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Zsolt Ablonczy, Samantha Niles, Christopher Schillo, Madhoo Patil, Sora Im, Kee Min Woo, Harold Patterson, Woo Jin Park; CCN5 gene delivery is beneficial in a sodium-iodate challenge model of dry age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4610 – F0402.
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Loss of vision in severe dry age-related macular degeneration (AMD) is secondary to retinal pigment epithelium and photoreceptor damage. The CCN family of matricellular proteins are key signaling molecules involved in many vital biological functions, including cell proliferation, angiogenesis, fibrosis, and wound healing. Recently, it has been shown that CCN5 (WISP-2) is efficacious in a laser induced choroidal neovascularization model. This is the first study assessing the efficacy of CCN5 gene delivery in a rat sodium-iodate challenge model.
Brown-Norway rats received a single 5 µL intravitreal or subretinal of either AAV2-GFP (5*1010 vg/eye) or AAV2-CCN5 in two doses (1*1010 or 5*1010 vg/eye). Naïve animals and intravitreally-delivered Met12 peptide (50 µg/eye) served as control. Sodium-iodate (NaIO3) was injected intravenously 3 weeks following AAV injections. Electroretinography (ERG), fundus imaging, autofluorescence, and optical coherence tomography (OCT) was used to evaluate the condition of the injected eyes for up to 4 weeks after sodium-iodate challenge. At the conclusion of the study, eyes were collected for histology. Data were expressed as means ± SEM and analyzed using one-way ANOVA.
No significant changes, other than the uniform expression of GFP across the retina in the AAV2-GFP group, was observed between AAV injection and NaIO3 challenge. After NaIO3 administration, lesions appeared on fundus images and on OCT in a week, and increasingly worsened till the end of the study in the AAV2-GFP group and ERG amplitudes gradually decreased for up to 50% of naive animals by day 28. In contrast, the high dose AAV2-CCN5 group performed just as well as naïve. The low dose AAV2-CCN5 group performed slightly but not significantly worse than the high dose group. Results with subretinally- or intravitreally-delivered AAV2-CCN5 were not significantly different in any applicable groups.
NaIO3 challenge can reaibly induce RPE and photoreceptor loss and is considered to model these dry-AMD symptoms. Our study demonstrated that AAV-mediated delivery of CCN5 to the retina was tolerable and equally beneficial for protecting against damage induced by NaIO3. These results pave the way to begin to utilize intravitreally- or subretinally-delivered CCN5 therapy for the treatment of severe dry-AMD and geographic atrophy.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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