Triazine-based compounds to promote regeneration in optic neuropathies

描述（由申请人提供）：在美国，非动脉性前缺血性视神经病变（NAION）是导致视神经相关性急性视力丧失的最常见原因；没有有效的治疗方法。NAION引起视神经轴突损伤，导致视网膜神经节细胞（RGCs）功能障碍和死亡。增强RGC再生的干预措施可以在RGC死亡之前应用，通过允许RGC与大脑中的目标重新连接来逆转功能障碍。增强视神经再生是NAION和其他神经病变患者的主要目标。在NAION和其他疾病中缺乏促进再生的疗法反映了受损中枢神经系统（CNS）的再生障碍，包括与髓磷脂和胶质瘢痕相关的生长抑制蛋白。通过克服这些障碍来促进再生的策略在动物模型中已经显示出有效性，但需要新的策略并将其转化为临床。我们利用一组新型药物样三嗪类化合物对哺乳动物原代神经元进行了表型筛选，并鉴定出4种能够在抑制性中枢神经系统髓鞘底物上促进神经突生长的化合物。这些化合物a)作用于不同的神经元类型，包括RGCs， b)是有效的，c)在几种与中枢神经系统损伤相关的实验中克服抑制，d)可能通过新的机制起作用。我们现在已经证明了一种化合物，AA4F05，在视网膜损伤的动物模型和脊髓损伤模型中促进再生。AA4F05及其相关基因是促进RGCs和其他中枢神经系统神经元再生的新药候选基因。虽然AA4F05具有良好的化学性质，在体外和体内都有活性，但目前还没有对其活性或药代动力学进行优化的尝试。目前的提案将以AA4F05作为开发新化合物的起点，这些化合物具有显著改善rgc受损轴突再生的潜力。衍生物将在体外原代神经元中进行测试（一级和二级筛选），并在2种视神经损伤模型中进行最佳候选物测试。

DESCRIPTION (provided by applicant): Non-arteritic anterior ischemic optic neuropathy (NAION) is the most common cause of optic nerve-related acute loss of vision in the US; there is no effective treatment. NAION causes injury to optic nerve axons, leading to dysfunction and death of retinal ganglion cells (RGCs). Interventions to enhance RGC regeneration could be applied before RGC death, to reverse dysfunction by allowing RGCs to reconnect with their targets in the brain. Enhancement of optic nerve regeneration is a major goal for patients with NAION and other neuropathies. The lack of regeneration-promoting therapies in NAION and other diseases reflects barriers to regeneration in the injured central nervous system (CNS), including growth-inhibitory proteins associated with myelin and the glial scar. Strategies to promote regeneration by overcoming these barriers have shown efficacy in animal models, but novel strategies and translation to the clinic are needed. We have performed a phenotypic screen using a library of novel drug-like triazine compounds on primary mammalian neurons, and have identified 4 compounds capable of increasing neurite growth on a substrate of inhibitory CNS myelin. These compounds a) act on different neuronal types, including RGCs, b) are potent, c) overcome inhibition in several assays relevant to CNS injury, and d) may act by novel mechanisms. We have now shown that one compound, AA4F05, promotes regeneration in an animal model of retinal injury, as well as in a model of spinal cord injury. AA4F05 and its relatives are exciting candidates to lead to novel drugs for promoting regeneration of RGCs and other CNS neurons. Although AA4F05 has favorable chemical properties and is active both in vitro and in vivo, there has been no attempt to optimize its activity or pharmacokinetics. The present proposal will use AA4F05 as a starting point for the development of new compounds with the potential to substantially improve regeneration of damaged axons from RGCs. Derivatives will be tested in primary neurons in vitro (primary and secondary screens), and the best candidates will be tested in 2 models of optic nerve injury. PUBLIC HEALTH RELEVANCE: Diseases of the optic nerve (optic neuropathies) are a leading cause of impaired vision in the US. This proposal is designed to develop and test novel therapeutic chemicals that can later be developed into drugs for treatment of optic neuropathies.