Precision medicine in Parkinson's disease patients with LRRK2 and GBA risk variants - Let's get even more personal.
Precision medicine in Parkinson's disease patients with LRRK2 and GBA risk variants - Let's get even more personal.
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LRRK2和GBA风险变异的帕金森病患者的精准医学——让我们更个人化。
DOI：
10.1186/s40035-020-00218-x
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发表时间：
2020-10-16
影响因子：
12.6
通讯作者：
Brundin P
中科院分区：
文献类型：
--
作者：
von Linstow CU;Gan-Or Z;Brundin P
帕金森氏病(PD)的特征是运动障碍和各种非运动症状。发病年龄、疾病进展速度以及运动和非运动症状的精确轮廓显示出相当大的个体差异。神经病理学上，黑质多巴胺能神经元的丢失是帕金森病的一个重要特征。绝大多数帕金森病患者在几个脑区表现出α-突触核蛋白聚集，但个体之间的神经病理也有很大的差异。虽然多巴胺替代疗法可以减少运动症状，但目前的疗法并不能改变疾病的进展。许多临床试验使用了各种各样的方法，但都未能实现疾病改良。有人认为，帕金森病的异质性是疾病修改试验失败的主要原因，而且一种治疗方法不太可能对所有患者有效。精确医学，使用针对帕金森病患者的病理生理学的药物，已经被认为是一种前进的方向。帕金森病患者可以根据他们是否携带与帕金森病风险升高相关的风险变量之一进行分层。在这篇综述中，我们评估了目前针对两种酶，富含亮氨酸的重复蛋白激酶2(LRRK2)和葡萄糖脑苷酶(GBA)的临床试验，这两种酶由两个最常见的帕金森病危险基因编码。由于与不同的LRRK2和GBA风险变量相关的致病过程的细节还没有完全了解，我们想知道这些基于精确医学的干预策略是否会被证明足够“精确”或“个性化”到足以改变PD患者的疾病过程。我们还考虑到这种策略在疾病的哪些阶段可能有效，因为这些基因首先与疾病发生的风险有关，而与疾病进展速度的联系不太明显。最后，我们批判性地评估了针对LRRK2和GBA的治疗可能与更广泛的PD患者相关的概念，而不仅仅是那些实际携带这些基因的风险变体的患者。
Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise” or “personalized” enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.
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DOI：
10.1016/s0140-6736(17)31585-4
发表时间：
2017-10-07
期刊：
Lancet (London, England)
影响因子：
--
作者：
Athauda D;Maclagan K;Skene SS;Bajwa-Joseph M;Letchford D;Chowdhury K;Hibbert S;Budnik N;Zampedri L;Dickson J;Li Y;Aviles-Olmos I;Warner TT;Limousin P;Lees AJ;Greig NH;Tebbs S;Foltynie T
通讯作者：
Foltynie T
影响因子：
8.6
作者：
Barone, Paolo;Antonini, Angelo;Del Dotto, Paolo
通讯作者：
Del Dotto, Paolo
影响因子：
9.9
作者：
De Pablo-Fernandez, Eduardo;Goldacre, Raph;Warner, Thomas T.
通讯作者：
Warner, Thomas T.
影响因子：
14.5
作者：
Blauwendraat, Cornelis;Reed, Xylena;Singleton, Andrew B.
通讯作者：
Singleton, Andrew B.
影响因子：
9.9
作者：
Anheim, M.;Elbaz, A.;Brice, A.
通讯作者：
Brice, A.