Combined cSLO-OCT imaging as a tool in preclinical ocular toxicity testing: A comparison to standard in-vivo and pathology methods

Soukup, Petr; Lenz, Barbara; Altmann, Bernd; Badillo, Solveig; Atzpodien, Elke-Astrid; Pot, Simon A.

doi:10.1016/j.vascn.2020.106873

Cited by 6 publications

(8 citation statements)

References 27 publications

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“…71,72 Confocal scanning laser ophthalmoscopy is useful for an en face fundus reflectance image of the outer retina and retinal pigment epithelium and has shown utility in nonrodents. 73,74 Confocal scanning laser ophthalmoscopy combined with OCT (cSLO-OCT) has been shown to improve toxicity readouts and facilitate longitudinal examination of single animals at multiple time points in rats 59,75 ; therefore, combined cSLO-OCT to enable location of retinal changes and then structural lesion evaluation in cross sections has promise in ocular toxicity studies in nonrodents as well. The cSLO-guided OCT also has the potential to assist navigation to area of interest in tissue blocks prepared for histology, and facilitation of longitudinal examination of single animals at multiple time points can lead to a marked reduction of animals in ocular toxicity studies according to the 3R principles.…”

Section: Ocular In-life Parametersmentioning

confidence: 99%

“…The cSLO-guided OCT also has the potential to assist navigation to area of interest in tissue blocks prepared for histology, and facilitation of longitudinal examination of single animals at multiple time points can lead to a marked reduction of animals in ocular toxicity studies according to the 3R principles. 75…”

Section: Ocular In-life Parametersmentioning

confidence: 99%

“…For pivotal ocular toxicity studies with NME or ocular drug product reformulations approved by another route, microscopic evaluation of a full systemic organ/tissue list is usually conducted on control and high-dose main study animals, with evaluation of target organs in intermediate groups, if present. As discussed previously, FDA's reformulation guidance 75 states that if systemic exposure from an ocular drug product reformulation has systemic exposure that is equivalent or less than that of an approved route, and there are no novel excipient concerns, microscopic evaluation may be limited to the eye and extraocular tissues. For this case, it is still advised to collect and retain a full systemic tissue list in case there are systemic effects or to address potential regulatory concerns.…”

Section: Ocular Toxicity Studies: Pathology Parameters and Proceduresmentioning

confidence: 99%

“…For gene and cell therapy ocular toxicity studies, special pathology procedures in ocular sections such as in immunohistochemistry for target protein and/or situ hybridization to identify the target gene or cell transfer in the eye is commonly conducted, along with other specialized immunological techniques such as lymph node immunophenotyping. 75…”

Section: Eye Fixation Trimming and Sectioningmentioning

confidence: 99%

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Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant’s Perspective

Short¹

2020

Toxicol Pathol

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Ocular toxicity studies are the bedrock of nonclinical ocular drug and drug–device development, and there has been an evolution in experience, technologies, and challenges to address that ensures safe clinical trials and marketing authorization. The expectations of a well-designed ocular toxicity study and the generation of a coherent, integrative ocular toxicology report and subreports are high, and this article provides a pathology/toxicology consultant’s perspective on achieving that goal. The first objective is to cover selected aspects of study designs for ocular toxicity studies including considerations for contract research organization selection, minipig species selection, unilateral versus bilateral dosing, and in-life parameters based on fit-for-purpose study objectives. The main objective is a focus on a high-quality ocular pathology report that includes ocular histology procedures to meet regulatory expectations and a report narrative and tables that correlate microscopic findings with key ophthalmic findings and presents a clear interpretation of test article-, vehicle-, and procedure-related ocular and extraocular findings with identification of adversity and a pathology peer review. The last objective covers considerations for a high-quality ophthalmology report, which in concert with a high-quality pathology report, will pave the way for a best quality toxicology report for an ocular toxicity study.

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Section: Ocular In-life Parametersmentioning

confidence: 99%

Section: Ocular In-life Parametersmentioning

confidence: 99%

Section: Ocular Toxicity Studies: Pathology Parameters and Proceduresmentioning

confidence: 99%

Section: Eye Fixation Trimming and Sectioningmentioning

confidence: 99%

See 2 more Smart Citations

Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant’s Perspective

Short¹

2020

Toxicol Pathol

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“…Despite this, OCT has become more popular as a screening tool that enables retinal structural assessment at multiple time points without needing several cohorts of animals to gather the same data using histopathology. 3 Optical coherence tomography is also used in non-GLP discovery research applications, with or without other biomarkers and in humans in both clinical research and practice. Additional benefits of OCT include the evaluation of retinal morphology without artifacts associated with tissue fixation and sectioning, the ability to develop treatment interventions for visualized abnormalities and track their progress over time, and to guide trimming and sectioning of globes in order to capture specific regions of interest for histological analysis.…”

Section: Introductionmentioning

confidence: 99%

Correlations Between Retinal Optical Coherence Tomography and Histopathology in Preclinical Safety Assessment of Ocular Therapies

2021

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Optical coherence tomography (OCT) is a valuable noninvasive imaging tool that may be used to help evaluate the structural integrity of the retina and pharmacological or toxicological drug effects at multiple time points in preclinical toxicological studies. Although ocular histopathology is still considered the gold standard for assessment of retinal morphology, OCT provides enhanced in vivo monitoring of ocular structures and may be used to guide tissue trimming and the interpretation of histopathological changes. Methods: Twelve studies that involved intravitreal or subretinal test article administration in multiple laboratory animal species and employed both OCT and histopathologic assessment were identified. These data were compared to determine the degree of correlation for each identified abnormality. Results: Severity of observed OCT and histopathological changes ranged from minimal to severe, with moderate and severe changes having a higher rate of agreement between the 2 techniques. Changes to well-defined structures, including the retinal blood vessels, optic nerve, and retinal pigment epithelium, also showed a strong correlation. Conclusions: There was a strong correlation between OCT and histopathology in both intravitreal and subretinal injection studies, demonstrating the value of collaboration between the study ophthalmologist and pathologist and offering translatable means to monitor pharmacological or toxicological effects in preclinical toxicological studies.

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Multiorgan Crystal Deposition of an Amphoteric Drug in Rats Due to Lysosomal Accumulation and Conversion to a Poorly Soluble Hydrochloride Salt

Lenz

Brink

Mihatsch

et al. 2021

Toxicological Sciences

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Poor solubility of drug candidates mainly affects bioavailability, but poor solubility of drugs and metabolites can also lead to precipitation within tissues, particularly when high doses are tested. RO0728617 is an amphoteric compound bearing basic and acidic moieties that has previously demonstrated good solubility at physiological pH but underwent widespread crystal deposition in multiple tissues in rat toxicity studies. The aim of our investigation was to better characterize these findings and their underlying mechanism(s), and to identify possible screening methods in the drug development process. Main microscopic features observed in rat RO0728617 toxicity studies were extensive infiltrates of crystal-containing macrophages in multiple organs. Matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance (MALDI-FTICR) mass spectrometry revealed that these crystals contained the orally administered parent compound, and locality was confirmed to be intra-cytoplasmic and partly intra-lysosomal by electron microscopic examination. Crystal formation was explained by lysosomal accumulation of the compound followed by precipitation of the hydrochloride salt under physiological conditions in the lysosomes, which have a lower pH and higher chloride concentration in comparison to the cytosol. This study demonstrates that risk of drug precipitation can be assessed by comparing the estimated lysosomal drug concentration at a given dose with the solubility of the compound at lysosomal conditions.

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Combined cSLO-OCT imaging as a tool in preclinical ocular toxicity testing: A comparison to standard in-vivo and pathology methods

Cited by 6 publications

References 27 publications

Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant’s Perspective

Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology Reports: A Pathology/Toxicology Consultant’s Perspective

Correlations Between Retinal Optical Coherence Tomography and Histopathology in Preclinical Safety Assessment of Ocular Therapies

Multiorgan Crystal Deposition of an Amphoteric Drug in Rats Due to Lysosomal Accumulation and Conversion to a Poorly Soluble Hydrochloride Salt

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