Ho Philip Wing-Lok, Chang Eunice Eun-Seo, Leung Chi-Ting, Liu Huifang, Malki Yasine, Pang Shirley Yin-Yu, Choi Zoe Yuen-Kiu, Liang Yingmin, Lai Weng Seng, Ruan Yuefei, Leung Kenneth Mei-Yee, Yung Susan, Mak Judith Choi-Wo, Kung Michelle Hiu-Wai, Ramsden David B, Ho Shu-Leong
Division of Neurology, Department of Medicine, School of Clinical Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong.
Division of Respiratory Medicine, Department of Medicine, School of Clinical Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong.
NPJ Parkinsons Dis. 2022 Sep 10;8(1):115. doi: 10.1038/s41531-022-00386-9.
Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in nigrostriatal and cortical brain regions associated with pathogenic α-synuclein (αSyn) aggregate/oligomer accumulation. LRRK2 hyperactivity is a disease-modifying therapeutic target in PD. However, LRRK2 inhibition may be associated with peripheral effects, albeit with unclear clinical consequences. Here, we significantly reduced αSyn oligomer accumulation in mouse striatum through long-term LRRK2 inhibition using GNE-7915 (specific brain-penetrant LRRK2 inhibitor) without causing adverse peripheral effects. GNE-7915 concentrations in wild-type (WT) mouse sera and brain samples reached a peak at 1 h, which gradually decreased over 24 h following a single subcutaneous (100 mg/kg) injection. The same dose in young WT and LRRK2 mutant mice significantly inhibited LRRK2 kinase activity (Thr73-Rab10 and Ser106-Rab12 phosphorylation) in the lung, which dissipated by 72 h post-injection. 14-month-old mutant mice injected with GNE-7915 twice weekly for 18 weeks (equivalent to ~13 human years) exhibited reduced striatal αSyn oligomer and cortical pSer129-αSyn levels, correlating with inhibition of LRRK2 hyperactivity in brain and lung to WT levels. No GNE-7915-treated mice showed increased mortality or morbidity. Unlike reports of abnormalities in lung and kidney at acute high doses of LRRK2 inhibitors, our GNE-7915-treated mice did not exhibit swollen lamellar bodies in type II pneumocytes or abnormal vacuolation in the kidney. Functional and histopathological assessments of lung, kidney and liver, including whole-body plethysmography, urinary albumin-creatinine ratio (ACR), serum alanine aminotransferase (ALT) and serum interleukin-6 (inflammatory marker) did not reveal abnormalities after long-term GNE-7915 treatment. Long-term inhibition of mutant LRRK2 hyper-kinase activity to physiological levels presents an efficacious and safe disease-modifying therapy to ameliorate synucleinopathy in PD.
帕金森病（PD）的特征是黑质纹状体和大脑皮质区域的多巴胺能神经退行性变，伴有致病性α-突触核蛋白（αSyn）聚集体/寡聚体的积累。LRRK2过度活跃是PD中一个可改变疾病进程的治疗靶点。然而，抑制LRRK2可能会产生外周效应，尽管其临床后果尚不清楚。在此，我们通过使用GNE-7915（一种特异性可穿透大脑的LRRK2抑制剂）长期抑制LRRK2，显著减少了小鼠纹状体中αSyn寡聚体的积累，且未引起外周不良反应。野生型（WT）小鼠血清和脑样本中的GNE-7915浓度在单次皮下注射（100mg/kg）后1小时达到峰值，并在24小时内逐渐下降。相同剂量在年轻的WT和LRRK2突变小鼠中显著抑制了肺中的LRRK2激酶活性（Thr73-Rab10和Ser106-Rab12磷酸化），该抑制作用在注射后72小时消失。14月龄的突变小鼠每周两次注射GNE-7915，持续18周（相当于约13个人类年），其纹状体αSyn寡聚体和皮质pSer129-αSyn水平降低，这与大脑和肺中LRRK2过度活跃被抑制至WT水平相关。没有接受GNE-7915治疗的小鼠出现死亡率或发病率增加的情况。与急性高剂量LRRK2抑制剂导致肺和肾异常的报道不同，我们接受GNE-7915治疗的小鼠在II型肺细胞中未表现出板层小体肿胀或肾中出现异常空泡化。对肺、肾和肝进行的功能和组织病理学评估，包括全身体积描记法、尿白蛋白-肌酐比值（ACR）、血清丙氨酸转氨酶（ALT）和血清白细胞介素-6（炎症标志物），在长期GNE-7915治疗后均未发现异常。将突变型LRRK2的过度激酶活性长期抑制至生理水平，为改善PD中的突触核蛋白病提供了一种有效且安全的可改变疾病进程的治疗方法。
