Participez à un projet de doctorat dans le cadre du projet EDITO, en travaillant sur une nouvelle stratégie pour traiter la maladie de Stargardt, une dégénérescence maculaire héréditaire causée par des mutations dans le gène ABCA4.
Résumé du projet :
This PhD project aims to develop an innovative therapeutic approach for Stargardt disease, a hereditary macular degeneration caused by mutations in the ABCA4 gene. Currently, AAV is the most effective vector for retinal transduction; however, its cargo capacity is insufficient to accommodate the full-length ABCA4 cDNA. To overcome this limitation, our strategy relies on Spliceosome-Mediated RNA Trans-splicing (SMaRT) technology, which corrects mutations at the transcriptome level by replacing the mutated exons of an endogenous mRNA through trans-splicing with an exogenous RNA. This exogenous RNA contains only a portion of the mRNA to be corrected, thus bypassing the cargo size constraint of the ABCA4 cDNA.
The success of SMaRT technology depends on the efficiency of this trans-splicing reaction, requiring the implementation of a screening strategy to identify the most effective exogenous RNA. The project includes multiple steps involving molecular and cellular biology techniques: construction of vectors to express the exogenous RNA, generation of cell lines to test the efficiency of this RNA in promoting trans-splicing, and screening of RNA libraries to optimize exogenous RNAs. Selected RNAs will then be tested in retinal organoid models and animal models to demonstrate their potential for treating this genetic disease. This project will open new therapeutic perspectives for Stargardt disease.
Techniques impliquées :
- Biologie moléculaire et cellulaire
- Criblage d’ARN
- Construction de vecteurs
- Modèles d’organoïdes rétiniens et validation in vivo
Profil du candidat :
We are looking for a highly motivated Master’s (or equivalent level) candidate with a strong background in molecular biology, an interest in developing new gene therapy strategies, and the ability to work autonomously within a multidisciplinary team. The project will involve a diverse set of techniques, including cloning, vectorology, cell line transduction, flow cytometry, and cellular models. Experience with iPS cells, retinal organoids, or in vivo retinal models would be a plus.
Condistions de la thèse:
The PhD will take place within the « Cellular Interactions in Neurodegenerative Diseases: Models and Biotherapies » team at UMR9199, MIRCen department, CEA Center of Fontenay-aux-Roses, under the supervision of Alexis Bemelmans. The project will be funded by a CEA research training contract, with a start date in autumn 2025.
Interested candidates should send their application (CV + motivation letter + contact details of references) as soon as possible and no later than May 8 to alexis.bemelmans@cea.fr.
Supervision: Alexis Bemelmans