DC11: Development of a disease gene agnostic ASO approach to treat inherited blindness

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Supervisor: Dr. F. Coppieters 

Host Institute: Ghent University, Belgium (www.ugent.be)

Secondments planned: Astherna, The Netherlands; Université de Versailles Saint-Quentin-en-Yvelines, France

Doctoral program: Medicine and Health Sciences PhD program of Ghent University

Anticipated starting date: September/October 1st, 2025

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Project description:

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Inherited retinal disease (IRD) is at the forefront of gene therapy development. IRD is a major cause of early-onset vision loss or blindness with an overall prevalence of ~1/3,000. The disease is characterized by a tremendous genetic heterogeneity, with thousands of different pathogenic variants identified in over 300 genes. The majority of ASO therapies currently investigated focus on specific mutations/exons in a single disease gene, hampering application to large patient cohorts.

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This PhD project aims to explore a novel therapeutic ASO approach targeting cis-acting elements that modulate translation. This strategy will be employed to increase translation of retinal genes enhancing photoreceptor survival in patients with IRD, thus representing a novel, disease gene agnostic approach. We previously performed both in silico and wet-lab analyses to identify cis-acting elements in the human retina. DC11 will first functionally dissect novel cis-acting elements using in vitro reporter assays in cellular models. Next, DC11 will design and evaluate ASOs to modulate these cis-acting elements and as such increase protein expression in wild-type retinal models. Finally, the efficacy of the most promising ASOs will be assessed in iPSC-derived retinal models from patients with mutations across IRD genes.

This project will provide new scientific insights in retinal gene regulation by elucidating the function of novel cis-regulatory elements, and will evaluate a novel, disease gene agnostic therapeutic strategy for IRD.