The Potential of Didox as an Oral Therapy for Multiple Sclerosis

描述(由申请人提供)： 项目摘要/摘要目前治疗多发性硬化症(MS)的方法减缓了疾病的进展，但不能促进康复。因此，需要额外的治疗方法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是一系列独特的多酚化合物中的一员，这些化合物具有多方面的生化特性，有可能在多发性硬化症中提供治疗益处。 假设我们使用注射用地多昔多和慢性实验性变态反应性脑脊髓炎(EAE)脱髓鞘疾病模型进行了实验。我们发现，以这种方式给药的Didox可以预防脱髓鞘疾病的发生和严重程度。这种药物还有能力完全逆转既定疾病的临床症状。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，导致水肿减轻，免疫细胞对中枢神经系统的免疫渗透减少；这种渗透通常在该模型中观察到。这项建议的目的是通过评估Didox的效力来进一步阐明其治疗潜力 在一些相关的EAE模型中作为口服药物给予。口服地多沙将通过口服给患有慢性EAE或复发缓解型EAE的小鼠灌胃。该药物将在发病前、疾病高峰期和疾病平台期后(对于慢性EAE)以及在疾病首次缓解期间和在第二次缓解期间(对于缓解期EAE)在发病之前给药。在将同样的研究扩展到MS的另外两个模型之前，我们将详细研究这两个模型：慢性进展性EAE模型和继发性进展性EAE模型。血液和中枢神经系统中的二恶英动力学将通过灵敏和特异的高效液相色谱/质谱学方法进行跟踪。将评估该药物在所有EAE模型中维持恢复的能力。将评估导致药物诱导恢复的分子、细胞和免疫学机制。如上所述，目前治疗多发性硬化症的方法大多可以阻止疾病的进展，但不能逆转多发性硬化症的症状。相比之下，Didox疗法可能通过抑制炎症、防止中枢神经系统的免疫渗透和减少水肿，促进易于恢复的中枢神经系统环境，从而使临床恢复和可能的髓鞘再生发生。更重要的是，这种化合物已经在人体上进行了测试，能够穿越中枢神经系统的血脑屏障，在其他疾病模型中口服耐受性良好。此外，迫切需要新的口服药物疗法来阻止慢性进展性多发性硬化症和继发性多发性硬化症，并计划进行初步研究，以评估这方面的二恶英。根据我们的初步观察，我们相信Didox有很好的潜力成为多发性硬化症的有效口服治疗药物。它是 预计这项提案的结果将为启动该新药的临床试验提供基础。

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.