Delivery of RNAi Therapeutics: Tackling A Billion Years of Evolution Defenses with New Chemistry

Steven F. Dowdy, Ph.D.
Professor of Cellular and Molecular Medicine
Department of Cellular and Molecular Medicine
UC San Diego, School of Medicine

Abstract: Cancer is a complex genetic moving target that requires a therapeutic modality capable of selectively targeting all driver oncogenes combined with the inherent ability to undergo pharmaco-evolution to target new mutations at pace with the cancer cell mutation rate.  siRNA RNA-interference (RNAi) therapeutics fulfill these criteria and have great potential to treat cancer and other human diseases.  However, due to their 14 kDa size and 40 negative anionic charges, siRNAs have no bioavailability to overcome a billion years of evolutionary defenses to prevent RNAs from crossing the endosomal lipid bilayer to enter the cytoplasm.  Consequently, developing anti-cancer RNAi therapeutics requires targeted delivery to malignant cells and paradigm-shifting technology to enhance endosomal escape into the cytoplasm, the critical rate-limiting delivery step.  Our research is focused on solving these problems by synthesis of bioreversible charge neutral RNAi prodrugs, called short interfering RiboNucleic Neutrals (siRNNs), and synthesis of novel hydrophilic-masked, hydrophobic endosomal escape domains (EEDs).  For targeting domains, we have focused on conjugating antibodies to siRNN RNAi triggers to generate Antibody-RNAi Conjugates (ARCs).