LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits
LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits
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DOI：
10.1126/scitranslmed.aav0820
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发表时间：
2020-04-22
影响因子：
17.1
通讯作者：
Sherer, Todd B.
中科院分区：
文献类型：
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作者：
Baptista, Marco A. S.;Merchant, Kalpana;Sherer, Todd B.
富含亮氨酸重复序列激酶2（LRRK 2）中的激酶激活突变G2019 S是帕金森病（PD）最常见的遗传原因之一，并刺激了LRRK 2抑制剂的开发。临床前研究已经引起了对LRRK 2抑制剂安全性的担忧，这是由于用这些化合物中的两种治疗的非人灵长类动物的肺中的组织病理学变化。在这里，我们研究了这些肺效应是否代表靶向药理学，以及它们在猕猴中停药后是否可逆。我们还检查了治疗是否与肺功能缺陷有关。我们在猕猴中进行了为期2周的重复给药毒理学研究，比较了三种不同的LRRK 2抑制剂：GNE-7915（30 mg/kg，每日两次，作为阳性对照）、MLi-2（15和50 mg/kg，每日一次）和PFE-360（3和6 mg/kg，每日一次）。在停药后2周评价给予GNE-7915或MLi-2的动物亚组的肺功能。所有化合物均诱导II型肺泡细胞的轻度胞质空泡化，无肺变性体征，涉及靶向药理学。在低剂量的PFE-360或MLi-2下，在脑组织中分别存在类似于50%或100%的LRRK 2抑制，但组织病理学肺变化不存在或极小。停止给药后，肺部效应可逆。肺功能测试表明，MLi-2和GNE-7915诱导的肺组织学变化并未导致肺功能障碍。我们的研究结果表明，在非人灵长类动物中观察到的LRRK 2抑制剂对肺部的影响不应排除这些化合物用于PD的临床试验。
The kinase-activating mutation G2019S in leucine-rich repeat kinase 2 (LRRK2) is one of the most common genetic causes of Parkinson's disease (PD) and has spurred development of LRRK2 inhibitors. Preclinical studies have raised concerns about the safety of LRRK2 inhibitors due to histopathological changes in the lungs of nonhuman primates treated with two of these compounds. Here, we investigated whether these lung effects represented on-target pharmacology and whether they were reversible after drug withdrawal in macaques. We also examined whether treatment was associated with pulmonary function deficits. We conducted a 2-week repeat-dose toxicology study in macaques comparing three different LRRK2 inhibitors: GNE-7915 (30 mg/kg, twice daily as a positive control), MLi-2 (15 and 50 mg/kg, once daily), and PFE-360 (3 and 6 mg/kg, once daily). Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated 2 weeks after drug withdrawal for lung function. All compounds induced mild cytoplasmic vacuolation of type II lung pneumocytes without signs of lung degeneration, implicating on-target pharmacology. At low doses of PFE-360 or MLi-2, there was similar to 50 or 100% LRRK2 inhibition in brain tissue, respectively, but histopathological lung changes were either absent or minimal. The lung effect was reversible after dosing ceased. Lung function tests demonstrated that the histological changes in lung tissue induced by MLi-2 and GNE-7915 did not result in pulmonary deficits. Our results suggest that the observed lung effects in nonhuman primates in response to LRRK2 inhibitors should not preclude clinical testing of these compounds for PD.