TY  - INPR
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
TI  - Reduction of Z alpha-1 antitrypsin polymers in human iPSC-hepatocytes and mice by LRRK2 inhibitors
Y1  - 2024/07/02/
AV  - restricted
JF  - Hepatology
A1  - Kent, Deniz
A1  - Ng, Soon Seng
A1  - Syanda, Adam M
A1  - Khoshkenar, Payam
A1  - Ronzoni, Riccardo
A1  - Li, Chao Zheng
A1  - Zieger, Marina
A1  - Greer, Cindy
A1  - Hatch, Stephanie
A1  - Segal, Joe
A1  - Blackford, Samuel Ji
A1  - Im, Yu Ri
A1  - Chowdary, Vivek
A1  - Ismali, Taylor
A1  - Danovi, Davide
A1  - Lewis, Patrick A
A1  - Irving, James A
A1  - Sahdeo, Sunil
A1  - Lomas, David A
A1  - Ebner, Daniel
A1  - Mueller, Christian
A1  - Rashid, S Tamir
N2  - 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.
ID  - discovery10194363
UR  - http://dx.doi.org/10.1097/hep.0000000000000969
PB  - Ovid Technologies (Wolters Kluwer Health)
SN  - 0270-9139
ER  -