A novel siRNA therapeutic to prevent scarring and bleb failure after trabeculectomy

Abstract Glaucoma is the leading cause of irreversible blindness, affecting tens of millions of citizens globally. Trabeculectomy surgery, is the gold standard for reducing intraocular pressure (IOP) in glaucoma patients who no longer respond to medical therapy. However, the long-term success of trabeculectomy is compromised by postoperative scarring. Scarring, which leads to increased IOP after surgery, occurs in 50% of patients within five years, significantly diminishing surgery effectiveness and increasing the risk of vision loss. Our project focuses on the development of DUB-001, an innovative therapeutic designed to prevent scarring after trabeculectomy surgery. DUB-001 is a fully modified self-delivering siRNA (sdRNA) targeting the USP10 gene which we have identified as a critical regulator of the fibrotic response in the eye. DUB-001 is unique in its design as it is conjugated to a cholesterol moiety, allowing for direct absorption into the wounded tissue without the need for encapsulation. Preclinical studies have demonstrated that a single administration of USP10-targeting sdRNA provides prolonged anti-fibrotic activity after surgery throughout the phases of wound healing, compared to the standard of care (Mitomycin C). By modulating USP10 activity, DUB-001 aims to reduce scar formation, thereby increasing long-term success of trabeculectomy procedures. The proposed research will advance DUB-001 through critical preclinical development stages including, therapeutic effect, safety, tolerability, and drug biodistribution studies in rabbit and minipig. In preparation for an IND-filing, the project will also support scaled-up production of DUB-001 in its GLP final formulation. The production runs will be used to conduct future IND-enabling studies including toxicology and PK experiments in minipigs. At the conclusion of the project, DUB Tx will have completed all required efficacy studies, demonstrated a clear safety profile for DUB-001 in a pharmacologically relevant animal model, and created a scaled-up manufacturing process ready for cGMP conversion. These data significantly derisk the therapeutic pipeline for this indication, enabling external investment to fund the remaining IND-enabling studies and early-stage clinical trials. By preventing postoperative scarring, DUB-001 has the potential to increase the success rate of trabeculectomy surgeries, reduce the need for repeat surgeries, and preserve vision in glaucoma patients. This will ultimately alleviate the global burden of glaucoma-related blindness and reduce healthcare costs associated with this chronic disease.