Conjugate-mediated Delivery of RNAi-based Therapeutics: Enhancing Pharmacokinetics–Pharmacodynamics Relationships of Medicinal Oligonucleotides

Therapeutic gene silencing using synthetic small interfering RNA (siRNA) holds great promise for the treatment of genetically-defined disorders by targeting disease-associated gene products for degradation. To date, one of the most clinically advanced configurations in the field consists of fully chemically modified siRNAs conjugated to N-acetylgalactosamine (GalNAc), which enables targeted delivery with potent and long-lasting gene silencing effects in hepatocytes. The revolutionary success of the GalNAc platform has rapidly expanded to various clinical programs to treat liver disorders. This success has spurred much interest in the field to explore other conjugate modalities, which are now being tested for their in vivo utility to achieve meaningful delivery to extrahepatic tissues. Establishing meaningful oligonucleotide delivery and durable gene-silencing effects requires careful consideration of the key aspects that govern the pharmacokinetics–pharmacodynamics (PK–PD) of conjugated oligonucleotides. In this chapter, we provide an overview of the chemical evolution of unformulated RNA interference (RNAi)-based technologies focusing on the major corner stones that determine productive PK–PD relationships: chemical stabilization, conjugation chemistries for modulation of biodistribution, clearance and intracellular localization and the effects of the route of administration.