Author:

Abstract:

Despite successful IOP lowering therapies, developing alternative treatment strategies is still necessary, to prevent/repair glaucomatous damage to the retina and optic nerve. Neuroprotective approaches are warranted to protect RGCs and halt further axonal degeneration. In addition, strategies that stimulate injured RGCs to regenerate are necessary to repair structural and functional connectivity. Here, the potential role of Rho-associated kinase (ROCK) inhibitors was elucidated by using both ex vivo and in vivo models. More in detail, AMA0428, a novel and potent ROCK inhibitor, developed by Amakem Therapeutics, was investigated in comparison to commercially available ROCK inhibitors. The ex vivo neuroprotective effect of ROCK inhibitors was evaluated by using adult mouse retinal explants. The potential neuroprotective effect of AMA0428 was also studied in vivo, using the optic nerve crush (ONC) model. Second, the regenerative potential of the ROCK inhibitors was investigated ex vivo on postnatal day 3 (P3) retinal explants. Finally, experiments are ongoing to assess the regeneration-promoting effect of AMA0428 in vivo. Adult explants, treated with AMA0428, showed enhanced RGC survival compared to vehicle-treated explants. In contrast, preliminary in vivo data indicated no neuroprotective potential of AMA0428. Administration of AMA0428 to P3 retinal explants showed a significant induction of neurite outgrowth. Strikingly, even when dosed ten times lower, AMA0428 was more potent than the reference ROCK inhibitors. Evaluation of AMA0428 via ex vivo approaches, suggests that this novel ROCK inhibitor holds very promising neuroprotective and regeneration potential. Additional in vivo experiments are currently being performed to confirm these exciting ex vivo results.