Preclinical development of a novel therapeutic for Parkinson's disease

项目摘要 帕金森病(PD)是第二常见的神经退行性疾病，约有100万人患病 美国人。左旋多巴是治疗帕金森病的黄金标准对症疗法，其作用是提高帕金森病患者体内的多巴胺水平。 大脑。尽管左旋多巴是最有效的治疗方法，但长期使用会导致1)衰弱的副作用， 左旋多巴诱导的运动障碍(LID)，以及2)左旋多巴疗效降低，导致PD波动 症状，即所谓的“疲惫”。这些担忧是PD中最大的两个未得到满足的需求，并影响到 医生会开出剂量和治疗方案，影响帕金森病必要药物的疗效。 在使用左旋多巴5年后，40%的帕金森病患者会出现眼盖和/或波动。不仅有一个 临床影响，但有此类并发症的PD患者每年需要近60,000美元的额外治疗 年。利用中国生物科学的计算平台，我们研究了由于 6-羟基多巴胺损毁帕金森病样小鼠给予左旋多巴。应用我们的计算工作流，我们确定了一个 小分子(SB-0107)是根据以下条件选择的：1)具有我们平台的最高分数之一，2)其 新的作用机制，3)老年患者既往临床暴露，4)其预测的中枢神经系统渗透 属性，以及5)其专利保护的潜力。随后，我们展示了该化合物的独特之处 治疗帕金森病症状和并发症的潜在变革性药理学 左旋多巴(即盖子)。在啮齿动物和灵长类动物模型中，SB-0107均表现出较大的效应大小。此外，我们 在帕金森病认知障碍灵长类动物模型中观察到SB-0107改善了受试者的表现 认知任务。因此，SB-0107代表了一种很有前途的帕金森病临床应用候选药物。在这 快速通道提案，我们将通过完成临床前开发研究来推动化合物的发展 对IND提交的预期。

Project Summary Parkinson’s Disease (PD) is the second most common neurodegenerative disorder, afflicting ~1 million Americans. Levodopa is the gold-standard symptomatic treatment for PD by elevating dopamine levels in the brain. Though the most effective treatment, prolonged levodopa use leads to 1) the debilitating side effect, levodopa-induced dyskinesia (LID), and 2) diminished levodopa efficacy which leads to fluctuations of PD symptoms, known as “wearing-off”. These concerns are two of the greatest unmet needs in PD and affect how doctors prescribe dosages and treatment options, impacting the efficacy of the necessary medications for PD. After 5 years of levodopa usage, 40% of PD patients will develop LID and/or fluctuations. Not only having a clinical impact, but PD patients with such complications require nearly $60,000 of additional therapeutics every year. Using Sinopia Biosciences’ computational platform, we studied gene expression changes due to levodopa administered to 6-OHDA lesioned PD-like mice. Applying our computational workflow, we identified a small molecule (SB-0107) that was selected based on: 1) having one of the top scores from our platform, 2) its novel mechanism of action, 3) previous clinical exposure to elderly patients, 4) its predicted CNS penetration properties, and 5) its potential for patent protection. Subsequently, we demonstrated the compound’s unique and potentially transformative pharmacology for treating both the symptoms of PD and complications of levodopa (i.e. LID). In both rodent and primate models, SB-0107 shows large effect sizes. Further, we observed in a cognitive deficit primate model of PD that SB-0107 improves performances in the tested cognitive tasks. Thus, SB-0107 represents a promising candidate for advancement to the clinic for PD. In this Fast-Track proposal, we will advance the compound by completing preclinical development studies for anticipation of IND submission.