Investigating new therapeutic targets for inherited photoreceptor degeneration: Secondary medical indications for PARP inhibitors used in cancer treatment

研究遗传性光感受器变性的新治疗靶点：用于癌症治疗的 PARP 抑制剂的次要医学适应症

• 批准号: 282211084
• 负责人: Dr. Ayse Sahaboglu Tekgoz, Ph.D.
• 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: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/282211084?language=en
• 关键词: Investigating; new; therapeutic; targets; inherited

Inherited retinal degenerations (RD) such as Retinitis Pigmentosa are initiated by gene defects in rods, cones, or the retinal pigment epithelium and often lead to an irreversible loss in visual function. So far, there is no cure or treatment for RD. Poly-ADP-ribosylation (PARylation) is an important post-translational modification of proteins and is involved in many critical cellular pathways such as transcription, DNA repair, and programmed cell death. PARylation is performed by poly-ADP-ribose-polymerase (PARP) using NAD+ and antagonized by poly-ADP-ribose-glycohydrolase (PARG) which hydrolyses PAR polymers from acceptor proteins.In 2007, it was shown that over-activation of PARP contributed to photoreceptor degeneration in the rd1 mouse, a well-known model for RD. Since then, excessive PARP activity was also found to be involved in photoreceptor degeneration in a variety of further animal models for RD. This suggests PARP activity as a common denominator of photoreceptor cell death and, by inference, PARP inhibitors as therapeutic agents for inherited retinal diseases. Recently, several PARP inhibitors were clinically tested for the treatment of different types of cancer and the first PARP inhibitors have already been approved for use in cancer therapy.Here, I aim to investigate the therapeutic potential of clinically tested PARP inhibitors (Olaparib, BMN 673, INO-1001) using in vitro organotypic explant cultures derived from the rd1, rd2, and cpfl1 mouse models for RD. The identification of PARP inhibitors suitable for the treatment of RD would allow to build on the already existing extensive clinical data and fast-forward the translation of basic research into clinical application and new therapies for hereditary blindness.

遗传性视网膜变性 (RD)，例如色素性视网膜炎，是由视杆细胞、视锥细胞或视网膜色素上皮细胞的基因缺陷引发的，通常会导致视觉功能不可逆转的丧失。迄今为止，RD 尚无治愈或治疗方法。多聚 ADP 核糖基化 (PARylation) 是一种重要的蛋白质翻译后修饰，参与许多关键的细胞途径，例如转录、DNA 修复和程序性细胞死亡。 PARylation 由聚 ADP 核糖聚合酶 (PARP) 使用 NAD+ 进行，并被聚 ADP 核糖糖水解酶 (PARG) 拮抗，后者从受体蛋白中水解 PAR 聚合物。 2007 年，研究表明，PARP 的过度激活会导致 rd1 小鼠（一种著名的 RD 模型）的光感受器变性。此后，在多种进一步的 RD 动物模型中，还发现过度的 PARP 活性与光感受器变性有关。这表明 PARP 活性是感光细胞死亡的一个共同点，并且由此推断，PARP 抑制剂可以作为遗传性视网膜疾病的治疗剂。最近，几种 PARP 抑制剂针对不同类型的癌症进行了临床测试，第一个 PARP 抑制剂已被批准用于癌症治疗。在这里，我的目的是使用来自 rd1、rd2 和 cpfl1 小鼠模型的体外器官型外植体培养物，研究经过临床测试的 PARP 抑制剂（Olaparib、BMN 673、INO-1001）的治疗潜力。 研发。鉴定适合治疗 RD 的 PARP 抑制剂将能够以现有的广泛临床数据为基础，并快速将基础研究转化为临床应用和遗传性失明的新疗法。