Preclinical development of a novel therapeutic for Parkinson's disease

帕金森病新型疗法的临床前开发

• 批准号: 10913244
• 负责人: Aarash Bordbar
• 金额: $ 9.99万
• 依托单位: SINOPIA BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913244
• 关键词: Affect; American; Biological Sciences; Brain; Clinic; Clinical; Cognitive deficits; Dopamine; Exposure to; Gene Expression; L-DOPA induced dyskinesia; Legal patent; Lesion; Levodopa; Modeling; Mus; Neurodegenerative Disorders; Oxidopamine; Parkinson Disease; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacology; Preclinical Drug Development; Primates; Property; Rodent; Symptoms; Testing; Therapeutic; Time; cognitive task; cognitive testing; computational platform; dosage; drug discovery; effective therapy; improved; novel; novel therapeutics; older patient; preclinical development; side effect; small molecule; symptom treatment

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.

项目摘要 帕金森氏病（PD）是第二个最常见的神经退行性疾病，折磨了约100万 美国人。 Levodopa是通过提高多巴胺水平的黄金标准症状治疗 脑。虽然最有效的治疗方法，但长时间的左旋多巴使用导致1）令人衰弱的副作用，但 左旋多巴引起的运动障碍（盖）和2）降低了左旋多巴效率，从而导致PD波动 症状，称为“佩戴”。这些问题是PD中两个最大的未满足需求，并影响 医生开了剂量和治疗选择，影响了PD必要的药物的效率。 经过5年的左旋多巴使用，有40％的PD患者会出现盖子和/或波动。不仅有一个 临床影响，但这种并发症的PD患者每次需要近60,000美元的其他疗法 年。使用Sinopia Biosciences的计算平台，我们研究了由于 左旋多巴施用至6-OHDA病变的PD样小鼠。应用计算工作流程，我们确定了 基于以下基础选择的小分子（SB-0107）：1）在我们平台中具有最高分数之一，2） 新型作用机理，3）先前临床暴露于古老的患者，4）其预测的中枢神经系统穿透 属性和5）具有专利保护的潜力。随后，我们演示了该化合物的独特 以及潜在的转化药理学治疗PD症状和并发症的症状 左旋多巴（即盖子）。在啮齿动物和灵长类动物模型中，SB-0107显示出较大的效果大小。此外，我们 在SB-0107的认知缺陷私有模型中观察到，改善了测试的性能 认知任务。这是SB-0107代表晋升为PD诊所的承诺候选人。在这个 快速提议，我们将通过完成临床前开发研究来推进化合物 预期提交。