Müller Thomas
Department of Neurology, St. Joseph Hospital Berlin-Weissensee, Berlin, Germany.
Expert Opin Investig Drugs. 2023 Jul-Dec;32(9):787-792. doi: 10.1080/13543784.2023.2263357. Epub 2023 Oct 13.
Pathogenic mutations of the abundant leucine-rich repeat kinase 2 gene support the onset of familial and sporadic forms of Parkinson's disease. These genetic variants catalyze kinase activity by substrate phosphorylation. They promote the nigrostriatal neurodegenerative process, i.e. characterized by Lewy body formation.
This narrative review discusses leucine-rich repeat kinase 2 inhibitors as therapeutic concept for beneficial disease modification following a literature search.
Leucine-rich repeat kinase 2 gene function contributes to the onset of microglia inflammation, cellular, and mitochondrial dysfunction. Leucine-rich repeat kinase 2 inhibition with oral application of DNL151, respectively DNL201, and intrathecal administration of the antisense oligonucleotide BIIB094 in a single and multiple ascending dose study was safe and well tolerated. Approval of Leucine-rich repeat kinase 2 inhibitors in case of positive clinical study outcomes will introduce personalized medicine for beneficial modification of progression as the most unmet need for treatment of patients with Parkinson's disease. In addition to the currently, preponderantly performed clinical rating with established scales, further clinical trial endpoints, such as dosing of dopamine substitution, may be considered in study designs to demonstrate therapeutic effects on the progression of Parkinson's disease.
富含亮氨酸重复激酶2基因的致病性突变支持家族性和散发性帕金森病的发病。这些基因变异通过底物磷酸化催化激酶活性。它们促进黑质纹状体神经退行性过程，即以路易小体形成为特征。
本叙述性综述在文献检索后讨论了富含亮氨酸重复激酶2抑制剂作为有益疾病修饰的治疗概念。
富含亮氨酸重复激酶2基因功能促成小胶质细胞炎症、细胞和线粒体功能障碍的发生。在单次和多次递增剂量研究中，口服DNL151或DNL201以及鞘内注射反义寡核苷酸BIIB094抑制富含亮氨酸重复激酶2是安全且耐受性良好的。如果临床研究结果呈阳性，富含亮氨酸重复激酶2抑制剂的获批将引入个性化药物，以实现有益的疾病进展修饰，这是帕金森病患者治疗中最未得到满足的需求。除了目前主要使用既定量表进行的临床评分外，在研究设计中可考虑进一步的临床试验终点，如多巴胺替代剂量，以证明对帕金森病进展的治疗效果。
