Assessment of lenalidomide to treat Alzheimer's disease

摘要 迄今为止，针对阿尔茨海默病（AD）的绝大多数治疗干预都集中在 单一疗法来改变单一的神经病理。不幸的是，所有这些方法都未能满足 在AD受试者中显著减缓或逆转认知下降的临床终点。这强调了 迫切需要新的治疗干预，以减少同时几个AD神经病理。 炎症在许多神经系统疾病中普遍存在，但没有临床试验证明其疗效 治疗AD的抗炎药我们的研究小组特别感兴趣的药物， 系统性和中枢性炎症，旨在预防或减缓AD的临床进展。我们 最有前途的化合物是免疫调节剂，抗癌剂来那度胺，这是一个非常 一些多效性药物，既降低促炎性因子（如TNFα、IL-6、IL-8）的表达， 增加抗炎细胞因子（如IL-10）的表达，以调节先天性和适应性 免疫反应。 利用我们以前临床试验的经验和我们的动物数据，在 目前的项目，我们的目标是测试的中心假设，来那度胺减少AD相关的 神经炎症和神经病理学，这可能导致改善的认知表现。为此我们 设计了一项关于单域和多域的Ib-IIa期、机制验证、安慰剂对照临床研究 遗忘型MCI受试者给予10 mg/天来那度胺12个月。因为来那度胺从来没有 在AD的背景下进行测试，我们将仔细监测MCI患者的安全性和耐受性。到 为了证明来那度胺在研究受试者中的作用，我们将测量受试者中的炎症标志物。 每3个月进行一次外围检查。我们将通过MCI敏感性测试来衡量认知能力。此外，我们将 在给药完成时评估靶点结合（CSF标志物）。这是非常重要的，因为如果 成功的话，来那度胺将成为极少数能够降低几个 与AD相关的神经病理学特征。此外，来那度胺的主要优点是， 药物I已经被FDA批准用于癌症治疗，因此它可以迅速在IIb期研究中重新使用。

ABSTRACT The vast majority of therapeutic interventions targeting Alzheimer's disease (AD) until now have focused on monotherapies to alter a single neuropathology. Unfortunately, all these approaches have failed to meet the clinical endpoint of significantly slowing or reversing cognitive decline in AD subjects. This emphasizes the urgent need for novel therapeutic interventions to reduce several AD neuropathologies simultaneously. Inflammation is pervasive to many neurological disorders, yet no clinical trial has demonstrated the efficacy of anti-inflammatory agents for AD. Our research group is particularly interested in drugs that lower both systemic and central inflammation aiming at preventing or slowing down the clinical progression of AD. Our most promising compound is the immunomodulator, anti-cancer agent lenalidomide, which is one of the very few pleiotropic agents that both lowers the expression of pro-inflammatory (e.g. TNFα, IL-6, IL-8), and increases the expression of anti-inflammatory cytokines (e.g. IL-10), to modulate both innate and adaptive immune responses. Capitalizing on our experience from a previous clinical trial with an analog and our animal data, in the current project we aim to test the central hypothesis that lenalidomide reduces AD-associated neuroinflammation and neuropathologies, which might result in improved cognitive performances. For this, we designed a Phase Ib-IIa, proof-of-mechanism, placebo-controlled clinical study on single and multiple domain amnestic MCI subjects administered 10 mg/day lenalidomide for 12 months. Because lenalidomide has never been tested in the context of AD, we will monitor carefully the safety and tolerability in MCI patients. To demonstrate the engagement of lenalidomide in study subjects, we will measure inflammatory markers in the periphery every 3 months. We will measure cognitive performance via MCI-sensitive tests. In addition, we will assess target engagement (CSF markers) at the completion of dosing. This is highly significant because, if successful, lenalidomide will become one of the very few compounds capable of lowering several neuropathological features associated with AD. Furthermore, the major advantage of lenalidomide is that the drug I already FDA-approved for cancer treatment, thus it could rapidly be repurposed in a Phase IIb study.