Investigation of PEGylated BA-210 for RGC neuroprotection

项目摘要 Rho GT3的抑制剂对视网膜神经节细胞（RGC）具有神经保护作用，并且可能是 有效治疗青光眼等眼部疾病。青光眼中的RGC死亡与 RGC轴突缺失。一旦神经元失去连接，正常的电路就会受到影响， 靶源信号导致细胞死亡。这种信号丢失可能是树突或轴突， 和防止RGC细胞死亡将通过刺激可塑性和/或 防止轴突死亡。BA-210是一种II期研究药物（用于急性脊髓损伤的临床试验）， 脊髓损伤），其具有强的神经保护作用并且还刺激树突可塑性， 轴突再生我们有强有力的临床前数据，用于RGC的神经保护， 玻璃体内注射在视神经轴突切断后的大鼠中和在升高的视神经轴突切断后的大鼠模型中， 眼内压（IOP）。提高BA-210的药效学和安全性， 在眼科，我们将制备聚乙二醇化BA-210。我们将确定剂量反应并比较 保留在视网膜和效力与BA-210，与rho激酶抑制剂。我们有初步的 结果显示PEG-BA-210保留了酶活性并且在视网膜中保留更长时间 BA-210 RGCS的神经保护作用将在视神经切断后和在一个 大鼠高眼压模型。在其他实验中，我们将研究PEG-BA-210的安全性 注射到兔眼后。对于这些实验，我们将跟踪临床体征， 组织病理学总之，这些实验将有助于转化RGC保护的临床前数据 走向临床发展。

Project summary Inhibitors of Rho GTPase are neuroprotective for retinal ganglion cell (RGCs) and may be effective in treating eye diseases such as glaucoma. RGC death in glaucoma is associated with RGC axonal loss. Once neurons lose connections, normal circuitry is affected, and the loss of target-derived signals contributes to cell death. Such loss of signals may be dendritic or axonal, and prevention of RGC cell death would be improved by drugs that stimulate plasticity and/or prevent axonal die back. BA-210 is a Phase II investigational drug (in clinical trial for acute spinal cord injury) that has strong neuroprotective effects and also stimulates dendritic plasticity and axonal regeneration. We have strong preclinical data for neuroprotection of RGCs after intravitreal injection in rats after axotomy of the optic nerve and in a rat model of elevated intraocular pressure (IOP). To improve the pharmacodynamics and safety of BA-210 for use in ophthalmology, we will make PEGylated BA-210. We will determine dose-response and compare retention in the retina and efficacy with BA-210, with rho kinase inhibitors. We have preliminary results to show that PEG-BA-210 retains enzymatic activity and is retained in the retinal longer than BA-210. Neuroprotection of RGCS will be investigated after optic nerve transection and in a rat glaucoma model of IOP. In additional experiments we will investigate safety of PEG-BA-210 after injection into rabbit eyes. For these experiments, we will follow clinical signs and histopathology. Together, these experiments will help translate preclinical data on RGC protection towards clinical development.