Neurorestorative Strategy for Chemotherapy-induced Peripheral Neuropathy

描述（由申请人提供）：化疗诱导的周围神经病变（CIPN）是许多常用化疗药物（包括铂类药物和紫杉烷类）的主要剂量限制性副作用。CIPN以外周轴突变性和脱髓鞘为特征，可致残且极度疼痛，导致功能能力的显著丧失和生活质量的降低。考虑到CIPN的发病率在接受化疗的患者中从30%到40%不等，受CIPN影响的总人口是巨大的。尽管已经提出了一些预防性策略来减轻CIPN的发展，但尚未发现有效的治疗CIPN的方法，因此，仍然迫切需要修复受损轴突的神经修复策略来减轻CIPN的症状。Cognosci创新性地创造并表征了一系列源自人载脂蛋白E（apoE）的肽，其通常被称为COG化合物。广泛的研究表明，COG化合物在体外和体内都具有有效的抗炎活性、神经保护和神经恢复活性。我们还获得的数据显示，最有效的载脂蛋白E模拟物之一的COG 112，可以显着防止轴突变性，促进轴突再生和髓鞘再生的坐骨神经挤压模型。类似的神经保护作用已经在各种神经障碍的动物模型中得到验证，所述神经障碍例如创伤性脑损伤、脊髓损伤、蛛网膜下腔出血和多发性硬化，暗示了对这些疾病的治疗功效。此外，Cognosci已经成功鉴定了COG化合物的结合蛋白，即SET，一种丝氨酸/苏氨酸蛋白磷酸酶2A（PP 2A）的内源性抑制剂。SET是一种核癌基因，与慢性淋巴细胞性白血病（CLL）、髓系白血病等多种肿瘤相关。随着COG 112作为抗癌药物的开发计划正在进行中，在此我们建议从以下方面检查COG 112是否可以预防化疗的神经毒性，修复组织学损伤并恢复已建立的CIPN的功能：1）具体目标1：为了检查COG 112在顺铂和紫杉醇中的潜在神经保护和神经再生作用，在原代背根神经节（DRG）培养物中诱导的轴突损伤和神经元细胞死亡; 2）具体目的2：通过在顺铂诱导的CIPN动物模型中的组织学和功能检查来检查COG 112是否发挥神经保护和神经恢复作用。公共卫生相关性：该项目的总体目标是获得概念证明，即COG 112可以作为化疗诱导的周围神经病变的治疗剂，具有神经保护和神经恢复的双重有利特性。此外，COG 112可以单独抑制癌症生长，也可以与其他抗癌药物联合使用，以增强其治疗活性，但减少其神经毒性副作用。如果这项研究得到证实，COG 112可能代表一种有希望的治疗癌症和化疗引起的周围神经病变的方法。

DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of many commonly used chemotherapeutic agents, including platinum drugs and taxanes. CIPN, characterized by peripheral axonal degeneration and demyelination, can be disabling and extremely painful, causing significant loss of functional abilities and decreasing quality of life. Considering the incidence of CIPN vary from 30 to 40% of patients receiving chemotherapy, the total population affected by CIPN is enormous. Although some preventive strategies have been proposed to attenuate the development of CIPN, effective treatment of established CIPN has yet to be found. Therefore, a neurorestorative strategy to repair damaged axons is still critically needed to alleviate the symptom of established CIPN. Cognosci has innovatively created and characterized a series of peptides derived human apolipoprotein E (apoE), which are generally designated as COG compounds. Extensive studies have demonstrated that COG compounds exert potent anti-inflammatory activities, neuroprotective and neurorestorative activities both in vitro and in vivo. We have also obtained data showing that COG112, one of the most potent apolipoprotein E mimetics, can significantly prevent axonal degeneration and promote axonal regeneration and remyelination in a sciatic nerve crush model. A similar neuroprotective effect has been validated in animal models of a variety of neurological disorders such as traumatic brain injury, spinal cord injury, subarachnoid hemorrhage and multiple sclerosis, implicating a therapeutic efficacy for these diseases. Furthermore, Cognosci had successfully identified the binding protein of COG compounds, which is SET, an endogenous inhibitor of serine/threonine protein phosphatase 2A (PP2A). SET is well known as a nuclear oncogene and has been associated with several types of cancers, such as chronic lymphocytic leukemia (CLL), myeloid leukemia. With ongoing program to develop COG112 as anticancer drug, here we propose to examine whether COG112 can prevent the neuotoxicity of chemotherapies, repair histological damage and restore the lost functions of established CIPN in the following aspects: 1) Specific aim 1: To examine the potential neuroprotective and neuroregenerative effects of COG112 in a cisplatin and paclitaxel-induced axonal damage and neuronal cell death in primary dorsal root ganglion (DRG) cultures; 2) Specific Aim 2: To examine if COG112 exerts neuroprotective and neurorestorative effects by histological and functional examination in a cisplatin-induced CIPN animal model. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to obtain proof of concept that COG112 can be a therapeutic agent for chemotherapy induced peripheral neuropathy with dual favorable properties of neuroprotection and neurorestoration. Moreover, COG112 can either independently inhibit cancer growth or be combined with other anticancer drugs to enhance their therapeutic activity but to reduce their neurotoxic side effects. If substantiated by this study, COG112 may represent a promising therapy for both cancer and chemotherapy induced peripheral neuropathy.