Multi-unit ribozyme inhibition of oncogene gene expression
AssigneeTemple University of the Commonwealth System of Higher Education
InventorsLance H. Leopold, Scott K. Shore, Moole V. R. Reddy, E. Premkumar Reddy
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Abstract
A novel multi-unit ribozyme is provided which is capable of selectively cleaving the mRNA transcript of a hybrid oncogene resulting from a chromosomal translocation. Specialized delivery vehicles such as liposomes, and growth factor conjugates for cellular uptake by receptor-mediated endocytosis, are also described. The multi-unit ribozyme is used for the treatment of neoplasms characterized by expression of the oncogene. In one embodiment, a multi-unit ribozyme is provided which cleaves the mRNA transcript of Philadelphia chromosome-positive cells, thereby blocking production of the tumorigenic p210.sup.bcr-abl fusion protein.
Claims21
A synthetic RNA molecule which cleaves bcr-abl bcr-abl mRNA comprising
- (a) a first ribozyme subunit comprising
- (i) a first flanking segment having a nucleotide sequence complementary to the nucleotide sequence of a portion of the oncogene mRNA transcript 5' of the oncogene translocation junction and being hybridizable to that mRNA portion;
- (ii) a second flanking segment having a nucleotide sequence complementary to the nucleotide sequence of a portion of the bcr-abl mRNA transcript 3' of the oncogene translocation junction and being hybridizable to that mRNA portion;
- (iii) a catalytically active segment disposed between the first and second flanking segments comprising a ribozyme of the nucleotide sequence SEQ ID NO:8 which cleaves the oncogene mRNA at a G-U-X site comprising nucleotides 6-4 upstream of the oncogene mRNA translocation junction, wherein X is the ribonucleotide A, U, or C;
- (b) a second ribozyme subunit comprising (i) a catalytically active segment comprising a ribozyme of the nucleotide Sequence SEQ ID NO:8 which cleaves the bcr-abl mRNA at a G-U-X site comprising nucleotides 34-32 upstream of the bcr-abl mRNA translocation junction, wherein X is the ribonucleotide A, U, or C, and (ii) flanking segments complementary to the bcr-abl mRNA transcript and hybridizable thereto;
- and
- (c) a third ribozyme subunit comprising (i) a catalytically active segment comprising a ribozyme of the nucleotide sequence SEQ ID NO:8 which cleaves the bcr-abl mRNA at a G-U-X site comprising nucleotides 18-20 downstream of the bcr-abl mRNA translocation junction, wherein X is the ribonucleotide A, U, or C, and (ii) flanking segments complementary to the bcr-abl mRNA transcript and hybridizable thereto.
Dependencies are inferred from the claim text.