Increasing 2-5A effectiveness through better chemistry

描述（由申请人提供）：核糖核蛋白复合物端粒酶与许多不同类型肿瘤的形成和发展有关。端粒酶活性在大约80%的所有肿瘤细胞类型中检测到，但在大多数正常细胞中不存在。因此，破坏端粒酶活性是治疗多种类型癌症的特别有吸引力的手段。里奇韦生物系统公司正在开发一类新型嵌合寡核苷酸用于反义治疗策略。这些2-5A寡核苷酸由反义组分和激活剂部分2 '，5'-寡腺苷酸（2-5A）组成，所述反义组分将化合物引导至互补RNA序列，所述激活剂部分2 '，5'-寡腺苷酸（2-5A）用于激活细胞酶核糖核酸酶L（RNA酶L），所述细胞酶切割靶向RNA。 初步研究表明，靶向端粒酶RNA降解的2-5A反义化合物在体外抑制卵巢癌细胞的生长和致瘤性。所提出的研究的目标是通过稳定2-5A部分，特别是其5 '-磷酸，增加其稳定性、对RNA酶L的亲和力和抗肿瘤潜力，使该化合物朝着商业化方向发展。如果成功，2-5A抗端粒酶化合物将广泛应用于许多肿瘤类型的治疗。预期这种治疗剂将被并入已建立的化疗方案中以增加其有效性。所提出的研究还提供了显著提高2-5A寡核苷酸方法的功效的潜力。里奇韦生物系统公司将成功的化学修饰应用于目前正在开发的其他疗法。

DESCRIPTION (provided by applicant): 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.