Advanced therapeutic for Parkinson's Disease

帕金森病的先进疗法

• 批准号: 10020202
• 负责人: Milton H. Werner
• 金额: $ 154.67万
• 依托单位: INHIBIKASE THERAPEUTICS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020202
• 关键词: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Adverse event; Affect; Amino Acyl-tRNA Synthetases; Animal Model; Antineoplastic Agents; Anxiety; Apoptosis; Automobile Driving; Autonomic Dysfunction; Brain; Brain Diseases; Cell Death; Characteristics; Chemicals; Chronic; Clinical; Complex; Data; Disease; Disease Progression; Disease model; Dopamine; Dose; Dyskinetic syndrome; Effectiveness; Etiology; Evaluation; Excision; Frequencies; Functional disorder; Gastrointestinal tract structure; Human; Imatinib; Immunologic Receptors; Impaired cognition; In Vitro; Lead; Mental Depression; Methods; Modeling; Modification; Motor; Movement Disorders; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Paris, France; Parkinson Disease; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phosphorylation; Population; Process; Production; Progressive Disease; Property; Protein Tyrosine Kinase; Proteins; Protocols documentation; Rattus; Replacement Therapy; Role; Safety; Severities; Sleep Disorders; Substantia nigra structure; Therapeutic; Toxicology; Tyrosine Kinase Inhibitor; Ubiquitin; Vesicle; alpha synuclein; brain tract; clinical toxicology; comparative; dopaminergic neuron; healthy volunteer; in vivo; inhibitor/antagonist; mitochondrial dysfunction; motor disorder; multicatalytic endopeptidase complex; neurotoxicity; nonhuman primate; novel; palliative; parkin gene/protein; pars compacta; pre-clinical; preclinical safety; prevent; process optimization; side effect; stressor; synuclein; synucleinopathy; ubiquitin-protein ligase

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.

帕金森氏病（PD）是一种进行性神经退行性疾病，影响美国约100万患者 全球一人和7至1000万人。 PD的特征是运动障碍， 由黑质nigra pars commacta（SNPC）的多巴胺神经元的进行性丧失引起 自主功能障碍，焦虑，抑郁，睡眠障碍和认知障碍 其他神经元种群的退化和功能障碍。迄今为止没有药物疗法 阻碍或阻止疾病的神经退行性特征。虽然替代了多巴胺 治疗减轻了症状运动功能障碍，随着疾病的发展，其有效性降低了， 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 姑息理论方法无法解决该疾病的潜在机制。虽然 PD的病因尚不完全清楚，有很多数据表明氧化应激增加 在SNPC的多巴胺能神经元中，显着促进了PD的发病机理。 C-ABL酪氨酸激酶 已被揭示为大脑中的关键检查点，C-ABL磷酸化（即激活）是牢固的 PD脑中的增加，在核核酸的动物模型中以及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。活化的C-ABL可以磷酸化 Parkin，导致抑制Parkin的E3连接酶功能和其有毒底物的积累，巴黎 （Parkin相互作用的底物）和氨基酰基TRNA合成酶复合物相互作用多功能蛋白2 （AIMP2）。 C-ABL1/2抑制剂恢复Parkin的E3连接酶活性，减少Parkin底物的积累， 并预防体外或体内MPTP诱导的神经毒性。活化的C-ABL还磷酸化A- 综合蛋白，驱动A-突触核蛋白的聚集以及负责的有毒聚集体的产生 神经变性。总之，这些结果表明抑制C-ABL激活可能是 有效修饰PD疗法。目前的建议将完成临床前毒理学 长期对帕金森患者的慢性药物管理要求，而铅药物IKT-148009是 完成最初的健康志愿者研究。

项目成果

Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity.

• DOI: 10.1002/mds.28858
• 发表时间: 2022-01
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Werner MH;Olanow CW
• 通讯作者: Olanow CW