Chemical engineering of therapeutic RNAs for extrahepatic delivery

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

Summary Small interfering RNAs (siRNAs) are informational drugs designed to treat genetically defined disorders and promise to reshape our approach to human medicine. The clinical utility of siRNAs depends on functional delivery to a tissue or cell type of interest, which is in turn defined by oligonucleotide chemistry. When a chemical architecture—e.g., oligonucleotide modification pattern—that provides functional, non-toxic delivery to a tissue is optimized, candidate drugs can be rapidly developed to treat diseases with the same tissue involvement. Clinical utility of siRNA is proven in liver, where conjugation of a trivalent N-acetylgalactosamine moiety enables efficient delivery to hepatocytes and therapeutic activity for a year after a single injection. To expand siRNA utility to tissues beyond liver, our lab and others have explored chemical approaches altering valency and lipophilicity, leading to two classes of siRNA chemical configurations that have opened a limited number of other tissues to therapeutic intervention and are in clinical trials. To build on this success and fully realize the potential of this technology, fundamental improvements are required in two areas: (i) siRNA potency and durability in extrahepatic tissues, and (ii) targeted delivery of siRNA to extrahepatic tissues. We have established the expertise in organic chemistry, combinatorial chemistry, oligonucleotide chemistry, RISC biology, and siRNA pharmacology needed to solve these problems. In the last funding period, we (i) discovered a novel biologically-compatible nucleic acid backbone—extended Nucleic Acid (exNA)—that, when placed in defined positions of the siRNA backbone, enhances extrahepatic tissue exposure by more than an order of magnitude; (ii) engineered novel siRNA chemical architectures that open lung, fat, muscle, placenta and heart to functional gene modulation; (iii) defined novel classes of serum protein binding architectures to dynamically modulate siRNA clearance; and (iv) advanced a “first in class” systemically-delivered lipophilic siRNA to clinical trials. Building on these recent advances, we propose three principal research directions that seek to (i) chemically engineer siRNA scaffolds that enable complete stability, modulate endosomal release, and support sustained siRNA efficacy in different tissues in vivo; (ii) engineer and discover novel ligands for targeted siRNA delivery to extrahepatic tissues; and (iii) work with a network of expert collaborators to investigate the therapeutic potential of novel chemical configurations in models of diseases with unmet medical needs. Completing these studies will establish chemical architectures that enable functional extrahepatic delivery of siRNAs and discover new compounds with potential to transform therapeutic approaches for many diseases.