eprintid: 10194363
rev_number: 8
eprint_status: archive
userid: 699
dir: disk0/10/19/43/63
datestamp: 2024-07-10 07:53:54
lastmod: 2025-07-03 06:10:07
status_changed: 2024-07-10 07:53:54
type: article
metadata_visibility: show
sword_depositor: 699
creators_name: Kent, Deniz
creators_name: Ng, Soon Seng
creators_name: Syanda, Adam M
creators_name: Khoshkenar, Payam
creators_name: Ronzoni, Riccardo
creators_name: Li, Chao Zheng
creators_name: Zieger, Marina
creators_name: Greer, Cindy
creators_name: Hatch, Stephanie
creators_name: Segal, Joe
creators_name: Blackford, Samuel Ji
creators_name: Im, Yu Ri
creators_name: Chowdary, Vivek
creators_name: Ismali, Taylor
creators_name: Danovi, Davide
creators_name: Lewis, Patrick A
creators_name: Irving, James A
creators_name: Sahdeo, Sunil
creators_name: Lomas, David A
creators_name: Ebner, Daniel
creators_name: Mueller, Christian
creators_name: Rashid, S Tamir
title: Reduction of Z alpha-1 antitrypsin polymers in human iPSC-hepatocytes and mice by LRRK2 inhibitors
ispublished: inpress
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: K71
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.
date: 2024-07-02
date_type: published
publisher: Ovid Technologies (Wolters Kluwer Health)
official_url: http://dx.doi.org/10.1097/hep.0000000000000969
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2292044
doi: 10.1097/HEP.0000000000000969
pii: 01515467-990000000-00945
lyricists_name: Lomas, David
lyricists_name: Ronzoni, Riccardo
lyricists_id: DALOM96
lyricists_id: RRONZ71
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: Hepatology
event_location: United States
issn: 0270-9139
citation:        Kent, Deniz;    Ng, Soon Seng;    Syanda, Adam M;    Khoshkenar, Payam;    Ronzoni, Riccardo;    Li, Chao Zheng;    Zieger, Marina;                                                             ... Rashid, S Tamir; + view all <#>        Kent, Deniz;  Ng, Soon Seng;  Syanda, Adam M;  Khoshkenar, Payam;  Ronzoni, Riccardo;  Li, Chao Zheng;  Zieger, Marina;  Greer, Cindy;  Hatch, Stephanie;  Segal, Joe;  Blackford, Samuel Ji;  Im, Yu Ri;  Chowdary, Vivek;  Ismali, Taylor;  Danovi, Davide;  Lewis, Patrick A;  Irving, James A;  Sahdeo, Sunil;  Lomas, David A;  Ebner, Daniel;  Mueller, Christian;  Rashid, S Tamir;   - view fewer <#>    (2024)    Reduction of Z alpha-1 antitrypsin polymers in human iPSC-hepatocytes and mice by LRRK2 inhibitors.                   Hepatology        10.1097/HEP.0000000000000969 <https://doi.org/10.1097/HEP.0000000000000969>.    (In press).    Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10194363/1/reduction_of_z_alpha_1_antitrypsin_polymers_in.945.pdf