Advanced therapeutic for Parkinson's Disease

帕金森氏病（PD）是一种进行性神经退行性疾病，在美国影响1000万患者。 每年有700万到1000万人。PD的特征是运动障碍， 由黑质腹侧部（SNpc）中多巴胺神经元的进行性丧失引起，以及 自主神经功能障碍，焦虑，抑郁，睡眠障碍和认知障碍，是由于 其他神经元群体的变性和功能障碍。到目前为止，还没有药物治疗 阻止或防止疾病的神经变性特征。虽然多巴胺替代疗法 治疗减轻了有症状的运动功能障碍，其有效性随着疾病的进展而降低， 导致不可接受的副作用，例如严重的运动波动和运动障碍。而且这 姑息治疗方法不能解决疾病的潜在机制。虽然 PD的病因尚不完全清楚，但大量数据表明，氧化应激增加 SNpc多巴胺能神经元的异常表达与PD的发病机制密切相关。c-Abl酪氨酸激酶 已被揭示为大脑中的关键检查点，并且c-Abl磷酸化（即激活）是强有力的。 在PD脑中、在α-突触核蛋白病的动物模型中以及在1-甲基-4-苯基-1，2，3，6- 四氢吡啶（MPTP）诱导的PD临床前动物模型。激活的c-Abl可以磷酸化 帕金，导致帕金E3连接酶功能的抑制及其毒性底物的积累，巴黎 （PARkin相互作用底物）和氨酰tRNA合成酶复合物相互作用多功能蛋白2 （AIMP2）。c-E3 1/2抑制剂恢复帕金E3连接酶活性，减少帕金底物的积累， 并在体外或体内保护免受MPTP诱导的神经毒性。活化的c-Abl也磷酸化a- 突触核蛋白，驱动α-突触核蛋白聚集和有毒聚集体的产生， 神经变性总之，这些结果表明，抑制c-Abl活化可能是一种抑制细胞凋亡的机制。 有效改善PD的疾病治疗。本提案将完成临床前毒理学 帕金森病患者长期用药的要求，而先导药物IkT-148009， 完成最初的健康志愿者研究。

Parkinson's Disease (PD) is a progressive neurodegenerative disorder that affects ≈1 million patient in the U.S. annually and 7 to 10 million people worldwide. PD is characterized by disorders of movement, which are caused by the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc), and autonomic dysfunction, anxiety, depression, sleep disorders and cognitive impairment that are due to the degeneration and dysfunction of other neuronal populations. To date there are no pharmaceutical therapies that impede or prevent the neurodegeneration characteristic of the disease. Although dopamine replacement therapy alleviates the symptomatic motor dysfunction, its effectiveness is reduced as the disease progresses, leading to unacceptable side effects, such as severe motor fluctuations and dyskinesias. Moreover, this palliative therapeutic approach does not address the underlying mechanism(s) of the disease. Although the etiology of PD is not yet entirely clear, there is an abundance of data indicating that increased oxidative stress in dopaminergic neurons of the SNpc significantly contributes to the pathogenesis of PD. c-Abl tyrosine kinase has been revealed as a key checkpoint in the brain and c-Abl phosphorylation (i.e. activation) is robustly increased in PD brain, in animal models of a-synucleinopathies and also in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced preclinical animal model of PD. Activated c-Abl can phosphorylate parkin, leading to inhibition of parkin's E3 ligase function and accumulation of its toxic substrates, PARIS (PARkin Interacting Substrate) and aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2). c-Abl1/2 inhibitors restore parkin's E3 ligase activity, reduce the accumulation of parkin substrates, and protects against MPTP-induced neurotoxicity in vitro or in vivo. Activated c-Abl also phosphorylates a- synuclein, driving both a-synuclein aggregation and production of toxic aggregates that are responsible for neurodegeneration. Taken together these results suggest that inhibition of c-Abl activation could be an effective disease modifying therapy for PD. The present proposal will complete the pre-clinical toxicology requirements for chronic drug administration to Parkinson's patients while the lead drug, IkT-148009, is completing initial healthy volunteer studies.