Assessment of lenalidomide to treat Alzheimer's disease

来那度胺治疗阿尔茨海默病的评估

基本信息

批准号：
9967978
负责人：
Boris Decourt
金额：
$ 63.97万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-10-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9967978
关键词：
Active Immunization Adverse event Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-42 Amyloid beta-Protein Anti-Inflammatory Agents Antineoplastic Agents Back Blood Brain Chronic Clinical Clinical Research Clinical Trials Cognition Data Dose Enzyme-Linked Immunosorbent Assay FDA approved Hematopoietic Neoplasms Human IL8 gene Immunomodulators Impaired cognition Inflammation Inflammatory Interleukin-1 beta Interleukin-10 Interleukin-2 Interleukin-6 Interleukins Measures Methods Monitor NF-kappa B Neuraxis Neutropenia Passive Immunization Patients Penetration Peripheral Pharmaceutical Preparations Phase Placebo Control Placebos Plasma Play Reader Recommendation Reporting Research Role Safety Spectrophotometry Study Subject TNF gene Testing Thalidomide Therapeutic Intervention Thrombocytopenia Visit adaptive immune response analog animal data beta-site APP cleaving enzyme 1 cancer therapy chemokine cognitive performance cytokine design disorder risk experience gamma secretase improved inflammatory marker inhibitor/antagonist interest lenalidomide mild cognitive impairment mortality nervous system disorder neuroinflammation neuropathology novel novel therapeutic intervention prevent tau Proteins tau-1

项目摘要

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.

抽象的迄今为止，绝大多数针对阿尔茨海默病 (AD) 的治疗干预措施都集中在不幸的是，所有这些方法都未能满足这一要求。缓慢显着或逆转 AD 受试者认知能力下降的临床终点这强调了这一点。迫切需要新的治疗干预措施来同时减少多种 AD 神经病理学。炎症普遍存在于许多神经系统疾病中，但尚无临床试验证明其疗效我们的研究小组对降低这两种疾病的药物特别感兴趣。全身和中枢炎症旨在预防或减缓 AD 的临床进展。最有前途的化合物是免疫调节剂、抗癌剂来那度胺，它是最有前景的化合物之一。少数多效药物既能降低促炎细胞的表达（例如 TNFα、IL-6、IL-8），增加抗炎细胞因子（例如 IL-10）的表达，以调节先天性和适应性免疫反应。利用我们之前的类似物临床试验经验和我们的动物数据，目前的项目我们旨在测试来那度胺减少AD相关的中心假设神经炎症和神经病理学，这可能会导致认知能力的改善。设计了一项针对单域和多域的 Ib-IIa 期、机制证明、安慰剂对照临床研究遗忘性 MCI 受试者每天服用 10 毫克来那度胺，持续 12 个月，因为来那度胺从未服用过。在 AD 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。为了证明来那度胺在研究对象中的作用，我们将测量体内的炎症标志物每 3 个月我们将通过 MCI 敏感测试来测量认知表现。在完成给药时评估目标参与度（CSF 标志物），这是非常重要的，因为，如果。如果成功的话，来那度胺将成为极少数能够降低数个指标的化合物之一。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 已获得 FDA 批准用于癌症治疗，因此可以迅速在 IIb 期研究中重新调整用途。