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Ellen Townes-Anderson, Eva Halasz, Ilene Sugino, Marco A Zarbin; Inhibition of ROCK activity improves morphological and functional outcomes of reattached retina. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2794.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal detachment (RD) disrupts the first synapse in the visual pathway. Retinal reattachment surgery does not fully restore these damaged synapses. Our previous work demonstrated that activation of RhoA signaling plays a role in rod terminal retraction from the outer plexiform layer. Inhibition of this pathway using different Rho kinase (ROCK) inhibitors successfully decreased structural synaptic disruption during a 2-hr detachment. In order to test for functional improvement we have used a longer, 2-day survival after detachment in which spontaneous reattachment occurred. We applied AR-13503 (Netarsudil-M1, Lin et al. 2018), a potent metabolite of the FDA-approved ROCK inhibitor netarsudil, as it was the most efficacious in the short-term experiments.
RDs were made in Yorkshire pigs by subretinal injection of a balanced salt solution with or without 0.5 µM AR-13503. 2 days after detachment eyes were harvested and fixed for immunocytochemistry and confocal microscopy. Retraction was quantified by image analysis of the amount of SV2-labeled synaptic vesicles in the outer nuclear layer (ONL) (Wang et al. 2016). For functional assessment full-field electroretinograms (ffERGs) were obtained before RD and prior to euthanasia. The protocol was based on the ISCEV standard for clinical ffERG. Reduction in retraction and amplitude recovery from baseline by 2 days was compared in the treated versus the fellow untreated eye by a paired t-test.
Morphological analysis of retina from the treated and control eyes showed reduced retraction of rod terminals into the ONL in the AR-13503-treated eyes by 34% (p<0.05, n=5 pigs). ERG analysis indicated improved rod-specific scotopic responses in the drug-treated eyes compared to the BSS-treated eyes by 46% (p<0.05, n=5 pigs). Additionally, our data suggested a correlation between the morphological rescue of rod cells and improved scotopic function.
The structural and functional outcomes of iatrogenic detachments were improved by a single injection of AR-13503 during the surgical creation of a retinal detachment. This treatment may be useful to improve procedures such as gene therapy or stem cell transplantation that use a subretinal approach. Moreover, ROCK inhibition may be successful more broadly in improving repair of detached retina.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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