Selective Activators of Nrf2 for Neurodegenerative Disease

类蛋白质聚合物(PLP)是下一代生物疗法，有可能改善患有破坏性神经退行性疾病的患者的治疗结果。我们已经开发出一种领先的PLP，它可以破坏Keap1-Nrf2细胞内蛋白质-蛋白质相互作用(PPI)，该相互作用限制了Nrf2(核因子-红系因子2相关因子2)的治疗活性，Nrf2是一个经过验证的转录因子靶标，它调控着数百个基因系统，这些基因参与了对氧化应激和蛋白稳态的保护反应，而这一系统一直未能得到选择性干预。这一应用与阿尔茨海默病/阿尔茨海默病相关痴呆(AD/ADRD)直接相关，因为在多种AD模型的小鼠大脑中增强的Nrf2激活表明，小鼠的AD相关病理显著减少。在这些模型中，β-淀粉样蛋白水平、斑块数量和tau病理的减少证明了Nrf2在减轻AD/ADRD方面的重要性。因此，本提案中的研究大纲将导致开发可用于治疗AD/ADRD的全新的Nrf2激活生物制品。初步数据表明，PLP在体外激活了原代皮质神经元中的Nrf2，在体内表现出4d的半衰期。我们的中心目标是优化我们的PLP Lead，通过调整其结构来平衡其生化效力和细胞进入，以提高其激活细胞内Nrf2的能力。来自这些研究的信息将被用来提名用于ARE-HPAP转基因报告基因和AD(APPK595N，M596L/PS1∆E9)模型的后续第二阶段药效学研究的高级先导，以提名开发候选药物，这将是我们第二阶段计划的重点。

Protein-like polymers (PLPs) are next generation biotherapeutics with the potential to improve treatment outcomes for patients suffering from devastating neurodegenerative diseases. We have developed a lead PLP that disrupts the Keap1-Nrf2 intracellular protein-protein interaction (PPI) that restricts the therapeutic activity of Nrf2 (nuclear factor-erythroid factor 2-related factor 2), a validated transcription factor target that regulates a system of hundreds of genes involved in protective responses against oxidative stress and proteostasis that has eluded selective intervention. This application is directly relevant to Alzheimer’s Disease/Alzheimer’s Disease Related Dementias (AD/ADRD) since enhanced Nrf2 activation in the brains of multiple mouse models of AD demonstrate significantly reduced AD associated pathology in the mice. The reduction in beta-amyloid levels, plaque numbers, and tau pathology in these models attest to the importance of Nrf2 in mitigating AD/ADRD. Thus, the studies outline in this proposal will lead to the development of completely novel Nrf2 activating biologics that could be used in the treatment of AD/ADRD. Preliminary data demonstrates that PLPs activate Nrf2 in primary cortical neurons in vitro and exhibit a 4d half-life in vivo. Our central objective is to optimize our PLP lead to improve its ability to activate Nrf2 in cells by tuning its architecture to balance its biochemical potency and cellular entry. Information from these studies will be used to nominate an advanced lead for follow-on Phase II pharmacodynamic studies in ARE-hPAP transgenic reporter and AD (APPK595N,M596L/PS1∆E9) models to nominate a development candidate, which will be the focus of our Phase II plan.