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: 8971973
• 负责人: Jeffrey L. Dupree
• 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/8971973
• 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; Health; 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; multiple sclerosis treatment; novel therapeutics; polyphenol; prevent; 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）： 项目摘要/摘要 目前多发性硬化症 (MS) 的治疗方法可以减缓疾病的进展，但不能促进康复。因此，需要额外的治疗来提供有利于神经元稳定和神经修复的中枢神经系统环境。 Didox 是独特的多酚化合物系列中的一员，这些化合物具有多方面的特性，具有可能为多发性硬化症提供治疗益处的生化特性。 为了测试这个 假设我们使用注射给药的二氧苯胺和脱髓鞘疾病的慢性实验性过敏性脑脊髓炎（EAE）模型进行了实验。我们发现以这种方式给予 Didox 可以预防脱髓鞘疾病的发作和严重程度。该药物还能够完全逆转已确定疾病的临床症状。与 EAE 研究相关的进一步数据表明，炎症细胞因子的产生减少，从而减少水肿并减少免疫细胞对中枢神经系统的免疫浸润；这种渗透通常在该模型中观察到。 该提案的目的是通过评估 Didox 的效力来进一步阐明其治疗潜力 在许多相关的 EAE 模型中作为口服药物给药时。将通过口服强饲法对患有慢性 EAE 或复发缓解型 EAE 的小鼠给予口服二氧苯胺。该药物将在疾病发作前、疾病高峰期和疾病平台期后（在慢性 EAE 的情况下）以及疾病发作前在第一次缓解期间和在第二次缓解期间（如果是慢性 EAE）给药。过去缓解型 EAE。在将相同的研究扩展到其他两种 MS 模型之前，将详细研究这两种 EAE 模型：慢性进展性 EAE 模型和继发性进展性 EAE 模型。将采用灵敏且特异的 HPLC/质谱法来追踪血液和中枢神经系统中的二恶英的动力学。 将评估该药物在所有 EAE 模型中维持恢复的能力。 将评估药物诱导恢复的分子、细胞和免疫学机制。 如前所述，目前多发性硬化症的治疗方法主要是预防疾病的进展，但不能逆转多发性硬化症的症状。相比之下，Didox 治疗可以通过抑制炎症、防止中枢神经系统的免疫浸润和减少水肿来促进适合恢复的中枢神经系统环境，从而允许临床恢复并可能发生髓鞘再生。更重要的是，这种化合物已经在人体中进行了测试，能够穿过中枢神经系统的血脑屏障，并且在其他疾病模型中口服耐受性良好。此外，还迫切需要新的口服药物疗法来阻止慢性进行性多发性硬化症以及继发性多发性硬化症，并且计划在这方面进行初步研究以评估 didox。根据我们的初步观察，我们相信 didox 具有成为多发性硬化症有效口服治疗药物的巨大潜力。这是 预计该提案的结果将为启动该新药的临床试验提供基础。