Abstract
Purpose :
Glaucoma is a heterogeneous group of eye diseases, which result in damage to the optic nerve causing irreversible vision loss. Current treatments for glaucoma focus on lowering intraocular pressure (IOP). However, only one-third to half of glaucoma patients have elevated IOP at the initial stages and disease progression can still occur despite adequate IOP control. Therefore, there is an urgent need to investigate novel therapeutic concepts that complement IOP regulation. We investigated novel compounds that increase cyclic GMP (cGMP) levels in retina by releasing NO and inhibiting PDE5 simultaneously. This dual mode of action may have neuroprotective potential by decreasing IOP and increasing ocular blood flow.
Methods :
Candidate compounds were tested in various neuronal and epithelial cell types of the retina. cGMP response profiles were generated for each retinal cell type following compound treatment. In addition, cell viability and phagocytosis of human RPE cells were investigated upon treatment. cGMP levels in retina were determined upon treatment of ex vivo isolated mouse retina with the compounds. For in vivo studies, TOP-V122 (1%) was applied topically using a newly developed formulation in 129S6 mice. To investigate potential physiological effects of the treatment, fundus photography, optical coherence tomography and electroretinography were applied.
Results :
Following compound treatment, cGMP levels increased in rMC-1, ARPE-19 and HRPEpiC cells in both time and dose dependent manner. Treatment did not affect the cell viability and phagocytosis of human RPE cells. 3-fold increased cGMP levels were measured in ex vivo isolated mouse retina upon TOP-V122 (1µM) treatment. The effect was not dependent on endogenous NO levels in retina, but on the presence of a functional soluble guanylate cyclase. In vivo, multiple topical applications of TOP-V122 (1%) increased cGMP levels in retina compared to the control treatment of the contralateral eye by 65% (27.87 ± 5.30 pmol/mg vs. 16.92 ± 1.67 pmol/mg, n=4, P=0.0076) without affecting retinal function.
Conclusions :
Novel compounds targeting PDE5 effectively increase cGMP levels in various retinal cell types and the retina. Repeated dosing did not affect retinal function and structure. The results obtained substantially contribute to understanding the potential use of PDE5 inhibitors specifically designed for retinal neuroprotection and pave the way for future research in this area.
This is a 2021 ARVO Annual Meeting abstract.