Developing a molecular surgical approach to repair and stabilize cone function in retinitis pigmentosa

• Applicant: Professor Volker Busskamp, Ph.D.
• Subject Area: Ophthalmology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542457924

The first stage of the inherited disease retinitis pigmentosa (RP) is the degeneration of rod photoreceptors that causes night blindness. Causative mutated genes are expressed specifically in rods. Subsequently, cone photoreceptors, which are important for daylight, color, and high-acuity vision, progressively lose their light-sensitive outer segments, resulting in total blindness. Since human vision is cone-dominated, the loss of cone function has a dramatic impact on the quality of life of RP patients. Preserving cone vision is a promising intervention. However, the molecular underpinnings of this bystander loss of cone function, which would serve as excellent therapeutic entry points, remain elusive. Therefore, we will investigate transcriptional changes in cones of RP mouse models over the entire time course of vision loss. Sophisticated system-level bioinformatics analyses will be used to uncover the underlying molecular insults and to disentangle causes from consequences. The overall idea is to decouple or interrupt the negative chain of molecular events driven by regulatory elements. Having identified the key regulatory elements that lead to outer segment loss and cone function, we aim to restore their expression levels to physiological levels using adeno-associated viral gene transfer. This gene therapy will first be tested in human stem cell-derived retinal organoids and cone photoreceptor cells, and ultimately in RP mouse models in vivo. We combine systems biology of gene regulation and precise manipulation with gene therapy approaches and visual neuroscience. We aim to pioneer a systems-level molecular surgical approach to repair and stabilize cone function and thereby preserve high-acuity vision.

• DFG Programme: Research Grants