We had the pleasure of speaking with Zhihong Huang, Director of Global Discovery Chemistry at Novartis, about the scientific opportunities, technical challenges and future potential of xRNA-based medicines.
Huang and his team focus on chemistry innovation and the advancement of Novartis’ xRNA portfolio across both hepatic and extrahepatic areas. While RNA therapeutics have achieved significant progress in the liver, supported by effective delivery mechanisms such as tri-antennary GalNAc conjugates targeting ASGPR, which is highly and selectively expressed in the liver, the next major opportunity and challenge lie beyond the liver, also known as extrahepatic space.
According to Huang, expanding into extrahepatic tissues will require selective delivery technologies. Antibodies, peptides and low-molecule weight (LMW) ligands could directly deliver RNA therapeutics to specific cells and tissues while achieving the appropriate pharmacokinetic (PK) and pharmacodynamic (PD) profile of overall drug conjugates, together with some necessary chemistry modifications.
The progress in RNA therapeutics could open new possibilities across a wide range of diseases. Local administration of ASO and siRNA in late-stage clinic trial already supports the potential treatments of brain diseases including Alzheimer’s disease, while systemic delivery could offer new approaches for neuromuscular, cardiovascular, metabolic, obesity-related and other conditions. As delivery technologies improve, xRNA medicines may move beyond rare diseases and begin addressing much broader patient populations.
However, significant challenges remain. Durability, safety, manufacturing and translation are all important considerations, but Huang identifies extrahepatic delivery as the key challenge and opportunity. Success will depend not only on identifying the correct cellular target, but also on pairing the RIGHT delivery ligands — antibody, peptide, or LMW ligands -- with the RIGHT RNA modality, such as ASO, siRNA, PMO, etc.
Looking ahead, Huang believes xRNA therapeutics could transform how medicines are administered. Instead of the frequent treatment required for many daily oral drugs, patients may receive a subcutaneous injection every month or even once every six months. Continued advances in RNA chemistry could potentially make vaccine-like annual dosing possible for certain therapies.
In summary, by combining precise biological targeting with durable RNA modulation, xRNA therapeutics have the potential to reshape treatment across a broad range of diseases —expanding beyond the liver while enabling increasingly infrequent and potentially transformative dosing.
