Monday, May 19, 2025
5/19/2025
Enhancing miRNA Therapeutics through Vehicle Free Delivery - PROJECT SUMMARY Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of two mRNA vaccines to prevent against SARS-CoV-2 and the first three FDA approved RNAi drugs targeted to the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this space is attributed to inability to deliver RNAi safely and effectively. A successful delivery agent requires multiple features. First, the agent must deliver the RNA specifically to the intended cells. Second, the agent must have a large therapeutic window, meaning that toxicity, if observed, should occur at doses that are orders of magnitude higher than the therapeutic dose. Third, if delivery of the RNA is by way of a specific ligand and receptor pair, as is the case herein, the RNA must successfully escape the endosome. Simply swelling the endosome is not enough if noncovalent interactions between the ligand and the receptor cannot be disrupted. Fourth, the RNA should include appropriate stabilizing modifications to increase intracellular half-life that will reduce dosing and cost. Through hard work and dedication in this space, we have come up with an inclusive, easily synthesized, intramolecular molecule that will achieve all of these essential features. Moreover, the ligand used to achieve successful delivery is also being evaluated for imaging tumors localized in the central nervous system. The premise for this work is based on conjugating the tumor suppressive microRNA, miR-34a to 5- methyltetrahydrofolate (5-MTHF), a ligand that is superior for the intended needs, in this case, release from the receptor when an endosomal escape agent is present. Our preliminary data and strong scientific premise supports our objective to i) advance 5-MTHF as a specific and non-toxic therapeutic ligand for delivery of therapeutic miRNAs to triple negative breast cancer (TNBC) and ii) to characterize and prepare 5-MTHF-nigericin conjugated to a fully modified version of miR-34a for clinical trial. To support these objectives, the following Aims will be conducted: 1) To test the hypothesis that both in vivo and intracellular biodistribution of 5-MTHF conjugates are superior to folate conjugates, and 2) To evaluate activity, efficacy, toxicity, pharmacokinetics, dynamics, and combinatorial effects of 5-MTHF-nigericin conjugated to fully modified miR-34a in vivo. At the completion of this work we will have the first an all-encompassing RNAi delivery vehicle that can deliver a stabilized RNA to the intended cells, into the correct subcellular location, with limited toxicity for the treatment of TNBC.
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