Glaucoma is the leading cause of irreversible blindness globally. The disease causes vision loss due to neurodegeneration of the retinal ganglion cell (RGC) projection to the brain through the optic nerve. Glaucoma is associated with sensitivity to intraocular pressure (IOP). Thus, mainstay treatments seek to manage IOP, though many patients continue to lose vision. To address neurodegeneration directly, numerous preclinical studies seek to develop protective or reparative therapies that act independently of IOP. These include growth factors, compounds targeting metabolism, anti-inflammatory and antioxidant agents, and neuromodulators. Despite success in experimental models, many of these approaches fail to translate into clinical benefits. Several factors contribute to this challenge. Firstly, the anatomic structure of the optic nerve head differs between rodents, nonhuman primates, and humans. Additionally, animal models do not replicate the complex glaucoma pathophysiology in humans. Therefore, to enhance the success of translating these findings, we propose two approaches. First, thorough evaluation of experimental targets in multiple animal models, including nonhuman primates, should precede clinical trials. Second, we advocate for combination therapy, which involves using multiple agents simultaneously, especially in the early and potentially reversible stages of the disease. These strategies aim to increase the chances of successful neuroprotective treatment for glaucoma.

中文翻译：

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解决青光眼神经变性：机制、挑战和治疗

青光眼是全球不可逆失明的主要原因。该疾病由于视网膜神经节细胞（RGC）通过视神经投射到大脑的神经变性而导致视力丧失。青光眼与眼压 (IOP) 敏感性有关。因此，尽管许多患者继续丧失视力，但主要治疗方法还是寻求控制眼压。为了直接解决神经退行性疾病，大量临床前研究寻求开发独立于 IOP 的保护性或修复性疗法。这些包括生长因子、靶向代谢的化合物、抗炎剂和抗氧化剂以及神经调节剂。尽管实验模型取得了成功，但其中许多方法未能转化为临床益处。有几个因素导致了这一挑战。首先，啮齿动物、非人类灵长类动物和人类的视神经乳头解剖结构不同。此外，动物模型无法复制人类复杂的青光眼病理生理学。因此，为了提高转化这些发现的成功率，我们提出了两种方法。首先，在临床试验之前应对多种动物模型（包括非人类灵长类动物）的实验目标进行彻底评估。其次，我们提倡联合治疗，即同时使用多种药物，特别是在疾病的早期和可能可逆的阶段。这些策略旨在增加青光眼神经保护治疗的成功机会。