The retina is particularly amenable to gene therapy because it is accessible via relatively non-invasive routes, it is small and enclosed allowing the use of small vector doses, and it is immuno-privileged due to sequestration from the systemic circulation by the blood-retina barrier. Moreover, retinal dystrophies are favourable candidates for gene therapy because they are often monogenic, have characteristic clinical signs allowing an early diagnosis, and progress slowly to blindness allowing a large therapeutic window.
However, there are a growing number of retinal diseases that lack an appropriate animal model, which compromises their chances of one day reaching the stage of a clinical therapeutic trial.
The aim of our work is to find a viable alternative to palliate this lack of animal models. One way would be to perform preclinical studies on human cellular models of the diseased retina. The caveat is that it is impossible to obtain retinal cells directly from a patient.Therefore, our work is aimed at generating these cells via the intermediate of an innovative and powerful tool, induced pluripotent stem cells (iPSc).
By taking skin fibroblasts from a patient affected with a specific retinal dystrophy, we can reprogram these cells into iPSc, which we can then differentiate into retinal cells such as the retinal pigment epithelium (RPE). In this way, we generate a human cellular model of the diseased retina.
We currently work on two different retinal dystrophies: choroideremia and retinitis punctata albescens. We have generated RPE for both of these disorders and by characterising the differences between control and patient RPE using a variety of techniques (molecular biology, cell biology, biochemical, imaging), we can obtain insights into the pathophysiology of the disease. Moreover, the generated RPE serves as a model for screening the efficiency of different therapeutics.
By transducing this epithelium with a gene therapy vector carrying a healthy copy of the causative gene, we can obtain the proof of principle for a restoration of a normal phenotype, a first step towards clinical translation. Similarly, the generated RPE can be used to screen the efficiency of novel pharmacological agents. Finally, such a model generated in vitro represents a first step towards cell therapy approaches.
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- Dr. Mariya Moosajee, University College London, RU
- Dr. Timor Basaav, Technion Insitute of Technology, Haifa, Israel
- Dr. Carmen Bertoni, UCLA, CA, USA
- Dr. Richard Harbottle, German Cancer Research Centre, Heidelberg, Allemagne
- Pr. Daniel Scherman, Université Paris Descartes, France
- Dr. Philippe Moullier, Institut de Recherche Thérapeutique , Nantes, France
- Pr. Carl Arndt, Service d'Ophtalmologie, CHU Reims, France
- Dr. Florence Cammas, IRCM, Montpellier, France
- Dr. John De Vos, IRB, Montpellier, France