@article{discovery10194363, publisher = {Ovid Technologies (Wolters Kluwer Health)}, title = {Reduction of Z alpha-1 antitrypsin polymers in human iPSC-hepatocytes and mice by LRRK2 inhibitors}, year = {2024}, journal = {Hepatology}, month = {July}, note = {This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.}, abstract = {Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by inheritance of the SERPINA1 'Z' genetic variant (PiZ) driving AAT protein misfolding in hepatocytes. There remain no approved medicines for this disease. Here, we report the results of a small molecule screen performed in patient derived iPSC-hepatocytes that identified Leucine-rich repeat kinase-2 (LRRK2) as a potentially new therapeutic target. Of the commercially available LRRK2 inhibitors tested, we identified CZC-25146, a candidate with favorable pharmacokinetic properties, as being capable of reducing polymer load, increasing normal AAT secretion, and reducing inflammatory cytokines in both cells and PiZ mice. Mechanistically, this effect was achieved through induction of autophagy. Our findings support the use of CZC-25146 and LRRK2 inhibitors in hepatic proteinopathy research and their further investigation as novel therapeutic candidates for A1ATD.}, issn = {0270-9139}, author = {Kent, Deniz and Ng, Soon Seng and Syanda, Adam M and Khoshkenar, Payam and Ronzoni, Riccardo and Li, Chao Zheng and Zieger, Marina and Greer, Cindy and Hatch, Stephanie and Segal, Joe and Blackford, Samuel Ji and Im, Yu Ri and Chowdary, Vivek and Ismali, Taylor and Danovi, Davide and Lewis, Patrick A and Irving, James A and Sahdeo, Sunil and Lomas, David A and Ebner, Daniel and Mueller, Christian and Rashid, S Tamir}, url = {http://dx.doi.org/10.1097/hep.0000000000000969} }