Research ArticleParkinson’s Disease

LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits

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Science Translational Medicine  22 Apr 2020:
Vol. 12, Issue 540, eaav0820
DOI: 10.1126/scitranslmed.aav0820

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Parsing the side effects of LRRK2 inhibitors

Preclinical studies have raised concerns about the safety of LRRK2 inhibitors—developed for treating Parkinson’s disease—specifically regarding lung function. Baptista et al. now report that several different LRRK2 inhibitors induce on-target histopathological changes in the lungs of nonhuman primates. However, they show that these morphological changes were reversible after drug withdrawal and had no effect on pulmonary function as demonstrated by a battery of lung function tests. These findings suggest that LRRK2 inhibitor–induced effects on lung tissue should not prevent the clinical testing of these compounds.

Abstract

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 ~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.

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