Evidence based experimental treatment for cone photoreceptor degeneration

01/12/2015 to 30/11/2018

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.