Direct Effect of Sodium Iodate on Neurosensory Retina

Wang, Jinmei; Iacovelli, Jared; Spencer, Carrie; Saint‐Geniez, Magali

doi:10.1167/iovs.13-13075

Cited by 122 publications

(140 citation statements)

References 37 publications

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“…[15][16][17] In these studies, the toxin was administered systemically resulting in patchy panretinal degeneration. To better mimic clinical GA we sought to explore subretinal administration of NaIO 3 .…”

Section: Resultsmentioning

confidence: 99%

“…These results essentially confirmed previous observations using systemically administered NaIO 3 , for which the morphologic and molecular effects have been characterized extensively in rabbit and rodent models. [15][16][17] Early ultrastructural studies in rabbit demonstrated the first retinal changes to occur in the RPE already after 7 to 10 hours with subsequent photoreceptor swelling and degeneration. 15 Later studies have shown that lower doses of NaIO 3 cause patchy RPE loss whereas higher doses lead to widespread RPE loss within 1 week.…”

Section: Discussionmentioning

confidence: 99%

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Integration of Subretinal Suspension Transplants of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in a Large-Eyed Model of Geographic Atrophy

Petrus‐Reurer

Bartuma

Aronsson

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Subretinal suspension transplants of human embryonic stem cell-derived retinal pigment epithelial cells (hESC-RPE) have the capacity to form functional monolayers in naive eyes. We explore hESC-RPE integration when transplanted in suspension to a large-eyed model of geographic atrophy (GA).METHODS. Derivation of hESC-RPE was performed in a xeno-free and defined manner. Subretinal bleb injection of PBS or sodium iodate (NaIO 3 ) was used to induce a GA-like phenotype. Suspensions of hESC-RPE were transplanted to the subretinal space of naive or PBS-/NaIO 3 -treated rabbits using a transvitreal pars plana technique. Integration of hESC-RPE was monitored by multimodal real-time imaging and by immunohistochemistry.RESULTS. Subretinal blebs of PBS or NaIO 3 caused different degrees of outer neuroretinal degeneration, RPE hyperautofluorescence, focal RPE loss, and choroidal atrophy; that is, hallmark characteristics of GA. In nonpretreated naive eyes, hESC-RPE integrated as subretinal monolayers with preserved overlying photoreceptors, yet not in areas with outer neuroretinal degeneration and native RPE loss. When transplanted to eyes with PBS-/NaIO 3 -induced degeneration, hESC-RPE failed to integrate. CONCLUSIONS.In a large-eyed preclinical model, subretinal suspension transplants of hESC-RPE did not integrate in areas with GA-like degeneration.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integration of Subretinal Suspension Transplants of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in a Large-Eyed Model of Geographic Atrophy

Petrus‐Reurer

Bartuma

Aronsson

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…13 Whether or not primary damage occurs in additional retinal structures is still a matter of debate. [14][15][16] However, because it allows controlled onset and progression (for instance, induction in an adult animal), this model may provide benefit for studying novel modalities for treatment of retinal degeneration caused by RPE dysfunction beyond the genetic models that are often used for this purpose.…”

mentioning

confidence: 99%

Course of Sodium Iodate–Induced Retinal Degeneration in Albino and Pigmented Mice

Chowers

Cohen

Marks-Ohana

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To characterize the course of sodium iodate (SI)-induced retinal degeneration in young adult albino and pigmented mice. (25, 50, and 100 mg/kg) were performed in 7-to 8-week-old BALB/c and C57Bl/6J mice. Retinal function and structure was assessed at baseline, 24 hours, 3 days, 1, 2, 3, and 4 weeks postinjection by optokinetic tracking response, ERG, optical coherence tomography (OCT), and histologic and immunohistochemical techniques. METHODS. Single intraperitoneal (IP) injections of SI RESULTS.The 50 mg/kg SI dosage was selected after dose ranging due to consistent retinal effects and lack of systemic toxicity. Time-dependent deterioration in retinal function and morphology was consistently observed between 1 and 4 weeks in all measured parameters. These include reduction of ERG responses, thinning of retinal layers as observed by OCT and histology, and loss of RPE nuclei. Immunohistochemistry revealed rapid RPE disorganization with loss of tight junctions and markedly reduced expression of RPE65 and rod opsin, accompanied by mislocalization of cone opsins. Earlier time points displayed variable results, including partial recovery of visual acuity at 1 week and supranormal ERG cone responses at 24 hours, suggesting possible limitations of early intervention and assessment in the SI model. CONCLUSIONS.A single IP injection of 50 mg/kg SI leads to severe RPE injury followed by vision impairment, dysfunction, and loss of photoreceptors in both BALB/c and C57Bl/6J mice. This easily induced and reproducible noninherited model may serve as a useful tool for seeking and evaluating novel therapeutic modalities for the treatment of retinal degenerations caused by primary failure of the RPE.Keywords: sodium iodate, RPE toxicity, retinal degeneration, mouse model D iseases such as AMD, Best disease, and subtypes of retinitis pigmentosa RP are major causes of visual disability. 1 In these diseases, primary dysfunction, degeneration, and loss of the RPE ultimately results in secondary death of photoreceptors, leading to visual loss. [2][3][4] Despite certain progress in the treatment of retinal degeneration, it remains an essentially irreversible process in which many patients eventually lose their sight. Animal models provide an invaluable tool for searching and testing of novel therapeutic modalities. Animals carrying natural mutations (usually in one gene) provide well-established models for inherited retinal diseases. 5,6 However, the pathogenesis of multifactorial retinal degenerations such as AMD involves complex genetic and environmental factors, leading to expression of disease at older ages. 7 The majority of geneticallyinherited animal models of ocular disease do not entirely mimic such conditions because of early disease onset and progression. 8 Regardless of etiology, maintaining proper RPE function is a major therapeutic target in these diseases, and currently pharmaceutical, genetic, and cellular approaches are being tested to this end in a variety of in vitro and in vivo models, as well as in clini...

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“…25 Our hypothesis stated that the increased miR-183 cluster in the circulating blood was due to the leakage of RPE and Bruch's membrane by NaIO 3 toxicity. There is a possibility that cells of the neurosensory retina (ganglion cell, amacrine, or horizontal cells) 45 and photoreceptors 46 may also be directly involved in NaIO 3 -mediated toxicity. To date, this is the first report describing the plasma miRNA profile in a nonhuman primate in response to toxic doses of intravenously administered NaIO 3 , therefore the translatability of the nonhuman primate data to the human as well as the neuronal/ neurotrophic factor pathways associated with the neuronal retina injury remains to be explored in future research.…”

Section: Discussionmentioning

confidence: 99%

Ocular safety assessment of sodium iodate in cynomolgus monkeys

Liu

Peng

Yates

et al. 2017

Toxicology Research and Application

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Although sodium iodate (NaIO 3 )-induced retinal injury model has been widely used in rodents, its application in large animal species has encountered variation in retinal toxicity. NaIO 3 induced retinal degeneration and functional changes in sheep, but not in swine. In monkeys, administration of NaIO 3 via a carotid artery affected only the cell function of ipsilateral retinal pigment epithelium. The aim of the present study was to identify the dosage and route of NaIO 3 administration resulting in morphologic and functional retinal changes in cynomolgus monkeys. Separate groups of animals received NaIO 3 intravenously in three different dosing paradigms. Vehicle control animals received phosphate-buffered saline. At selected time points following dosing, flash electroretinograms (ERGs) were recorded followed by necropsy. The eyes were examined microscopically post-necropsy and the levels of circulating microRNA-183 cluster were evaluated in the blood samples collected on days 1, 4, and 5 postdose. A statistically significant reduction in both scotopic awave and scotopic and photopic b-wave signals (p < 0.05) were observed between the ERG signals acquired from NaIO 3 -treated and vehicle control animals, coupled with time-dependent elevations in plasma miR-183 cluster. Mild to moderate retinal degeneration was observed in the outer layer of the retina, which correlated well with the functional and clinical observations. There were no statistically significant differences in scotopic oscillatory potentials. These findings suggest that intravenous injection of sublethal NaIO 3 markedly damaged the cone and rod photoreceptors both functionally and morphologically, and plasma miR-183 reflected the retinal toxicity in those animals with moderate retinal damage.

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Direct Effect of Sodium Iodate on Neurosensory Retina

Cited by 122 publications

References 37 publications

Integration of Subretinal Suspension Transplants of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in a Large-Eyed Model of Geographic Atrophy

Integration of Subretinal Suspension Transplants of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in a Large-Eyed Model of Geographic Atrophy

Course of Sodium Iodate–Induced Retinal Degeneration in Albino and Pigmented Mice

Ocular safety assessment of sodium iodate in cynomolgus monkeys

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