Assessment of lenalidomide to treat Alzheimer's disease

摘要 到目前为止，绝大多数针对阿尔茨海默病(AD)的治疗干预措施都集中在 改变单一神经病理的单一疗法。不幸的是，所有这些方法都未能满足 显著减缓或逆转AD受试者认知衰退的临床终点。这强调了 迫切需要新的治疗干预措施来同时减少几种阿尔茨海默病的神经病理。 炎症在许多神经系统疾病中普遍存在，但还没有临床试验证明其疗效。 治疗阿尔茨海默病的抗炎药。我们的研究小组对降低这两项指标的药物特别感兴趣 全身性和中枢性炎症，旨在预防或减缓AD的临床进展。我们的 最有希望的化合物是免疫调节剂，抗癌剂来那度胺，它是非常 几种既能降低促炎因子(如肿瘤坏死因子α、IL-6、IL-8)表达的多效性药物，又能 增加抗炎细胞因子(如IL-10)的表达，以调节先天和适应性 免疫反应。 利用我们之前的临床试验的经验和我们的动物数据，在 目前的项目，我们的目标是测试来那度胺减少AD相关的中心假说 神经炎症和神经病理，这可能会导致认知能力的改善。为此，我们 设计了一项针对单个和多个领域的Ib-IIa期、机制验证、安慰剂对照临床研究 遗忘型MCI患者每天服用来那度胺10 mg，疗程12个月。因为来那度胺从来没有 在AD的背景下进行了测试，我们将仔细监测MCI患者的安全性和耐受性。至 证明来那度胺在研究对象中的参与度，我们将在 每3个月外围一次。我们将通过MCI敏感测试来衡量认知表现。此外，我们还将 在给药结束时评估目标参与(脑脊液标记物)。这一点非常重要，因为如果 成功地，来那度胺将成为极少数能够降低几种 阿尔茨海默病相关的神经病理特征。此外，来那度胺的主要优点是 已经获得FDA批准用于癌症治疗的药物I，因此它可能会在IIb阶段研究中迅速改变用途。

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.