Ebola virus-induced eye sequelae: a murine model for evaluating glycoprotein-targeting therapeuticsResearch in context

Ha-Na Lee; Biying Xu; Aaron P. Lewkowicz; Kaliroi Engel; Logan Kelley-Baker; Ian L. McWilliams; Derek D.C. Ireland; Jennifer L. Kielczewski; Jinbo Li; Robert N. Fariss; Mercedes M. Campos; Alina Baum; Christos Kyratsous; Kristen Pascal; Chi-Chao Chan; Rachel R. Caspi; Mohanraj Manangeeswaran; Daniela Verthelyi

EBioMedicine (Jun 2024)

Ebola virus-induced eye sequelae: a murine model for evaluating glycoprotein-targeting therapeuticsResearch in context

Ha-Na Lee,
Biying Xu,
Aaron P. Lewkowicz,
Kaliroi Engel,
Logan Kelley-Baker,
Ian L. McWilliams,
Derek D.C. Ireland,
Jennifer L. Kielczewski,
Jinbo Li,
Robert N. Fariss,
Mercedes M. Campos,
Alina Baum,
Christos Kyratsous,
Kristen Pascal,
Chi-Chao Chan,
Rachel R. Caspi,
Mohanraj Manangeeswaran,
Daniela Verthelyi

Affiliations

Ha-Na Lee: Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Biying Xu: Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Aaron P. Lewkowicz: Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Kaliroi Engel: Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Logan Kelley-Baker: Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Ian L. McWilliams: Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Derek D.C. Ireland: Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Jennifer L. Kielczewski: Biological Imaging Core, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Jinbo Li: Biological Imaging Core, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Robert N. Fariss: Biological Imaging Core, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Mercedes M. Campos: Biological Imaging Core, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Alina Baum: Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
Christos Kyratsous: Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
Kristen Pascal: Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA
Chi-Chao Chan: Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Rachel R. Caspi: Laboratory of Immunology, National Eye Institute, NIH, Bethesda, MD, 20892, USA
Mohanraj Manangeeswaran: Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
Daniela Verthelyi: Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA; Corresponding author.

Journal volume & issue: Vol. 104
p. 105170

Abstract

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Summary: Background: Ebola virus disease (EVD) survivors experience ocular sequelae including retinal lesions, cataracts, and vision loss. While monoclonal antibodies targeting the Ebola virus glycoprotein (EBOV-GP) have shown promise in improving prognosis, their effectiveness in mitigating ocular sequelae remains uncertain. Methods: We developed and characterized a BSL-2-compatible immunocompetent mouse model to evaluate therapeutics targeting EBOV-GP by inoculating neonatal mice with vesicular stomatitis virus expressing EBOV-GP (VSV-EBOV). To examine the impact of anti-EBOV-GP antibody treatment on acute retinitis and ocular sequelae, VSV-EBOV-infected mice were treated with polyclonal antibodies or monoclonal antibody preparations with antibody-dependent cellular cytotoxicity (ADCC-mAb) or neutralizing activity (NEUT-mAb). Findings: Treatment with all anti-EBOV-GP antibodies tested dramatically reduced viremia and improved survival. Further, all treatments reduced the incidence of cataracts. However, NEUT-mAb alone or in combination with ADCC-mAb reduced viral load in the eyes, downregulated the ocular immune and inflammatory responses, and minimized retinal damage more effectively. Interpretation: Anti-EBOV-GP antibodies can improve survival among EVD patients, but improved therapeutics are needed to reduce life altering sequelae. This animal model offers a new platform to examine the acute and long-term effect of the virus in the eye and the relative impact of therapeutic candidates targeting EBOV-GP. Results indicate that even antibodies that improve systemic viral clearance and survival can differ in their capacity to reduce acute ocular inflammation, and long-term retinal pathology and corneal degeneration. Funding: This study was partly supported by Postgraduate Research Fellowship Awards from ORISE through an interagency agreement between the US DOE and the US FDA.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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