Visual recovery after repair of a retinal detachment is often disappointing with more than half of treated patients reporting below normal visual acuity. Retinal neurons undergo dramatic structural plasticity after detachment including retraction of rod axons, rounding of cone terminals, and sprouting by bipolar and horizontal cells. Some of these changes occur within hours after retinal injury in animal models. It has been suggested that this synaptic remodeling contributes to poor visual recovery. In retinal cell cultures, activation of the RhoA-Rho kinase (ROCK) signaling cascade is primarily responsible for rod axon retraction. Thus, this application tests the hypothesis that a combined therapy of RhoA-antagonists and retinal surgery may significantly improve the visual outcome after repair of a detached retina by preventing or reducing synaptic plasticity. This hypothesis will be tested on adult pigs, whose eyes are similar to human eyes, focusing on the following specific aims: 1) To test whether RhoA antagonists which inhibit the activity of RhoA, ROCK, or their substrates will prevent the structural synaptic changes caused by detachment including rod axon retraction, rod-bipolar synaptic dissolution, cone terminal morphological change, and bipolar cell sprouting. The effect on glial cell reactivity will also be examined; 2) To determine whether RhoA-related drugs can be applied after a detachment, a more therapeutically relevant scenario, and if so, how long after the injury; and 3) To determine if detached retinas treated with RhoA-related drugs indeed help visual structural and functional recovery after reattachment surgery. Morphology will be assessed by immunohistochemistry, image analysis and confocal laser scanning and electron microscopy. Levels of activity and the time-course of Rho signaling will be determined by biochemical assays for multiple components including RhoA activation and myosin light chain phosphorylation. Retinal function after reattachment will be assessed by electroretinograms. Some of the drugs that will be tested (Ct-04 and fasudil) have already been approved for human use. We hope to establish the approximate dosage and mode of application to be tested in patients, if RhoA antagonists prove to be a useful adjunct to surgical reattachment.

Public Health Relevance

Visual outcomes after repair of retinal detachment remain disappointing even years after successful reattachment surgery. Based on the effectiveness of preventing deleterious photoreceptor synaptic change, in vitro, a new therapy is proposed for retinal detachment. The therapy consists of intraocular application of RhoA antagonists combined with relatively rapid retinal reattachment.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDPE-N (09))
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Neuhold, Lisa
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Rutgers University
Schools of Medicine
United States
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Townes-Anderson, Ellen; Wang, Jianfeng; Halász, Éva et al. (2017) Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment. Transl Vis Sci Technol 6:22
Kung, Frank; Wang, Weiwei; Tran, Tracy S et al. (2017) Sema3A Reduces Sprouting of Adult Rod Photoreceptors In Vitro. Invest Ophthalmol Vis Sci 58:4318–4331
Townes-Anderson, Ellen; Sugino, Ilene; Zarbin, Marco (2017) Using Rho Kinase Inhibitors for Retinal Detachment. JAMA Ophthalmol 135:895
Wang, Weiwei; Townes-Anderson, Ellen (2016) Lim kinase, a bi-functional effector in injury-induced structural plasticity of synapses. Neural Regen Res 11:1029-32
Wang, Jianfeng; Zarbin, Marco; Sugino, Ilene et al. (2016) RhoA Signaling and Synaptic Damage Occur Within Hours in a Live Pig Model of CNS Injury, Retinal Detachment. Invest Ophthalmol Vis Sci 57:3892-906
Wang, Weiwei; Townes-Anderson, Ellen (2015) LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury. Invest Ophthalmol Vis Sci 56:7847-58