Inhibiting NLRP3 has demonstrated the potential to modulate the trabecular meshwork and lower IOP • The trabecular meshwork (TM) plays a crucial role in maintaining the aqueous outflow pathway Preclinical studies demonstrated that inhibiting NLRP3/caspase - 1 pathway protects the TM and lowered IOP • Elevated levels of NLRP3 and Caspase - 1 were found in TM samples from glaucoma patients • Oxidative damage in human TM cells led to upregulation of NLRP3, caspase - 1, and IL - 1 β , resulting in decreased cell viability • Caspase - 1 inhibitor VX - 765 has been shown to protect TM cells from pyroptosis (cell death) and lowered IOP in rat acute ocular hypertension model 21 Treatment with VX - 765 improved elevated IOP due to AOH *P < 0.05, **P < 0.01, ***P < 0.001 vs. control, ## P < 0.01, ### P < 0.001 vs. AOH Feng, Xiaomei et al. Role for NLRP3 inflammasome - mediated, Caspase1 - dependent response in glaucomatous trabecular meshwork cell death and regulation of aqueous humor outflow. Heliyon , Volume 10, Issue 19, e38258 NLRP3, caspase - 1 and IL1 β mRNA levels are elevated in TM with oxidative stress

Unmet Needs in Retinal Disease Therapeutics - Page 21 Unmet Needs in Retinal Disease Therapeutics Page 20 Page 22