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岁或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，部分视野丧失和眼内视神经肿胀。不幸的是，不仅视力很少恢复，而且没有成功的治疗，尽管有2个中型随机临床试验和几个小规模的研究。作为寻找治疗视神经病变新方法的计划的一部分，我们开发了化学还原二硫键并保护视网膜神经节细胞轴突的新型药物，这些轴突是通过视神经从眼睛投射到大脑的纤维。这些“膦-硼烷配合物”对大鼠视神经横断和实验性青光眼有效。它们可能减少一个或多个关键靶蛋白中的分子内或分子间二硫键。然而，我们不知道在AION等疾病中发生氧化二硫键形成的蛋白质的身份。如果这些靶点能够被识别出来，它们就可以作为制造更特异性的膦-硼烷复合物的基础，然后可以用作新的AION治疗剂。我们建议使用敏感的氧化还原蛋白质组学筛选来鉴定视神经内在啮齿动物AION后经历巯基氧化的蛋白质靶标，然后使用推定的靶标来合成20-30种可能更特异的膦-硼烷复合物的文库。然后，我们将通过找到最佳减少关键目标来确定领先候选人，并在rAION模型中对其进行测试。然后，这种铅膦硼烷复合物可以成为转化为灵长类动物模型的候选物，并最终成为临床试验计划的候选物。

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.