The Potential of Didox as an Oral Therapy for Multiple Sclerosis

Didox 作为多发性硬化症口服疗法的潜力

• 批准号: 8436711
• 负责人: George Henry De Vries
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436711
• 关键词: Affect; Animal Model; Biochemical; Biological Process; Blood; Blood - brain barrier anatomy; Cells; Chronic; Chronic Progressive Multiple Sclerosis; Clinical; Clinical Trials; Data; Demyelinating Diseases; Didox; Disease; Disease Progression; Disease model; Disease remission; Dose; Edema; Environment; Exhibits; Experimental Autoimmune Encephalomyelitis; FDA approved; Goals; High Pressure Liquid Chromatography; Human; Immune; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Kinetics; Mass Spectrum Analysis; Methods; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Neurons; Onset of illness; Oral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Production; Progressive Disease; Property; Recovery; Relapse; Series; Severities; Staging; Symptoms; Testing; Therapeutic; Toxic effect; Veterans; abstracting; base; bench to bedside; cytokine; drug withdrawal; improved; member; mouse model; novel; polyphenol; prevent; public health relevance; remyelination; repaired; research study

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Current therapies for multiple sclerosis (MS) slow the progression of the disease but do not promote recovery. Therefore additional therapies are required to provide a CNS environment conducive for neuronal stabilization and neurorepair. Didox is a member of a unique series of polyphenol compounds that are multifaceted and have biochemical properties that have the potential to provide therapeutic benefit in MS. To test this hypothesis we conducted experiments using didox administered by injection and the chronic experimental allergic encephalomyelitis (EAE) model of demyelinating disease. We found that Didox given in this manner can prevent the onset and severity of demyelinating disease. The drug also had the ability to completely reverse the clinical symptoms of established disease. Further data associated with the EAE studies demonstrated that the production of inflammatory cytokines are reduced, leading to reduction of edema and decreased immune infiltration of immune cells into the CNS; this infiltration is normally observed in this model. The objective o this proposal is to further elucidate the therapeutic potential of Didox by evaluating its potency when given as an oral drug in a number of relevant EAE models. Oral didox will be administered by oral gavage to mice affected with either chronic EAE or relapsing remitting EAE. The drug will be given prior to the onset of disease, at the peak of disease and after the disease plateaus (in the case of chronic EAE) and prior to the onset of disease during the first remission and during the second remission in the case of elapsing remitting EAE. These two EAE models will be studied in detail before extending the same studies to two other models of MS: the chronic progressive EAE model and the secondary progressive EAE model. The kinetics of didox in the blood and CNS will be followed with a sensitive and specific HPLC/Mass spectrometry method. The ability of the drug to sustain recovery in all EAE models will be evaluated. The molecular, cellular and immunological mechanisms responsible for the drug- induced recovery will be evaluated. As noted, current therapies for multiple sclerosis mostly prevent the progression of the disease but do not reverse the symptoms of MS. In contrast Didox treatment may promote a CNS environment amenable to recovery by suppressing inflammation, preventing immune infiltration of the CNS and reducing edema, allowing clinical recovery and possibly remyelination to occur. Of additional importance, this compound has already been tested in humans, is able to traverse the blood-brain barrier of the CNS, and is tolerated well orally in other disease models. Also there is an urgent need for new oral drug therapies to arrest chronic progressive MS as well as secondary MS and preliminary studies to evaluate didox in this regard are planned. Based on our preliminary observations, we believe that didox has excellent potential to be an effective oral treatment for multiple sclerosis. It is anticipated that the results of this proposal will provide the basis for initiating clinical trial of this novel drug.

描述（由申请人提供）： 多发性硬化症（MS）的项目摘要/抽象当前疗法降低了疾病的进展，但不会促进康复。因此，需要额外的疗法以提供有利于神经元稳定和神经层的CNS环境。 DODOX是独特的多酚化合物系列的成员，这些化合物具有多面并且具有生化特性，具有在MS中提供治疗益处的潜力。 测试这个 假设我们使用注射剂和慢性实验过敏性脑脊髓炎（EAE）模型进行了脱髓鞘疾病的模型进行了实验。我们发现以这种方式给出的狄克斯可以防止脱髓鞘疾病的发作和严重程度。该药物还具有完全扭转已建立疾病的临床症状的能力。与EAE研究相关的进一步数据表明，炎性细胞因子的产生减少，导致水肿减少并降低免疫细胞的免疫浸润到中枢神经系统中。通常在此模型中观察到这种浸润。 该提议的目标是通过评估其效力进一步阐明狄克斯的治疗潜力 当在许多相关的EAE模型中作为口服药物。口服DDOX将通​​过口服烤面包给患有慢性EAE或复发恢复EAE的小鼠。该药物将在疾病发作之前，疾病高峰和疾病高原之后（对于慢性EAE）以及在第一次缓解期间疾病发作之前以及在第二次缓解期间在疾病发作之前给药。将对这两个EAE模型进行详细研究，然后再将相同的研究扩展到MS的其他两个模型：慢性渐进式EAE模型和二级渐进式EAE模型。血液和中枢神经系统中DDOX的动力学将采用灵敏的HPLC/质谱法。 将评估该药物在所有EAE模型中维持恢复的能力。 将评估负责药物诱导恢复的分子，细胞和免疫机制。 如前所述，当前多发性硬化症的疗法主要阻止该疾病的进展，但不会扭转MS的症状。相比之下，DODOX治疗可能会通过抑制炎症，防止CNS的免疫浸润并减少水肿，从而促进CNS环境，从而恢复恢复，从而促进临床恢复，并可能发生透明度。更重要的是，该化合物已经在人类中进行了测试，能够横穿中枢神经系统的血脑屏障，并且在其他疾病模型中口服良好。还计划在这方面迫切需要新的口服药物疗法来阻止慢性进行的MS以及次要的MS和初步研究以评估DIDOX。根据我们的初步观察，我们认为Dodox具有有效的口服治疗多发性硬化症的巨大潜力。这是 预计该提案的结果将为启动这种新药物的临床试验提供基础。