Preclinical development of a novel therapeutic for Parkinson's disease

项目摘要 帕金森病（PD）是第二大常见的神经退行性疾病，约有100万人患有帕金森病。 美国人左旋多巴是帕金森病的金标准对症治疗，通过提高多巴胺水平， 个脑袋虽然是最有效的治疗方法，但长期使用左旋多巴会导致1）使人衰弱的副作用， 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，称为“磨损”。这些问题是PD中两个最大的未满足需求， 医生规定剂量和治疗方案，影响PD所需药物的疗效。 在使用左旋多巴5年后，40%的PD患者会出现LID和/或波动。不仅有一个 临床影响，但患有此类并发症的PD患者每年需要近60，000美元的额外治疗 年使用Sinopia Biosciences的计算平台，我们研究了基因表达变化， 向6-OHDA损伤的PD样小鼠施用左旋多巴。应用我们的计算工作流程，我们确定了一个 小分子（SB-0107）的选择基于：1）具有我们平台的最高分数之一，2）其 新的作用机制，3）老年患者的既往临床暴露，4）其预测的CNS渗透 5）专利保护的潜力。随后，我们证明了该化合物的独特性 和潜在的变革性药理学治疗PD的症状和并发症， 左旋多巴（即LID）。在啮齿动物和灵长类动物模型中，SB-0107显示出较大的效应量。我们还 在PD的认知缺陷灵长类动物模型中观察到，SB-0107改善了受试动物的表现， 认知任务因此，SB-0107代表了一种有希望的候选药物，可用于临床治疗PD。在这 快速通道提案，我们将通过完成临床前开发研究来推进该化合物， 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.