Investigation of PEGylated BA-210 for RGC neuroprotection

聚乙二醇化 BA-210 对 RGC 神经保护作用的研究

基本信息

批准号：
8643711
负责人：
Lisa J McKerracher
金额：
$ 22.37万
依托单位：
BIOAXONE BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643711
关键词：
ADP ribosylation Acute Affect Animals Antibodies Apoptosis Axotomy Back Blindness Cell Count Cell Death Cell Survival Clinical Clinical Research Clinical Trials Complex Crush Injury Cytoprotection Data Development Disease Dose Drops Drug Kinetics Evaluation Eye Eye diseases Future Glaucoma Histology Histopathology Hour Injection of therapeutic agent Investigation Investigational Drugs Label Modeling Modification Molecular Weight Mydriatics Neurons Norway Ophthalmology Ophthalmoscopy Optic Nerve Optic Nerve Transections Oryctolagus cuniculus PC12 Cells Paraffin Patients Pharmaceutical Preparations Pharmacodynamics Phase Physiologic Intraocular Pressure Preclinical Testing Prevention Primates Property Rattus Reaction Time Retina Retinal Retinal Ganglion Cells Rho-associated kinase Safety Series Signal Pathway Signal Transduction Spinal cord injury Spinal cord injury patients Staging Testing Time Toxic effect Translating Variant Veins Western Blotting axon regeneration comparative efficacy drug candidate drug development effective therapy experience immunocytochemistry improved inhibitor/antagonist intravenous injection intravitreal injection kinase inhibitor neuron apoptosis neuroprotection ophthalmic artery pre-clinical prevent public health relevance regenerative research study response rho rho GTP-Binding Proteins safety study

项目摘要

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.

项目摘要 Rho GTPase的抑制剂是视网膜神经节细胞（RGC）的神经保护剂，可能是有效治疗眼部疾病，例如青光眼。青光眼中的RGC死亡与 RGC轴突损失。一旦神经元失去连接，正常电路就会受到影响，损失目标信号导致细胞死亡。这种信号的损失可能是树突状的或轴突的，刺激可塑性和/或防止轴突死。 BA-210是II期研究药物（在急性脊柱的临床试验中脐带损伤）具有强大的神经保护作用，还刺激树突状可塑性和轴突再生。我们有强大的临床前数据用于RGC的神经保护视神经的轴切开术后大鼠的玻璃体内注射和大鼠升高的大鼠模型眼内压（IOP）。改善BA-210的药效和安全性眼科，我们将制作pegyated BA-210。我们将确定剂量反应并比较带有Rho激酶抑制剂的视网膜保留和BA-210的功效。我们有初步结果表明，PEG-BA-210保留酶促活性，并保留在视网膜中比BA-210。 RGC的神经保护将在视神经横向和A中进行研究 IOP的大鼠青光眼模型。在其他实验中，我们将研究PEG-BA-210的安全性注射到兔子眼中。对于这些实验，我们将遵循临床标志，并组织病理学。这些实验将有助于翻译有关RGC保护的临床前数据致力于临床发展。