title: A novel therapeutic technology of specific RNA inhibition for acute promyelocytic leukemia: improved design of maxizymes against PML/RARalpha mRNA.
abstract: Targeting of PML/RARalpha using a loss of function strategy in acute promyelocytic leukemia (APL) is a direct therapeutic approach for patients and may be the basis of future gene therapy for this leukemia. To achieve this, we designed specific maxizymes, novel allosterically controllable ribozymes, against both short and long PML/RARalpha isoforms. The maxizyme has sensor arms that can only recognize target sequences, and it can form a cavity that captures catalytically indispensable Mg2+. We deleted 1 base nucleotide in the Mg2+-binding pocket designed MzPRT50 and MzPRK55. The distance from the PML/RARalpha junction site to the center of effectors is only 2 bases, and there are 8 and 9 complementary bases in their inactive forms, respectively. Both maxizymes specifically cleaved PML/RARalpha mRNA but not wild-type RARalpha mRNA in a cell-free system. Modification of the sequence of the Mg2+-binding pocket will be important in designing the sequence-specific maxizymes against oncogenic genes.
authors.affiliation: Division of Hematology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Suwanai
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsushita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kizaki
mesh_terms: D002474:Cell-Free System; D015195:Drug Design; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016372:RNA, Antisense / Q000494:pharmacology; D016337:RNA, Catalytic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors*; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D016372:RNA, Antisense; D016337:RNA, Catalytic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein