p190) involved in disease pathogenesis. In this study, we have designed a Mz that specifically cleaves e1a2 mRNA and transduced this e1a2Mz into Ph+ ALL cells using a third-generation lentiviral vector system. In 3 of 5 Ph+ ALL cell lines, e1a2Mz transduction resulted in a significant decrease in viability and increased cell apoptosis. We observed a decrease in e1a2 mRNA in all Ph+ ALL cells transduced with e1a2Mz, and the e1a2 mRNA level was higher in e1a2Mz-resistant cells than in e1a2Mz-sensitive cells. All samples of primary Ph+ ALL cells tested showed e1a2Mz-induced growth inhibition and apoptosis. Importantly, e1a2Mz did not influence the colony formation of normal CD34+ cord blood cells. These results indicate that e1a2Mz kills Ph+ ALL cells specifically, suggesting that it may be used as a novel gene therapy strategy for Ph+ ALL. (Blood. 2004;104:356-363)


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M. Harata, Y. Soda, K. Tani, J. Ooi, T. Takizawa, M. Chen, Y. Bai, K. Izawa, S. Kobayashi, A. Tomonari, et al.
CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells
Blood, September 1, 2004; 104(5): 1442 - 1449.
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