IMPROVED SPECIFICITY OF RIBOZYME-MEDIATED CLEAVAGE OF BCR-ABL MESSENGER-RNA

Ribozyme-mediated cleavage of bcr-abl mRNA has been shown to be associ ated with the concomitant cleavage of bcr mRNA. The possible role of t his ribozyme as a clinical therapeutic constrained us to improve its t arget specificity. Consequently, three modified ribozymes (Rz7-9) were created, each carrying a single base mismatch in the sequence immedia tely 5' of the cleavage site, while a fourth ribozyme (Rz10) was targe ted to a nearby site. Each was compared with the parent ribozyme for i ts ability to cleave synthetic bcr-abl and bcr substrates, and it was shown that alteration of the second base 5' of the cleavage site creat ed a ribozyme with significantly improved specificity for its substrat e. Rz10 was shown to exclusively act on bcr-abl, but the efficiency of cleavage was reduced compared to that shown by ribozymes 6, 8, and 9.