LRRK2 as a target for the treatment of Parkinson’s disease

LRRK2作为治疗帕金森病的靶点

• 批准号: 414868630
• 负责人: Professor Dr. Thomas Gasser
• 金额: --
• 依托单位: Zentrum für Regenerative Therapien Dresden - CRTD
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/414868630?language=en
• 关键词: LRRK2; target; treatment; Parkinson; disease

Small molecules inhibiting LRRK2 are promising new drug candidates to protect neurons against Parkinson’s disease (PD) pathology. However, PD is a heterogeneous neurodegenerative disorder consisting of multiple subtypes with patients differing widely in their symptoms and progression, making it very difficult for a clinical trial to detect an effective drug. Thus, biomarkers are urgently needed to identify patient subgroups that would respond to LRRK2 inhibitors as well as biomarkers of to monitor target engagement. In order to identify these biomarkers, it is first necessary to understand the mechanism by which LRRK2 affects neurodegeneration. Using neurons differentiated from induced pluripotent stem cells (iPSCs) from patients with mutant LRRK2 and isogenic mutation-corrected controls, we have developed one of the first robust neurodegenerative phenotypes using axonal trafficking, and this trafficking defect is completely rescued by treating with LRRK2 inhibitors. Using quantitative phospho-proteomics, we found that LRRK2 activity is associated with increased phosphorylation of microtubule associated proteins (MAPs), which leads to disruption of the cytoskeleton, causing axonal degeneration. It is likely that these changes are indirect since LRRK2 is expressed at very low levels, and many kinases are known to mediate MAP phosphorylation. Rab proteins have been shown to be directly phosphorylated by LRRK2 and have been linked to axonal trafficking, making them good candidate biomarkers for target engagement. Here, we propose: (1) identifying the specific phospho-Rab(s) mediating axonal phenotypes and aberrant phosphorylation of MAPs in neurons with LRRK2 G2019S, (2) assessing phospho-Rab and phospho-MAPs as possible biomarkers of target engagement for LRRK2 inhibitors in iPSCs-derived neurons, (3) validating the candidate biomarkers of LRRK2 target engagement using samples from patient cohorts, and (4) using iPSC-based models of idiopathic PD (iPD) stratified by common LRRK2 risk polymorphisms to determine if LRRK2 inhibitors could also be effective in subsets of iPD patients. Because we propose focusing on compounds that are being tested in phase I clinical trials, we argue that our proposal is poised to have a direct impact on the structure of clinical trials, which could lead to the first approved drug that effectively protects against PD pathogenesis.

抑制LRRK 2的小分子是保护神经元免受帕金森病（PD）病理影响的有前途的新候选药物。然而，PD是一种异质性神经退行性疾病，由多种亚型组成，患者的症状和进展差异很大，因此临床试验很难检测到有效的药物。因此，迫切需要生物标志物来鉴定对LRRK 2抑制剂有反应的患者亚组以及监测靶标接合的生物标志物。为了鉴定这些生物标志物，首先需要了解LRRK 2影响神经变性的机制。使用从突变型LRRK 2患者的诱导多能干细胞（iPSC）分化的神经元和同基因突变校正的对照，我们已经开发了第一个强大的神经退行性表型使用轴突运输，这种运输缺陷完全通过LRRK 2抑制剂治疗来挽救。使用定量磷酸蛋白质组学，我们发现LRRK 2活性与微管相关蛋白（MAP）的磷酸化增加有关，这导致细胞骨架破坏，引起轴突变性。这些变化可能是间接的，因为LRRK 2以非常低的水平表达，并且已知许多激酶介导MAP磷酸化。Rab蛋白已被证明可被LRRK 2直接磷酸化，并与轴突运输有关，使其成为靶点接合的良好候选生物标志物。在此，我们建议：（1）鉴定具有LRRK 2 G2019 S的神经元中介导轴突表型和MAP异常磷酸化的特异性磷酸化-Rab，（2）评估磷酸化-Rab和磷酸化-MAP作为iPSC衍生的神经元中LRRK 2抑制剂的靶标接合的可能生物标志物，（3）使用来自患者组群的样品验证LRRK 2靶标接合的候选生物标志物，和（4）使用根据常见LRRK 2风险多态性分层的基于iPSC的特发性PD（iPD）模型来确定LRRK 2抑制剂是否也可以在iPD患者亚组中有效。因为我们建议专注于正在I期临床试验中测试的化合物，我们认为我们的建议有望对临床试验的结构产生直接影响，这可能导致第一个批准的有效预防PD发病机制的药物。