Despite the sound epidemiologic and basic science rationales underpinning numerous "disease modification" trials in manifest Parkinson disease (PD), none has convincingly demonstrated that a treatment slows progression. Rapidly expanding knowledge of the genetic determinants and prodromal features of PD now allows realistic planning of prevention trials with initiation of putatively neuroprotective therapies earlier in the disease. In this article, we outline the principles of drug selection for PD prevention trials, focused on proof-of-concept opportunities that will help establish a methodological foundation for this fledgling field. We describe prototypical, relatively low-risk drug candidates for such trials (e.g., albuterol, ambroxol, caffeine, ibuprofen), tailored to specific at-risk populations ranging from pathogenic LRRK2 or GBA gene variant carriers to those defined by prodromal PD and α-synucleinopathy. Finally, we review gene-targeted approaches currently in development targeting clinically manifest PD for their potential in future prevention trials.

中文翻译：

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帕金森病预防试验中要测试什么？重新利用、低风险和基因靶向药物。

尽管针对明显帕金森病（PD）的众多“疾病修饰”试验有合理的流行病学和基础科学原理，但没有一个试验能够令人信服地证明治疗可以减缓进展。随着对帕金森病遗传决定因素和前驱特征的了解不断加深，现在可以通过在疾病早期启动推定的神经保护疗法来制定现实的预防试验计划。在本文中，我们概述了 PD 预防试验的药物选择原则，重点关注概念验证机会，这将有助于为这个新兴领域建立方法学基础。我们描述了用于此类试验的原型、相对低风险的候选药物（例如沙丁胺醇、氨溴索、咖啡因、布洛芬），这些药物针对特定的高危人群，从致病性 LRRK2 或 GBA 基因变异携带者到前驱 PD 和 α- 定义的人群。突触核蛋白病。最后，我们回顾了目前正在开发的针对临床明显帕金森病的基因靶向方法，以了解其在未来预防试验中的潜力。