Development of Small Molecules that Enhance the Delivery and the Pharmacological Effects of Oligonucleotides

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 DESCRIPTION (provided by applicant): Antisense and siRNA oligonucleotides offer the promise of highly precise manipulation of genes involved in disease pathogenesis. However, despite the investment of enormous resources, that promise has been fulfilled to only a limited degree. A key impediment to oligonucleotide-based therapeutics is the difficulty in delivering these large, highly polar molecules to their sites of action in the cytosol or nucleus of tissue cells. While chemical modification of oligonucleotides and the utilization of various nanotechnology-based delivery approaches have been helpful, the delivery problem remains challenging. Much of the oligonucleotide accumulated by cells remains non-productively entrapped in endosomes. The complex pathways of endocytosis and intracellular trafficking are being increasingly understood at the molecular level; however, there is a paucity of small molecule probes for these pathways. Here we describe a novel technology based on the use of small organic molecules to enhance the functional delivery and pharmacological effectiveness of oligonucleotides by manipulating their intracellular trafficking. We have established a proof of principle for this strategy by identifying compounds using a high throughout screen of >100,000 small molecules. Three distinct compound series were discovered from this screen that significantly enhance oligonucleotide effects in cell culture, and in one case in a transgenic mouse model. We now propose medicinal chemistry efforts to build structure activity relationships and improve both potency and pharmacological properties with the end goal of creating molecules that can effectively and safely be used in vivo. Promising leads will be examined for their pharmacokinetic and biodistribution behavior. Finally, these leads will be evaluated in a xenograft tumor model. The identification of potent and non-toxic enhancing molecules will likely have a major impact on the entire field of oligonucleotide therapeutics.