The ribonucleoprotein complex telomerase has been implicated in the establishment and progression of many different types of tumors. Telomerase activity is detected in roughly 80% of all tumor cell types, but is absent in most normal cells. Thus, the disruption of telomerase activity is a particularly attractive means of treating multiple types of cancer. Ridgeway Biosystems, Inc. is developing a novel class of chimeric oligonucleotides for use in antisense therapeutic strategies. These 2-5A oligonucleotides are comprised of an antisense component, which directs the compound to the complimentary RNA sequences, and an activator moiety, 2',5'-oligoadenylate (2-5A) that serve to activate a cellular enzyme, ribonuclease L (RNase L), which cleaves the targeted RNA. Preliminary studies have shown that a 2-5A antisense compound that targets telomerase RNA for degradation inhibits the growth and tumorigenicity of ovarian carcinoma cells in vitro. The goals of the proposed studies are to progress this compound toward commercialization by increasing its stability, affinity to RNase L, and anti-tumor potential through stabilizing the 2-5A moiety, in particular its 5'-phosphate. If successful, the 2-5A anti-telomerase compound will have widespread application to the treatment of many tumor types. It is anticipated that such a therapeutic would be incorporated into established chemotherapeutic regimens to increase their effectiveness. The proposed studies also offer the potential to dramatically improve the efficacy of the 2-5A oligonucleotide approach. Ridgeway Biosystems Inc. will apply successful chemical modifications to other therapeutics currently under development.
