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.

项目概要 帕金森病 (PD) 是第二大常见的神经退行性疾病，约有 100 万人受其困扰 美国人认为，左旋多巴是通过提高体内多巴胺水平来治疗 PD 的黄金标准。 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， 左旋多巴诱发的运动障碍 (LID)，以及 2) 左旋多巴疗效减弱，导致 PD 波动 症状，即所谓的“逐渐消失”，这些担忧是 PD 中两个最大的未满足需求，并影响其效果。 医生开具剂量和治疗方案，影响帕金森病必要药物的疗效。 使用左旋多巴 5 年后，40% 的 PD 患者会出现 LID 和/或波动。 临床影响，但患有此类并发症的 PD 患者每次需要近 60,000 美元的额外治疗 今年，我们使用 Sinopia Biosciences 的计算平台研究了基因表达的变化。 将左旋多巴给予 6-OHDA 损伤的 PD 样小鼠，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之一，2) 其 新的作用机制，3）既往对老年患者的临床暴露，4）其预测的中枢神经系统渗透 特性，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性。 以及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 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。 在 PD 认知缺陷灵长类动物模型中观察到 SB-0107 改善了测试对象的表现 因此，SB-0107 是进入 PD 临床的有希望的候选者。 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的发展 预计 IND 提交。