Development of redox-active therapies for ischemic optic neuropathy

描述（由申请人提供）：前部缺血性视神经病变（AION）是50岁以上男性和女性急性视神经疾病的最常见原因。它会导致无痛性视力丧失，部分视野丧失，以及眼睛内部视神经肿胀。不幸的是，不仅视力很少恢复，而且没有成功的治疗方法，尽管有2个中型随机临床试验和几项小规模研究。作为寻找治疗视神经病变新方法项目的一部分，我们开发了一种新型药物，可以通过化学方法减少二硫键，保护视网膜神经节细胞轴突，这些纤维通过视神经从眼睛投射到大脑。这些“膦硼烷复合物”对大鼠视神经横断和实验性青光眼有效。它们可能会减少一个或多个关键靶蛋白的分子内或分子间二硫键。然而，我们不知道在诸如AION等疾病中发生氧化二硫形成的蛋白质的身份。如果这些靶点能够被确定，它们可以作为制造更特异的膦-硼烷复合物的基础，然后可以用作新的AION疗法。我们建议使用敏感的氧化还原蛋白质组学筛选来鉴定鼠类AION后视神经内发生巯基氧化的蛋白质靶点，然后使用假定的靶点合成20-30个可能更具特异性的磷化氢-硼烷络合物库。然后，我们将通过找到最优地减少关键目标来确定主要候选，并在rAION模型中进行测试。这种膦-硼烷铅复合物可以被翻译成灵长类动物模型，并最终用于临床试验计划。

DESCRIPTION (provided by applicant): Anterior ischemic optic neuropathy (AION) is the most common cause of acute optic nerve disease in men and women aged 50 years or more. It causes painless visual loss, loss of part of the visual field, and swelling of the optic nerve insie the eye. Unfortunately not only does vision rarely recover, but there is no successful treatment, despite 2 medium-sized randomized clinical trials and several small-scale studies. As part of a program to find new ways of treated optic neuropathy, we developed novel drugs that chemically reduce disulfide bonds and protect retinal ganglion cell axons, the fibers that project through the optic nerve from the eye to the brain. These "phosphine- borane complexes" are effective in rat optic nerve transection and experimental glaucoma. They presumably reduce intra- or intermolecular disulfide bonds in one or more critical target proteins. However, we do not know the identity of the proteins undergoing oxidative disulfide formation in diseases such as AION. If those targets can be identified, they can serve as the basis for making more specific phosphine-borane complexes, which then could be used as novel AION therapeutics. We propose to use a sensitive redox proteomic screen to identify the protein target(s) within the optic nerve that undergo sulfhydryl oxidation after rodent AION, and then use the putative target(s) to synthesize a library of 20-30 potentially more specific phosphine- borane complexes. We then will determine a lead candidate by finding which optimally reduces the critical targets, and test it in the rAION model. This lead phosphine-borane complex could then be a candidate for translation into primate models and eventually clinical trial planning.