Evidence based experimental treatment for cone photoreceptor degeneration

• Applicant: Dr. Dragana Trifunovic
• Subject Area: Ophthalmology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289152019

Cone photoreceptor loss leads to dramatic vision impairment and blindness. In inherited neurodegenerative diseases of the retina, cone death can be induced by primary genetic defects in cones themselves or by genetic defects in rod photoreceptors, causing first rod- and then secondary, mutation independent cone loss, as in the case of Retinitis Pigmentosa. While the loss of rods has only relatively minor consequences for human vision, and indeed often goes unnoticed in patients, loss of cones causes blindness. The design of novel rational therapies aiming to prevent cone death requires an in-depth knowledge on the molecular processes leading to cone cell death. However, knowledge on these neurodegenerative mechanisms is still very limited. We have previously shown that primary cone degeneration is governed by non-apoptotic mechanisms, involving in particular the excessive activation of histone deacetylases (HDAC). Hence, the first aim of this study is to investigate the in vivo neuroprotective properties of various HDAC inhibitors on primary cone degeneration mouse models, namely cone photoreceptor function loss 1 (cpfl1) and cone-specific cyclic nucleotide gated channel knockout mice (Cnga3 KO). Here, the use of HDAC inhibitors already clinically approved for other indications will facilitate a rapid clinical translation. The second aim is to improve the understanding of the mechanisms of secondary, mutation-independent cone degeneration in rd1 and rd10 mouse models. This project part will focus on identifying key players in secondary cone cell death using in vitro analysis of characteristic apoptotic and non-apoptotic processes and markers. Their involvement and potential to serve as targets for neuroprotective treatments will be validated and evaluated ex vivo, on organotypic retinal explant cultures. The research proposed will help identifying off the shelf HDAC inhibitors able to prevent primary cone degeneration thus paving the way for further pre-clinical and clinical studies. At the same time the project will determine the mechanisms of secondary cone degeneration providing novel targets for therapy development for photoreceptor degeneration in general.

• DFG Programme: Research Grants