Retinoid receptor modulators as novel disease-modifying therapeutics for Parkinson's disease

帕金森氏病(PD)是增长最快的神经系统疾病。这是一个复杂的情况，有多个相互关联的病理机制组件。这使得在帕金森氏症中解决疾病修饰问题成为一项挑战。帕金森氏症患者可以获得有助于缓解他们运动症状的治疗。然而，目前还没有任何治疗方法可以保存或修复渐进性退化的多巴胺能神经元。导致这种退化的机制很复杂：氧化应激、线粒体功能障碍、蛋白酶体功能障碍、内质网应激、自噬缺陷、炎症和兴奋毒性都与细胞凋亡的途径有关。到目前为止，对这些机制的单独药理干预还没有产生任何在临床试验中被证明成功的药物。维甲酸调节与神经元维持和发育有关的多个保护性基因的转录，因此被认为是治疗帕金森病等神经退行性疾病的有希望的疾病修饰靶点(Clark等人，2020)。到目前为止，关于视黄醇信号功能障碍是否也是帕金森病发病的原因因素，直接信息有限。然而，它们的药理学特征本身就为靶向这一系统以实现帕金森病的神经保护和修复提供了强有力的理由。事实上，维甲酸本身可以防止MPTP治疗的帕金森病小鼠模型中的多巴胺能退化。然而，这在临床上是不可行的，因为它对维甲酸X受体的作用会产生不想要的不良反应。为了解决这个问题，nevargenics开发了一种创新的双靶点(基因组和非基因组)方法来创建新的RAR特异性配体。NVG0645就是这样一种有效的配体，它具有良好的粘附性，在体外产生多种与逆转PD病理相适应的作用，包括：抗炎；抗兴奋毒性；诱导神经保护基因；轴突延长(Khatib等人，2019年)。在初步实验中，我们发现NVG0645可以保护6-OHDA损毁大鼠的多巴胺神经元变性和运动损伤。在这个项目中，我们将收集支持RAR调制器有益效果的证据，并充分描述支持这些效果的详细分子信号机制。我们预测RAR调节剂将提供神经保护、神经可塑性和神经修复以帮助缓解症状。我们还将探讨RAR系统在帕金森病人脑中的地位。总体而言，这些研究将支持这类RAR-M进入临床研究。这个项目有5个主要目标，将在下一节加以润色。目的1：确定RAR-ms引导RAR信号通路的有效给药方案。目的2：观察RAR-ms对6-OHDA损伤性帕金森病大鼠的神经保护作用，并探讨其作用机制。目标3：加深对药物发现计划中的翻译步骤的理解。目的4：建立最佳RAR-M修复6-OHDA大鼠模型和α-突触核蛋白表达模型的能力，并确定其潜在的机制。目的5：建立PD患者视黄醇系统是否受损

Parkinson's disease (PD) is the fastest growing neurological disease. It is a complex condition with multiple inter-related pathomechanistic components. This makes tackling disease modification in PD a challenge. People with PD can access treatments that help relieve their motor symptoms. However, no treatment can yet preserve or repair the dopaminergic neurones that progressively degenerate. The mechanisms underlying this degeneration are complex: oxidative stress, mitochondrial dysfunction, proteasome dysfunction, ER stress, autophagy deficits, inflammation and excitotoxicity have all been implicated in the pathway towards apoptotic cell death. To date, pharmacological interference with these mechanisms individually has not yielded any agents that have proven successful in clinical trials. Retinoids regulate transcription of multiple protective genes involved in neuronal maintenance and development and as such are proposed as a promising target for disease modification in neurodegenerative disease like PD (Clark et al., 2020). To date, there is limited direct information on whether dysfunctional retinoid signalling is also a contributing causal factor in the pathogenesis of PD. However, their pharmacological profile alone provides a strong rationale for targeting this system to achieve neuroprotection and repair in PD. Indeed, retinoid acid itself prevents dopaminergic degeneration in the MPTP-treated mouse model of PD. However, this is not viable for clinical use because its action on retinoid X receptors produces unwanted adverse effects. To address this, Nevrargenics have developed an innovative dual-target (genomic and non-genomic) approach to create novel RAR-specific ligands. NVG0645 is one such potent ligand that has good ADMET qualities and produces multiple actions in-vitro that are compatible with reversing PD pathology including: anti-inflammatory; anti-excitotoxic; induction of neuroprotective genes; neurite extension (Khatib et al., 2019). In preliminary experiments, we showed that NVG0645 could protect against dopamine neuron degeneration and motor impairment in the 6-OHDA lesioned rat. In this project we will gather evidence supporting the beneficial effects of the RAR modulators and fully characterise the detailed molecular signalling mechanisms underpinning these effects. We predict RAR-modulators will provide neuroprotection, neuroplasticity and neurorepair to aid symptom relief. We will also explore the status of RAR systems in PD human brain. Overall, these studies will support progression of this class of RAR-M into clinical studies. There are 5 key aims to this project, embellished on in the next section. AIM 1: To determine the effective dosing regimen of the lead RAR-Ms for driving RAR signalling AIM 2: To establish the neuroprotective efficacy of RAR-Ms in the 6-OHDA lesioned rat model of PD and define the underlying mechanisms. AIM 3: To develop understanding of the translational steps in a drug discovery programme. AIM 4: To establish the ability of the best RAR-M to repair an established or developing lesion in 6-OHDA rat model and an alpha-synuclein expressing model of choice, and define underlying mechanisms AIM 5: To establish whether the retinoid system is impaired in PD patients