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）如色素性视网膜炎是由杆状、锥状或视网膜色素上皮的基因缺陷引发的，通常导致视觉功能的不可逆转丧失。到目前为止，还没有治愈或治疗RD的方法。poly - adp -核糖基化（PARylation）是一种重要的蛋白质翻译后修饰，涉及许多关键的细胞途径，如转录、DNA修复和程序性细胞死亡。PARylation是由使用NAD+的聚adp -核糖聚合酶（PARP）完成的，并被从受体蛋白中水解PAR聚合物的聚adp -核糖糖水解酶（PARG）拮抗。2007年，研究表明，PARP的过度激活导致了rd1小鼠（一种众所周知的RD模型）的光感受器变性。此后，在各种进一步的RD动物模型中，PARP活性过高也被发现与光感受器变性有关。这表明PARP活性是光感受器细胞死亡的共同因素，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抑制剂被临床试验用于治疗不同类型的癌症，第一批PARP抑制剂已经被批准用于癌症治疗。在这里，我的目标是研究临床测试的PARP抑制剂（Olaparib, BMN 673, INO-1001）的治疗潜力，使用来自rd1， rd2和cpfl1小鼠模型的体外器官型外植体培养物来治疗RD。识别适合治疗RD的PARP抑制剂将允许建立在已经存在的广泛临床数据的基础上，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。

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.