Targeting CNG-Ca2+ channels: Evaluation of pharmacological and antisense oligonukleotide approaches for the treatment of retinitis pigmentosa.

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The aim of this study is to identify and evaluate pharmacological or antisense oligonucleotide (AON) mediated, knock-down neuroprotectors that target cyclic nucleotide gated Ca2+ channels (CNG channels) to prevent photoreceptor degeneration in retinitis pigmentosa (RP). While numerous clinically-tested pharmacological inhibitors of CNG channels are readily available, possibly allowing for a rapid clinical translation, AONs bear the potential for improved specificity and reduced side-effects. The study will be split up into in vitro screening and validation in the first 18-24 project months, to then be carried forward to in vivo testing in relevant RP animal models (rd1, rd2, and rd10 mouse). The effect of pharmacological compounds and AONs on CNG channels will be tested in cell cultures and organotypic retinal explant cultures in vitro, to quickly establish proof-of-principle and to obtain dose-response curves. This will be supplemented by in vitro Ca2+ imaging on retinal slice preparations to weigh up potential off-target effects. The most promising compound or AON will be taken to the in vivo level using either systemic (intraperitoneal) or local (intravitreal) application paradigms, in three different RP animal models. Here, we will use scanning laser ophthalmoscopy (SLO) and optic coherence tomography (OCT) in vivo imaging techniques to assess treatment effects in longitudinal studies, combined with electroretinography (ERG) for functional testing. The study program is designed to clearly establish whether CNG channel targeting approaches constitute a viable therapeutic strategy for the treatment of RP and to yield first in vivo data to facilitate later pre-clinical and clinical testing of such approaches.