Meiling Li, a technical project leader at Roche, presented her research on enhancing ocular delivery of siRNA through topical applications like eye drops. She began by highlighting Roche's commitment to advancing small molecules, large molecules, and RNA molecules, with RNA offering unique mechanisms by targeting RNA directly and addressing previously undruggable diseases.
Li explained that RNA therapeutics had shown long tissue half-life and rapid delivery potential, making them promising for creating long-lasting treatments. However, she noted that delivering RNA molecules posed significant challenges due to their size, charge, and hydrophobicity, which hindered their ability to passively diffuse across cell membranes. Additionally, she mentioned that even after entering cells, a large percentage of RNA molecules were trapped and degraded by endolysosomes.
To address these delivery challenges, various technologies such as devices, carriers, and encapsulation methods were explored. In this presentation, Li focused on lipid and fatty acid conjugation and lipid nanoparticles as potential solutions. She discussed an internal programme at Roche aimed at treating dry eye disease by delivering oligonucleotides to the front of the eye using eye drops. However, she acknowledged the complexity of the tear film, and the rapid clearance of eye drops as significant obstacles.
Li shared the results of a rabbit study where lipid nanoparticle and fatty acid conjugated delivery methods for ASOs and siRNAs were compared. The study found that lipid nanoparticle delivery showed no meaningful exposure or pharmacodynamics (PD) effects, while fatty acid conjugated siRNA demonstrated significant exposure and PD effects in conjunctiva cells. Among the tested conjugates, C22 showed the best balance of exposure and PD effect without safety concerns associated with cholesterol.
In conclusion, Li emphasised that the switch from ASO to siRNA and the use of fatty acid conjugates led to breakthroughs in front-of-eye delivery in rabbits, indicating a promising platform for ocular disease treatment by eye drops. She stressed the need for further optimisation and safety evaluation to advance this technology for clinical applications.
