One of the most common monogenic forms of Parkinson disease (PD) is caused by mutations in the LRRK2 gene that encodes leucine-rich repeat kinase 2 (LRRK2). LRRK2 mutations, and particularly the most common mutation Gly2019Ser, are observed in patients with autosomal dominant PD and in those with apparent sporadic PD, who are clinically indistinguishable from those with idiopathic PD. The discoveries that pathogenic mutations in the LRRK2 gene increase LRRK2 kinase activity and that small-molecule LRRK2 kinase inhibitors can be neuroprotective in preclinical models of PD have placed LRRK2 at the centre of disease modification efforts in PD. Recent investigations also suggest that LRRK2 has a role in the pathogenesis of idiopathic PD and that LRRK2 therapies might, therefore, be beneficial in this common subtype of PD. In this Review, we describe the characteristics of LRRK2-associated PD that are most relevant to the development of LRRK2-targeted therapies and the design and implementation of clinical trials. We highlight strategies for correcting the effects of mutations in the LRRK2 gene, focusing on how to identify which patients are the optimal candidates and how to decide on the timing of such trials. In addition, we discuss challenges in implementing trials of disease-modifying treatment in people who carry LRRK2 mutations.

中文翻译：

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帕金森病中的LRRK2：临床试验的挑战。

帕金森病（PD）最常见的单基因形式之一是由LRRK2基因的突变引起的，该基因编码富含亮氨酸的重复激酶2（LRRK2）。LRRK2突变，尤其是最常见的Gly2019Ser突变，在常染色体显性PD患者和明显散发性PD患者中观察到，在临床上与特发性PD患者没有区别。LRRK2基因中的致病性突变会增加LRRK2激酶活性，而小分子LRRK2激酶抑制剂在PD的临床前模型中具有神经保护作用，这一发现使LRRK2成为PD疾病改良努力的中心。最近的研究还表明，LRRK2在特发性PD的发病机理中具有作用，因此LRRK2治疗可能对PD的这一常见亚型有益。在这篇评论中，我们描述了与LRRK2相关的PD的特征，这些特征与LRRK2靶向疗法的开发以及临床试验的设计和实施最相关。我们重点介绍了纠正LRRK2基因突变影响的策略，重点在于如何确定哪些患者是最佳候选人，以及如何决定此类试验的时机。此外，我们讨论了在携带LRRK2突变的人中实施疾病改善治疗试验的挑战。重点在于如何确定哪些患者是最佳候选人，以及如何确定此类试验的时间。此外，我们讨论了在携带LRRK2突变的人中实施疾病改善治疗试验的挑战。重点在于如何确定哪些患者是最佳候选人，以及如何确定此类试验的时间。此外，我们讨论了在携带LRRK2突变的人中实施疾病改善治疗试验的挑战。