Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.
Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease.
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DOI：
10.1016/j.expneurol.2017.07.019
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发表时间：
2017-12
影响因子：
5.3
通讯作者：
West AB
中科院分区：
文献类型：
--
作者：
West AB
在将发现从实验室转化为临床的过程中，在神经退行性疾病中开发疾病修饰疗法的记录很差。根据临床前模型和患者人群的发现建立精心设计的开发管道是优化成功机会的必要条件。富含亮氨酸重复序列激酶2基因（LRRK2）的遗传变异与帕金森病（PD）易感性有关。致病性突变，特别是LRRK2 GT3（Roc）和COR结构域中的那些，增加细胞和组织中的LRRK2激酶活性。在一些PD模型中，阻断这些活性的小分子LRRK2激酶抑制剂也提供神经保护。在此，遗传和生化证据支持参与LRRK2激酶活性在PD易感性进行审查。与LRRK2抑制的治疗窗口的定义和长期给药的安全性有关的问题进行了讨论。最后，建议在PD患者中进行生物标志物引导的LRRK2激酶抑制剂初始治疗。在PD中使用LRRK2激酶抑制剂实现神经保护必须考虑四个关键领域：1）鉴定最有可能受益于LRRK 2激酶抑制剂的患者群体，2）基于药物性能的公开披露对上级LRRK 2小分子抑制剂进行优先排序，3）在临床试验中结合生物标志物和LRRK 2激酶抑制的经验测量，以及4）部分地由严格的临床前建模指导的适当的功效测量的利用。谨慎和合理的开发决策可以潜在地防止令人难以置信的昂贵错误，并为LRRK2抑制剂减缓PD进展提供最佳机会。
In the translation of discoveries from the laboratory to the clinic, the track record in developing disease-modifying therapies in neurodegenerative disease is poor. A carefully designed development pipeline built from discoveries in both pre-clinical models and patient populations is necessary to optimize the chances for success. Genetic variation in the leucine-rich repeat kinase two gene (LRRK2) is linked to Parkinson disease (PD) susceptibility. Pathogenic mutations, particularly those in the LRRK2 GTPase (Roc) and COR domains, increase LRRK2 kinase activities in cells and tissues. In some PD models, small molecule LRRK2 kinase inhibitors that block these activities also provide neuroprotection. Herein, the genetic and biochemical evidence that supports the involvement of LRRK2 kinase activity in PD susceptibility is reviewed. Issues related to the definition of a therapeutic window for LRRK2 inhibition and the safety of chronic dosing are discussed. Finally, recommendations are given for a biomarker-guided initial entry of LRRK2 kinase inhibitors in PD patients. Four key areas must be considered for achieving neuroprotection with LRRK2 kinase inhibitors in PD: 1) identification of patient populations most likely to benefit from LRRK2 kinase inhibitors , 2) prioritization of superior LRRK2 small molecule inhibitors based on open disclosures of drug performance, 3) incorporation of biomarkers and empirical measures of LRRK2 kinase inhibition in clinical trials, and 4) utilization of appropriate efficacy measures guided in part by rigorous pre-clinical modeling. Meticulous and rational development decisions can potentially prevent incredibly costly errors and provide the best chances for LRRK2 inhibitors to slow the progression of PD.
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DOI：
10.1038/s41531-017-0010-8
发表时间：
2017
期刊：
NPJ Parkinson's disease
影响因子：
--
作者：
Cook DA;Kannarkat GT;Cintron AF;Butkovich LM;Fraser KB;Chang J;Grigoryan N;Factor SA;West AB;Boss JM;Tansey MG
通讯作者：
Tansey MG
DOI：
10.1523/jneurosci.4357-09.2009
发表时间：
2009-12-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Andres-Mateos E;Mejias R;Sasaki M;Li X;Lin BM;Biskup S;Zhang L;Banerjee R;Thomas B;Yang L;Liu G;Beal MF;Huso DL;Dawson TM;Dawson VL
通讯作者：
Dawson VL
大鼠富含亮氨酸重复激酶 2 (LRRK2) 的缺失会导致外周器官逐渐出现异常表型。
影响因子：
3.7
作者：
Baptista MA;Dave KD;Frasier MA;Sherer TB;Greeley M;Beck MJ;Varsho JS;Parker GA;Moore C;Churchill MJ;Meshul CK;Fiske BK
通讯作者：
Fiske BK
影响因子：
8.6
作者：
Fraser, Kyle B.;Rawlins, Ashlee B.;Clark, Rachel G.;Alcalay, Roy N.;Standaert, David G.;Liu, Nianjun;West, Andrew B.
通讯作者：
West, Andrew B.
影响因子：
11.2
作者：
Funayama, M;Hasegawa, K;Obata, F
通讯作者：
Obata, F