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Reduction of Z alpha-1 antitrypsin polymers in human iPSC-hepatocytes and mice by LRRK2 inhibitors.
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 J I; Im, Yu Ri; Chowdary, Vivek; Ismaili, Taylor; Danovi, Davide; Lewis, Patrick A; Irving, James A; Sahdeo, Sunil; Lomas, David A; Ebner, Daniel; Mueller, Christian; Rashid, S Tamir.
Afiliação
  • Kent D; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
  • Ng SS; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.
  • Syanda AM; Gene Therapy Center, University of Massachusetts, Worchester, Massachusetts, USA.
  • Khoshkenar P; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
  • Ronzoni R; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
  • Li CZ; Gene Therapy Center, University of Massachusetts, Worchester, Massachusetts, USA.
  • Zieger M; UCL Respiratory and the Institute of Structural and Molecular Biology, University College London, London, UK.
  • Greer C; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.
  • Hatch S; Gene Therapy Center, University of Massachusetts, Worchester, Massachusetts, USA.
  • Segal J; Gene Therapy Center, University of Massachusetts, Worchester, Massachusetts, USA.
  • Blackford SJI; National Phenotypic Screening Centre, University of Oxford, Headington, Oxford, UK.
  • Im YR; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.
  • Chowdary V; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
  • Ismaili T; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
  • Danovi D; Gene Therapy Center, University of Massachusetts, Worchester, Massachusetts, USA.
  • Lewis PA; Discovery Sciences, Janssen Research and Development, San Diego, California, USA.
  • Irving JA; Centre for Stem Cells and Regenerative Medicine, King's College London, London, UK.
  • Sahdeo S; Royal Veterinary College, Royal College Street, London, UK.
  • Lomas DA; UCL Respiratory and the Institute of Structural and Molecular Biology, University College London, London, UK.
  • Ebner D; Discovery Sciences, Janssen Research and Development, San Diego, California, USA.
  • Mueller C; UCL Respiratory and the Institute of Structural and Molecular Biology, University College London, London, UK.
  • Rashid ST; National Phenotypic Screening Centre, University of Oxford, Headington, Oxford, UK.
Hepatology ; 2024 Jul 02.
Article em En | MEDLINE | ID: mdl-38954820
ABSTRACT

BACKGROUND:

Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by the inheritance of the serpin family A member 1 "Z" genetic variant driving alpha-1 antitrypsin (AAT) protein misfolding in hepatocytes. There are no approved medicines for this disease.

METHODS:

We conducted a high-throughput image-based small molecule screen using patient-derived induced pluripotent stem cell-hepatocytes (iPSC-hepatocytes). Identified targets were validated in vitro using 3 independent patient iPSC lines. The effects of the identified target, leucine-rich repeat kinase 2 (LRRK2), were further evaluated in an animal model of A1ATD through histology and immunohistochemistry and in an autophagy-reporter line. Autophagy induction was assessed through immunoblot and immunofluorescence analyses.

RESULTS:

Small-molecule screen performed in iPSC-hepatocytes identified 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 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 the induction of autophagy.

CONCLUSIONS:

Our findings support the use of CZC-25146 and leucine-rich repeat kinase-2 inhibitors in hepatic proteinopathy research and their further investigation as novel therapeutic candidates for A1ATD.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article