scholarly journals Ocular safety assessment of sodium iodate in cynomolgus monkeys

2017 ◽  
Vol 1 ◽  
pp. 239784731769637 ◽  
Author(s):  
Chang-Ning Liu ◽  
Qinghai Peng ◽  
David W Yates ◽  
Wenhu Huang ◽  
Heather Devantier ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Cell Function ◽  
Retinal Pigment ◽  
Vehicle Control ◽  
Retinal Toxicity ◽  
Circulating Microrna ◽  
Large Animal ◽  
Sodium Iodate ◽  
Cynomolgus Monkeys ◽  
Functional Changes

Although sodium iodate (NaIO3)-induced retinal injury model has been widely used in rodents, its application in large animal species has encountered variation in retinal toxicity. NaIO3 induced retinal degeneration and functional changes in sheep, but not in swine. In monkeys, administration of NaIO3 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 NaIO3 administration resulting in morphologic and functional retinal changes in cynomolgus monkeys. Separate groups of animals received NaIO3 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 a-wave and scotopic and photopic b-wave signals ( p < 0.05) were observed between the ERG signals acquired from NaIO3-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 NaIO3 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.

scholarly journals Retinal degeneration rat model: A study on the structural and functional changes in the retina following injection of sodium iodate

2019 ◽  
Vol 196 ◽  
pp. 111514 ◽  
Author(s):  
Avin Ee-Hwan Koh ◽  
Hiba Amer Alsaeedi ◽  
Munirah binti Abd Rashid ◽  
Chenshen Lam ◽  
Mohd Hairul Nizam Harun ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Rat Model ◽  
Sodium Iodate ◽  
Functional Changes

Intravitreal Administration of Acetyl Triethyl Citrate and Benzyl Benzoate Is Retinotoxic in Rabbits but Not in Cynomolgus Monkeys

2020 ◽  
pp. 019262332097157
Author(s):  
Roxanne Andaya ◽  
Helen Booler ◽  
Denise de Almeida Nagata ◽  
Chris Lawson ◽  
Jennifer Vogt ◽  
...  
Keyword(s):  
Retinal Pigment ◽  
Safety Data ◽  
Retinal Toxicity ◽  
Retinal Pigment Epithelial Cells ◽  
Benzyl Benzoate ◽  
Dose Frequency ◽  
Cynomolgus Monkeys ◽  
Triethyl Citrate

Sustained drug delivery formulations are developed to reduce dose frequency while maintaining efficacy of intravitreal (ITV) administered therapeutics. Available safety data for components novel to the eye’s posterior segment may be limited, requiring preclinical assessments to identify potential toxicities. We evaluated the in vivo and in vitro safety of two solvents, acetyl triethyl citrate (ATEC) and benzyl benzoate (BB), as novel sustained delivery formulations for ITV administration. In vivo tolerability was assessed following ITV administration of ATEC and BB to rabbits and cynomolgus monkeys. In rabbits, ITV solvent administration resulted in moderate to severe retinal toxicity characterized by focal retinal necrosis and/or degeneration, sometimes accompanied by inflammation, with a clear association between the physical presence of the solvent and areas of retinal damage. In contrast, solvent administration in monkeys appeared well tolerated, producing no histologic abnormalities. Toxicity in primary human retinal pigment epithelial cells, characterized by cellular toxicity and mitochondrial injury, corroborated the retinal toxicity in rabbits. In conclusion, ITV solvent depots of ATEC or BB result in chemical and focal retinal toxicity in rabbits, but not monkeys. Additional investigation is needed to demonstrate a sufficient margin of safety prior to use of ATEC or BB in ITV drug products.

scholarly journals An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease

2018 ◽  
Author(s):  
Suvi Mäkeläinen ◽  
Marta Gòdia ◽  
Minas Hellsand ◽  
Agnese Viluma ◽  
Daniela Hahn ◽  
...  
Keyword(s):  
Visual Impairment ◽  
Retinal Degeneration ◽  
Autosomal Recessive ◽  
Retinal Pigment ◽  
Clinical Signs ◽  
Premature Stop Codon ◽  
Large Animal ◽  
Loss Of Function ◽  
Stargardt Disease ◽  
Abca4 Gene

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in humans and dogs. Currently, no standard treatment is available but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs1395) was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium. The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.

scholarly journals Establishment of a Rapid Lesion-Controllable Retinal Degeneration Monkey Model for Preclinical Stem Cell Therapy

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2468
Author(s):  
Guanjie Gao ◽  
Liwen He ◽  
Shengxu Liu ◽  
Dandan Zheng ◽  
Xiaojing Song ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Therapy ◽  
Retinal Degeneration ◽  
Stem Cell Therapy ◽  
Structural Changes ◽  
Pigment Epithelium ◽  
Outer Nuclear Layer ◽  
Retinal Pigment ◽  
Functional Changes ◽  
Monkey Model

Background: Retinal degenerative disorders (RDs) are the main cause of blindness without curable treatment. Our previous studies have demonstrated that human-induced pluripotent stem cells can differentiate into retinal organoids with all subtypes of retina, which provides huge promise for treating these diseases. Before these methods can be realized, RD animal models are required to evaluate the safety and efficacy of stem cell therapy and to develop the surgical tools and procedures for cell transplantation in patients. This study involved the development of a monkey model of RD with controllable lesion sites, which can be rapidly prepared for the study of preclinical stem cell therapy among other applications. Methods: Sodium nitroprusside (SNP) in three doses was delivered into the monkey eye by subretinal injection (SI), and normal saline was applied as control. Structural and functional changes of the retinas were evaluated via multimodal imaging techniques and multifocal electroretinography (mfERG) before and after the treatment. Histological examination was performed to identify the target layer of the affected retina. The health status of monkeys was monitored during the experiment. Results: Well-defined lesions with various degrees of retinal degeneration were induced at the posterior pole of retina as early as 7 days after SNP SI. The damage of SNP was dose dependent. In general, 0.05 mM SNP caused mild structural changes in the retina; 0.1 mM SNP led to the loss of outer retinal layers, including the outer plexiform layer (OPL), outer nuclear layer (ONL), and retinal pigment epithelium (RPE); while 0.2 mM SNP impacted the entire layer of the retina and choroid. MfERG showed reduced amplitude in the damaged region. The structural and functional damages were not recovered at 7-month follow-up. Conclusion: A rapidly induced lesion site-controllable retinal degeneration monkey model was established by the subretinal administration of SNP, of which the optimal dose is 0.1 mM. This monkey model mimics the histological changes of advanced RDs and provides a valuable platform for preclinical assessment of stem cell therapy for RDs.

scholarly journals Protection of Kaempferol on Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Weiwei Du ◽  
Yuanlong An ◽  
Xiangdong He ◽  
Donglei Zhang ◽  
Wei He
Keyword(s):  
Oxidative Stress ◽  
Retinal Degeneration ◽  
Cell Damage ◽  
Retinal Pigment Epithelial Cell ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Sodium Iodate ◽  
Rpe Cells ◽  
Age Related

The protection of retinal pigment epithelium (RPE) injury plays an important role in the prevention of or in delaying the pathological progress of retinal degeneration diseases, like age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa. Oxidative stress has been identified as a major inducer of RPE injury, which eventually could lead to a loss of vision. Kaempferol is a natural flavonoid widely distributed in many edible plants, fruits, and traditional medicines and has been reported to have antioxidant, anti-inflammatory, anticancer, and antimicrobial activities. The present study demonstrates that the total antioxidant capacity of kaempferol is approximately two times stronger than that of lutein which is also a natural antioxidant that is widely used in the prevention or treatment of AMD. Our data indicates that kaempferol protects human RPE cells (ARPE-19) from hydrogen peroxide- (H2O2-) induced oxidative cell damage and apoptosis through the signaling pathways involving Bax/Bcl-2 and caspase-3 molecules proofed by real-time PCR and Western blot results. Kaempferol also inhibits the upregulated vascular endothelial growth factor (VEGF) mRNA expression levels induced by H2O2 in ARPE-19 cells and affects the oxidation and antioxidant imbalanced system in ARPE-19 cells treated by H2O2 through the regulations of both the activities of reactive oxygen species (ROS) and superoxide dismutase (SOD). Furthermore, our in vivo experimental results show that in sodium iodate-induced retinal degeneration rat model, kaempferol could protect sodium iodate-induced pathological changes of retina tissue and retinal cells apoptosis as well as the upregulated VEGF protein expression in RPE cells. In summary, these novel findings demonstrate that kaempferol could protect oxidative stressed-human RPE cell damage through its antioxidant activity and antiapoptosis function, suggesting that kaempferol has a potential role in the prevention and therapeutic treatment of AMD or other retinal diseases mediated by oxidative stress.

scholarly journals Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina

2021 ◽  
Vol 22 (17) ◽  
pp. 9218
Author(s):  
Anne Enzbrenner ◽  
Rahel Zulliger ◽  
Josef Biber ◽  
Ana Maria Quintela Pousa ◽  
Nicole Schäfer ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Mouse Serum ◽  
Sodium Iodate ◽  
Complement Components ◽  
Age Related ◽  
Inflammatory Processes

Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been progress in the treatments for the neovascular form of AMD, no therapy is yet available for the more common dry form, also known as geographic atrophy. We analysed the retinal tissue in a mouse model of retinal degeneration caused by sodium iodate (NaIO3)-induced retinal pigment epithelium (RPE) atrophy to understand the underlying pathology. RNA sequencing (RNA-seq), qRT-PCR, Western blot, immunohistochemistry of the retinas and multiplex ELISA of the mouse serum were applied to find the pathways involved in the degeneration. NaIO3 caused patchy RPE loss and thinning of the photoreceptor layer. This was accompanied by the increased retinal expression of complement components c1s, c3, c4, cfb and cfh. C1s, C3, CFH and CFB were complement proteins, with enhanced deposition at day 3. C4 was upregulated in retinal degeneration at day 10. Consistently, the transcript levels of proinflammatory ccl-2, -3, -5, il-1β, il-33 and tgf-β were increased in the retinas of NaIO3 mice, but vegf-a mRNA was reduced. Macrophages, microglia and gliotic Müller cells could be a cellular source for local retinal inflammatory changes in the NaIO3 retina. Systemic complement and cytokines/chemokines remained unaltered in this model of NaIO3-dependent retinal degeneration. In conclusion, systemically administered NaIO3 promotes degenerative and inflammatory processes in the retina, which can mimic the hallmarks of geographic atrophy.

scholarly journals Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 159
Author(s):  
Hao-Yu Tsai ◽  
Henkie Isahwan Ahmad Mulyadi Lai ◽  
Zhang-Yuan Chen ◽  
Tai-Chi Lin ◽  
Winnie Khor ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Autophagic Flux ◽  
Erk Pathway ◽  
Sodium Iodate ◽  
Autophagy Flux

Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase (ERK) pathway. However, the complex interplay between DUSP6 and autophagy induced by ROS in RPE is yet to be investigated. To investigate the relationship between DUSP6 and autophagy, we exposed the ARPE-19 cell line and C57BL/6N mice to sodium iodate (NaIO3) as an oxidative stress inducer. Our data showed that the inhibition of DUSP6 activity promotes autophagy flux through the ERK pathway via the upregulation of immunoblotting expression in ARPE-19 cells. Live imaging showed a significant increase in autophagic flux activities, which suggested the restoration autophagy after treatment with the DUSP6 inhibitor. Furthermore, the mouse RPE layer exhibited an irregular structure and abnormal deposits following NaIO3 injection. The retina layer was recovered after being treated with DUSP6 inhibitor; this suggests that DUSP6 inhibitor can rescue retinal damage by restoring the mouse retina’s autophagy flux. This study suggests that the upregulation of DUSP6 can cause autophagy flux malfunctions in the RPE. The DUSP6 inhibitor can restore autophagy induction, which may serve as a potential therapeutic approach for retinal degeneration disease.

High-voltage electron microscopy of subretinal scar formation

1992 ◽  
Vol 50 (1) ◽  
pp. 486-487
Author(s):  
G.E. Korte ◽  
M. Marko ◽  
G. Hageman
Keyword(s):  
Electron Microscopy ◽  
Monoclonal Antibody ◽  
Retinal Pigment Epithelium ◽  
Glial Cells ◽  
High Voltage ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Sodium Iodate ◽  
High Voltage Electron Microscopy ◽  
Voltage Electron

Sodium iodate iv. damages the retinal pigment epithelium (RPE) in rabbits. Where RPE does not regenerate (e.g., 1,2) Muller glial cells (MC) forma subretinal scar that replaces RPE. The MC response was studied by HVEM in 3D computer reconstructions of serial thick sections, made using the STEREC0N program (3), and the HVEM at the NYS Dept. of Health in Albany, NY. Tissue was processed for HVEM or immunofluorescence localization of a monoclonal antibody recognizing MG microvilli (4).

scholarly journals The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 64
Author(s):  
Annamaria Tisi ◽  
Marco Feligioni ◽  
Maurizio Passacantando ◽  
Marco Ciancaglini ◽  
Rita Maccarone
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Blood Retinal Barrier ◽  
Functional Changes ◽  
Beneficial Effects ◽  
Age Related ◽  
The Impact

The blood retinal barrier (BRB) is a fundamental eye component, whose function is to select the flow of molecules from the blood to the retina and vice-versa, and its integrity allows the maintenance of a finely regulated microenvironment. The outer BRB, composed by the choriocapillaris, the Bruch’s membrane, and the retinal pigment epithelium, undergoes structural and functional changes in age-related macular degeneration (AMD), the leading cause of blindness worldwide. BRB alterations lead to retinal dysfunction and neurodegeneration. Several risk factors have been associated with AMD onset in the past decades and oxidative stress is widely recognized as a key factor, even if the exact AMD pathophysiology has not been exactly elucidated yet. The present review describes the BRB physiology, the BRB changes occurring in AMD, the role of oxidative stress in AMD with a focus on the outer BRB structures. Moreover, we propose the use of cerium oxide nanoparticles as a new powerful anti-oxidant agent to combat AMD, based on the relevant existing data which demonstrated their beneficial effects in protecting the outer BRB in animal models of AMD.

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