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

遗传性视网膜变性（RD），如视网膜色素变性是由杆，锥或视网膜色素上皮细胞中的基因缺陷引发的，通常会导致视觉功能的不可逆丧失。到目前为止，还没有治愈或治疗RD的方法。聚腺苷二磷酸核糖基化（PAR化）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，如转录，DNA修复和程序性细胞死亡。PAR化是由聚ADP-核糖聚合酶（PARP）使用NAD+进行的，并被聚ADP-核糖-糖水解酶（PARG）拮抗，聚ADP-核糖-糖水解酶（PARG）从受体蛋白水解PAR聚合物。从那时起，在各种进一步的RD动物模型中，也发现过度的PARP活性参与感光细胞变性。这表明PARP活性是光感受器细胞死亡的共同特征，并且通过推断，PARP抑制剂是遗传性视网膜疾病的治疗剂。最近，几种PARP抑制剂进行了临床试验，用于治疗不同类型的癌症和第一个PARP抑制剂已经被批准用于癌症therapy. There，我的目的是研究临床测试的PARP抑制剂（奥拉帕尼，BMN 673，INO-1001）的治疗潜力，使用来自RD的rd 1，rd 2和cpfl 1小鼠模型的体外器官型外植体培养。鉴定适合治疗RD的PARP抑制剂将允许建立在现有的广泛临床数据基础上，并将基础研究快速转化为临床应用和遗传性失明的新疗法。

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.