Karuppagounder Senthilkumar S, Wang Hu, Kelly Terence, Rush Roger, Nguyen Richard, Bisen Shivani, Yamashita Yoko, Sloan Nicholas, Dang Brianna, Sigmon Alexander, Lee Hyeun Woo, Marino Lee Shirley, Watkins Leslie, Kim Erica, Brahmachari Saurav, Kumar Manoj, Werner Milton H, Dawson Ted M, Dawson Valina L
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sci Transl Med. 2023 Jan 18;15(679):eabp9352. doi: 10.1126/scitranslmed.abp9352.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.
帕金森病（PD）是中枢神经系统第二常见的神经退行性疾病，全球估计有500万病例。PD的病理学特征是错误折叠的α-突触核蛋白的积累，这种蛋白被认为在该疾病的发病机制中起关键作用。PD动物模型表明，阿贝尔森酪氨酸激酶（c-Abl）的激活在α-突触核蛋白病理学的起始和进展中起重要作用，并启动导致多巴胺能和非多巴胺能神经元退化的过程。鉴于c-Abl在PD中的潜在作用，开发了一个c-Abl抑制剂文库，以根据预定义的特征鉴定能够穿过血脑屏障的口服生物可利用的c-Abl抑制剂，从而发现了IkT-148009。IkT-148009是一种具有良好毒理学特征的脑渗透性c-Abl抑制剂，在缓慢进展的、α-突触核蛋白依赖性PD动物模型中分析其治疗潜力。在遗传性和散发性PD小鼠模型中，从疾病开始后4周起，通过每日一次口服灌胃进行治疗给药时，IkT-148009将c-Abl激活抑制到基线水平，并显著保护多巴胺能神经元免于退化。PD小鼠的运动功能在开始治疗后8周内恢复，同时小鼠脑中α-突触核蛋白病理学减少。这些发现表明，IkT-148009可能具有作为PD疾病修饰疗法的潜力。
