Inducible nonhuman primate models of retinal degeneration for testing end-stage therapies

Author:

Ail Divya1ORCID,Nava Diane1,Hwang In Pyo1ORCID,Brazhnikova Elena1ORCID,Nouvel-Jaillard Céline1,Dentel Alexandre123ORCID,Joffrois Corentin1,Rousseau Lionel4,Dégardin Julie1,Bertin Stephane12ORCID,Sahel José-Alain1256ORCID,Goureau Olivier1ORCID,Picaud Serge1ORCID,Dalkara Deniz1ORCID

Affiliation:

1. Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France.

2. CHNO des Quinze-Vingts, INSERM-DGOS CIC 1423, F-75012 Paris, France.

3. Department of Ophthalmology, Pitié-Salpêtrière University Hospital, F-75013 Paris, France.

4. ESYCOM, Université Eiffel, CNRS, CNAM, ESIEE Paris, F-77454 Marne-la-Vallée, France.

5. Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

6. Fondation Ophtalmologique Adolphe de Rothschild, F-75019 Paris, France.

Abstract

The anatomical differences between the retinas of humans and most animal models pose a challenge for testing novel therapies. Nonhuman primate (NHP) retina is anatomically closest to the human retina. However, there is a lack of relevant NHP models of retinal degeneration (RD) suitable for preclinical studies. To address this unmet need, we generated three distinct inducible cynomolgus macaque models of RD. We developed two genetically targeted strategies using optogenetics and CRISPR-Cas9 to ablate rods and mimic rod-cone dystrophy. In addition, we created an acute model by physical separation of the photoreceptors and retinal pigment epithelium using a polymer patch. Among the three models, the CRISPR-Cas9–based approach was the most advantageous model in view of recapitulating disease-specific features and its ease of implementation. The acute model, however, resulted in the fastest degeneration, making it the most relevant model for testing end-stage vision restoration therapies such as stem cell transplantation.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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