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

靶向 CNG-Ca2 通道：治疗色素性视网膜炎的药理学和反义寡核苷酸方法的评估。

• 批准号: 384355007
• 负责人: Professor Dr. Francois Paquet-Durand
• 金额: --
• 依托单位: Forschungsinstitut für Augenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/384355007?language=en
• 关键词: Targeting; CNG; Ca2+; channels; Evaluation

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.

本研究的目的是鉴定和评估靶向环核苷酸门控Ca2+通道（CNG通道）的药理学或反义寡核苷酸（AON）介导的敲低神经保护剂，以防止视网膜色素变性（RP）的光感受器变性。虽然许多经过临床测试的CNG通道药理学抑制剂很容易获得，可能允许快速临床转化，但AONs具有提高特异性和减少副作用的潜力。该研究将在项目的前18-24个月内分为体外筛选和验证，然后在相关RP动物模型（rd1， rd2和rd10小鼠）中进行体内测试。药物化合物和AONs对CNG通道的影响将在细胞培养和体外器官型视网膜外植体培养中进行测试，以快速建立原理证明并获得剂量-反应曲线。这将通过体外Ca2+成像视网膜切片制剂来补充，以权衡潜在的脱靶效应。在三种不同的RP动物模型中，最有希望的化合物或AON将通过全身（腹腔）或局部（玻璃体内）应用范式进入体内水平。在这里，我们将使用扫描激光检眼镜（SLO）和光学相干断层扫描（OCT）体内成像技术在纵向研究中评估治疗效果，并结合视网膜电图（ERG）进行功能测试。该研究项目旨在清楚地确定CNG通道靶向方法是否构成RP治疗的可行治疗策略，并首次获得体内数据，以促进后期对此类方法的临床前和临床试验。