I-Corps: Repurposing Serotoninergic Compounds for Improved Treatment of Parkinson's Disease

I-Corps：重新利用血清素能化合物以改善帕金森病的治疗

• 批准号: 2148598
• 负责人: Christopher Bishop
• 金额: $ 5万
• 依托单位: SUNY at Binghamton
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2148598&HistoricalAwards=false
• 关键词: Corps; Repurposing; Serotoninergic; Compounds; Improved

The broader impact/commercial potential of this I-Corps project is the development of target-specific drugs that reduce severity and incidence of levodopa-induced dyskinesia in Parkinson’s disease. Dyskinesia is a debilitating side effect of levodopa therapy characterized by abnormal involuntary movements that can interfere with daily activities present in up to 90% of nearly 10 million Parkinson’s disease patients worldwide. Considering the increased economic burden felt by caregivers and patients resulting from the development of dyskinesia, in addition to the associated reductions in quality of life, providing dyskinesia relief to patients represents a largely unmet need in the clinic. Reducing dyskinesia may allow some patients to regain more control of their lives. Some may be able to begin feeding and bathing themselves again, others may once again play with their children or grandchildren, and others may regain enough movement control to return to work. Commercially, dyskinesia relief presents an opportunity to repurpose FDA-approved drugs into patentable combinations and/or formulations that increase the likelihood of successful translation into the clinic.This I-Corps project is based on the development of newly repurposed dual-action selective serotonin (5-HT) reuptake inhibitor (SSRI)/5-HT1A receptor agonist compounds that reduce the expression and incidence of dyskinesia. Over a decade of research has validated the capability of drugs with either SSRI or 5HT1A receptor agonist actions to reduce dyskinesia, however, a breakthrough discovery has uncovered evidence that drugs acting on both targets produce an unprecedented reduction of dyskinesia exceeding 90% suppression. Fortunately for patients, two FDA-approved drugs have been identified that meet these criteria and produce substantial effects in pre-clinical models. Using repurposed, as opposed to novel, drugs increase chances of successful translation into the clinic, as these compounds already have been de-risked and trialed for safety and tolerability. In addition, the mechanisms of action of these drugs are well validated through prior trials, reducing development costs by hundreds of millions of dollars. The use of repurposed drugs is safer, cheaper, and more successful, which is why 30% of all newly-FDA approved treatments involve the use of repurposed drugs.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这个i-Corps项目的更广泛的影响/商业潜力是开发针对目标的药物，降低帕金森病左旋多巴诱导的运动障碍的严重程度和发生率。运动障碍是左旋多巴疗法的一种衰弱副作用，其特征是异常的不自主运动，可能会干扰日常活动，全世界近1000万帕金森氏病患者中高达90%的患者存在这种情况。考虑到护理人员和患者因运动障碍的发展而感受到的经济负担增加，除了相关的生活质量下降外，向患者提供运动障碍缓解在临床上是一个基本上没有得到满足的需求。减少运动障碍可能会让一些患者重新获得对生活的更多控制。一些人可能会重新开始喂食和洗澡，其他人可能会再次与他们的子女或孙子玩耍，还有一些人可能会重新获得足够的运动控制来重返工作岗位。在商业上，缓解运动障碍提供了一个机会，将FDA批准的药物重新用于专利组合和/或配方，从而增加成功转化为临床的可能性。这个I-Corps项目基于新改变用途的双重作用选择性5-羟色胺(5-HT)再摄取抑制剂(SSRI)/5-HT1a受体激动剂化合物的开发，这些化合物可以减少运动障碍的表达和发生率。十多年的研究已经验证了具有SSRI或5HT1A受体激动剂作用的药物减少运动障碍的能力，然而，一项突破性发现发现，作用于这两个靶点的药物可以史无前例地减少超过90%抑制的运动障碍。对患者来说幸运的是，已经确定了两种FDA批准的药物，它们符合这些标准，并在临床前模型中产生了实质性的效果。与使用新药相反，使用重新用途的药物增加了成功转化到临床的机会，因为这些化合物已经降低了风险，并进行了安全性和耐受性试验。此外，这些药物的作用机制通过先前的试验得到了很好的验证，从而减少了数亿美元的开发成本。改变用途的药物的使用更安全、更便宜、更成功，这就是为什么FDA新批准的所有治疗中有30%涉及使用改变用途的药物。这一奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。