Discovering a Disease Modifying Therapeutic to Treat Huntington's Disease

蛋白质错误折叠和聚集导致慢性炎症、突触功能障碍和神经元死亡是包括阿尔茨海默病（AD）和亨廷顿病（HD）在内的神经退行性疾病的常见标志。虽然超过500万美国人患有AD，超过30，000人患有HD，但目前的疗法靶向症状，而不是蛋白质错误折叠、聚集及其下游后遗症的潜在病理生理学，这些疾病是痴呆和其他临床症状的基础。 热休克转录因子1（HSF 1）是一种主要的调节因子，通过激活参与蛋白质折叠、清除和自噬的基因以及通过抑制促进炎症的基因来保护神经元免受错误折叠蛋白质的破坏性影响。在AD和HD患者以及这些疾病的啮齿动物模型的尸检脑组织中，与对照组相比，HSF1蛋白水平异常低。我们证明，在HD组织HSF 1水平低，由于其磷酸化的蛋白激酶CK2，刺激蛋白酶体依赖性降解的HSF 1。在HD和AD中，CK2水平逐渐增加，表明AD脑中观察到的降低可能是由于CK2的这种异常升高。我们通过在HD小鼠模型中基因消融一个CK2等位基因，加强了CK2作为治疗靶点的验证，并证明了HSF 1水平的恢复，同时病理学（不溶性突变亨廷顿蛋白聚集体），病理生理学（纹状体中等多刺神经元丰度和突触，肌肉和体重）和行为减少。虽然在AD小鼠模型中不存在类似的数据，但我们已经在HD模型中看到了HSF 1对tau蛋白表达的调节，并且有一项已发表的研究表明，CK2抑制剂抑制了AD啮齿动物模型中原代星形胶质细胞中的炎症标志物。基于涉及CK 2在AD和HD的发病机制和病理生理学中的作用的多条证据线，我们专注于开发专有的CK 2抑制剂先导物作为阿尔茨海默病和亨廷顿病的新型疗法。本申请概述了以下具体目的：（1）鉴定具有药物样性质的有效的和选择性的CK2抑制剂（2）改进在小鼠体内表现出最佳药代动力学、脑转移和靶点接合的分子，和（3）验证先导化合物在亨廷顿病小鼠模型中的功效。虽然我们在战略上专注于HD作为一个小的初创公司，铅的发展和候选人的选择范式是适用于广告。 总之，考虑到HD和AD中HSF 1水平较低，而CK 2水平升高，通过CK 2抑制恢复HSF 1水平为亨廷顿病和阿尔茨海默病的疾病改善疗法提供了有希望的途径。我们自己的数据和文献使我们投资于专有CK2抑制剂的治疗开发，以防止蛋白质通过细胞伴侣错误折叠，并阻止错误折叠蛋白质的破坏性影响，导致突触丢失，慢性炎症和神经元死亡。

Protein misfolding and aggregation, leading to chronic inflammation, synaptic dysfunction and neuronal death are common hallmarks of neurodegenerative diseases including Alzheimer’s disease (AD) and Huntington’s disease (HD). While over 5 million Americans suffer from AD, and over 30,000 suffer from HD, current therapies target symptoms but not the underlying pathophysiology of protein misfolding, aggregation and its downstream sequalae underlying dementia and other clinical symptoms. Heat Shock Transcription Factor 1 (HSF1) is a master regulator that protects neurons from destructive effects of misfolded proteins by activating genes involved in protein folding, clearance and autophagy and by repressing genes that promote inflammation. In autopsied brain tissue from both AD and HD patients as well as in rodent models of these diseases, HSF1 protein levels are abnormally low compared to controls. We demonstrated that in HD tissues HSF1 levels are low due to its phosphorylation by protein kinase CK2, which stimulates proteasome-dependent degradation of HSF1. CK2 levels progressively increase in both HD and AD indicating that the observed reduction in AD brain may be due to this abnormal elevation of CK2. We strengthened the validation of CK2 as a therapeutic target through genetic ablation of one CK2 allele in a HD mouse model and demonstrated restoration of HSF1 levels concurrently with a reduction in pathology (insoluble mutant Huntingtin protein aggregates), pathophysiology (striatal medium spiny neuron abundance and synapses, muscle and body mass) and behavior. Although similar data do not exist in an AD mouse model, we have seen regulation of tau protein expression by HSF1 in an HD model and there is a published study demonstrating that CK2 inhibitors dampen inflammatory markers in primary astrocytes from an AD rodent model. Based on the multiple lines of evidence implicating the role of CK2 in pathogenesis and pathophysiology of AD and HD, we have focused on developing proprietary CK2 inhibitor leads as novel therapeutics for Alzheimer’s and Huntington’s disease. This application outlines specific aims to: (1) identify potent and selective CK2 inhibitors with drug-like properties (2) advance molecules that exhibit optimal pharmacokinetics, brain penetrance and target engagement in vivo in the mouse and (3) validate lead compounds for efficacy in a mouse model of Huntington’s disease. Although we have strategically focused on HD as a small start-up company, the lead development and candidate selection paradigm is applicable to AD. In summary, given that HSF1 levels are low, and CK2 levels are elevated in both HD and AD, the restoration of HSF1 levels through CK2 inhibition presents a promising route to a disease modifying therapy for Huntington’s and Alzheimer’s disease. Our own data and literature have led us to invest in therapeutic development of proprietary CK2 inhibitors to prevent protein misfolding via cellular chaperones and stemming the destructive effects of misfolded proteins leading to synapse loss, chronic inflammation and neuronal death.