Investigation of PEGylated BA-210 for RGC neuroprotection

项目总结 Rho GTP酶抑制剂对视网膜神经节细胞(RGCs)具有神经保护作用 有效治疗青光眼等眼科疾病。青光眼患者RGC死亡与 RGC轴突丢失。一旦神经元失去连接，正常的电路就会受到影响，而 靶点衍生的信号导致细胞死亡。这种信号丢失可以是树突或轴突， 而RGC细胞死亡的预防将通过刺激可塑性和/或 防止轴突回缩。BA-210是一种II期研究药物(正在进行急性脊髓损伤的临床试验 脊髓损伤)，具有很强的神经保护作用，还刺激树突状可塑性和 轴突再生。我们有强有力的临床前数据用于视网膜神经节细胞的神经保护 大鼠视神经切断后玻璃体腔内注射及高压性视网膜病变大鼠模型 眼压(IOP)。为提高BA-210的药效学和安全性 眼科，我们将生产聚乙二醇化的BA-210。我们将测定剂量反应并比较 视网膜滞留和BA-210与Rho激酶抑制剂的疗效。我们有初步的 结果表明，聚乙二醇BA-210保持了酶活性，并在视网膜中保留了更长的时间 而不是BA-210。视神经切断后视网膜神经节细胞的神经保护作用将在 大鼠青光眼眼压模型。在其他实验中，我们将研究聚乙二醇BA-210的安全性 注射入兔眼后。对于这些实验，我们将遵循临床症状和 组织病理学。总之，这些实验将有助于转化有关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.