Research conducted at Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, has reported three approaches to test novel strategies to treat a range of retinal degenerations. Given the anatomical differences between the human retina and other retinas in animal models, there are limitations how to obtain relevant data required to testing treatments. The closest model for humans is the non-human primate (NHP) however, researchers have commented that “there is a lack of relevant NHP models of retinal degeneration (RD) suitable for preclinical studies”. While some natural NHP models exist with retinal degenerations, such models are righlty limited in terms of ethical prohibitions across many countries, and other limitations arise in terms of resources required for maintenance, breeding and durations of such models, all provide time and monetary constraints. One way to circumvent these challenges is to assess three distinct inducible models – optogenetics, CRISPR-Cas-9 and a surgical “polymer patch”, all strategies of which may be capable to address effectiveness and translatability for NHPs.
The first approach uses an optogenetic strategy where a photoactivatable protein (called “KillerRed” [KR]) induces photoreceptor (PR) ablation in a spatially and temporally controlled manner. This leads to oxidative stress and eventual cell death within ~6 months and then the relevant treatment aims to rescue the pathology. In a second approach, CRISPR-Cas9 creates a disruption of a specific gene (for example, rhodopsin) in the rod photoreceptor cell population, leading to cell death, following cone loss, and then treatments may be used for gene therapies, or a wide range of other therapeutic approaches. Thirdly, the French team applied a surgical placement of a polymer patch between the retinal pigment epithelium (RPE) and the photoreceptors, creating a barrier causing a disruption of vital functions leading to cell stress and cell death and then subsequently introduced to rescue the pathology.
According to the researchers, the CRISPR-Cas9–based approach appeared to be the most advantageous model in terms “of recapitulating disease-specific features and its ease of implementation”. While the surgical model resulted in the fastest degeneration, “making it the most relevant model for testing end-stage vision restoration therapies such as stem cell transplantation.” In conclusion, the researchers stated that, “we have addressed an important unmet need in the field and propose three preclinical models that cause degeneration by distinct mechanisms following different timelines corresponding to the various needs of translational researchers working in the field of retinal disease”.