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Editors Selection IGR 11-4
Basic Science: Effects of ROCK Inhibitors
Comment by Douglas Rhee & Rahul Raghu on:
79411 RKI-1447, a Rho kinase inhibitor, causes ocular hypotension, actin stress fiber disruption, and increased phagocytosis, Dang Y; Wang C; Shah P et al., Graefe's Archive for Clinical and Experimental Ophthalmology, 2019; 257: 101-109
Rho-associated protein kinase (ROCK) inhibitors have been an area of active investigation, particularly for their ocular hypotensive effects in the treatment of glaucoma. Dang et al. investigated the hypotensive effect of RKI-1447, a ROCK 1/2 inhibitor previously used in breast cancer treatment, in a porcine ex vivo pigmentary glaucoma model. In the study, 28 of 40 total porcine anterior chambers were infused with medium contained pigment particles for 48 hours. Sixteen of the 28 pigment infused chambers subsequently received treatment with RKI-1447, versus the 12 chambers which remained untreated after pigment infusion and served as the vehicle control group.
As intended, after 48 hours of infusion with pigment, TM outflow facility (microliter/ min-mmHg) decreased from 0.27 ± 0.03 to 0.18 ± 0.02, p = 0.003. Treatment with RKI-1447 appeared to reverse the decreased outflow facility, and when compared to the 12 chambers not infused with pigment, there was no statistically significant difference (0.230 ± 0.010 and 0.287 ± 0.017, p = 0.209). IOP in the RKI-1447 group also decreased significantly from 20.14 ± 2.59 to 13.38 ± 0.91 mmHg, while the untreated pigment group IOP remained significantly higher than its baseline (all P < 0.05).
Based on their immunostaining analysis, the authors posit that the most likely mechanisms by which RKI-1447 lowers IOP and increases outflow facility, are via its roles in disrupting formation of actin stress fibers and increasing TM phagocytosis, as well the TM cell morphologic changes induced by other ROCK inhibitors (cell rounding, contraction, and decreased adhesion). Interestingly, changes in TM cell motility were not observed between groups.
The authors acknowledge the established limitations of in-vitro and animal model studies, and their work provides compelling evidence for the potential therapeutic applications of RKI-1447, particularly for pigmentary glaucoma The authors also briefly mention a potentially increased safety profile of RKI-1447, 'due to lack of cross-reactivity with AKT, MEK, PKA, and PKG even at high concentrations'. With the known importance of ROCK in virtually all tissues, minimizing systemic side effects must remain a high priority, particularly in a glaucoma population who may be on treatment for decades. Ongoing surveillance for cumulative ROCK inhibitor exposure should be an important area of investigation.
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