A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease

Pascale Gluais Dagorn; Bjoern Buchholz; Andre Kraus; Battsetseg Batchuluun; Hester Bange; Laura Blockken; Gregory R Steinberg; David E Moller; Sophie Hallakou-Bozec

doi:10.1016/j.kint.2023.01.026

A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease

Kidney Int. 2023 May;103(5):917-929. doi: 10.1016/j.kint.2023.01.026. Epub 2023 Feb 18.

Authors

Pascale Gluais Dagorn¹, Bjoern Buchholz², Andre Kraus², Battsetseg Batchuluun³, Hester Bange⁴, Laura Blockken⁵, Gregory R Steinberg³, David E Moller¹, Sophie Hallakou-Bozec⁶

Affiliations

¹ Poxel SA, Lyon, France.
² Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
³ Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
⁴ Crown Bioscience Netherlands B.V., The Netherlands.
⁵ InnoSer België NV, Belgium.
⁶ Poxel SA, Lyon, France. Electronic address: sophie.bozec@poxelpharma.com.

PMID: 36804411
DOI: 10.1016/j.kint.2023.01.026

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) mainly results from mutations in the PKD1 gene, which encodes polycystin 1. It is the most common inherited kidney disease and is characterized by a progressive bilateral increase in cyst number and size, often leading to kidney failure. The cellular energy sensor and regulator adenosine monophosphate stimulated protein kinase (AMPK) has been implicated as a promising new therapeutic target. To address this hypothesis, we determined the effects of a potent and selective clinical stage direct allosteric AMPK activator, PXL770, in canine and patient-derived 3D cyst models and an orthologous mouse model of ADPKD. PXL770 induced AMPK activation and dose-dependently reduced cyst growth in principal-like Madin-Darby Canine Kidney cells stimulated with forskolin and kidney epithelial cells derived from patients with ADPKD stimulated with desmopressin. In an inducible, kidney epithelium-specific Pkd1 knockout mouse model, PXL770 produced kidney AMPK pathway engagement, prevented the onset of kidney failure (reducing blood urea by 47%), decreased cystic index by 26% and lowered the kidney weight to body weight ratio by 35% compared to untreated control Pkd1 knockout mice. These effects were accompanied by a reduction of markers of cell proliferation (-48%), macrophage infiltration (-53%) and tissue fibrosis (-37%). Thus, our results show the potential of direct allosteric AMPK activation in the treatment of ADPKD and support the further development of PXL770 for this indication.

Keywords: ADPKD; AMPK; PXL770; fibrosis; inflammation; mitochondria.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics
AMP-Activated Protein Kinases / metabolism
Adenosine Monophosphate / metabolism
Animals
Cysts* / drug therapy
Disease Progression
Dogs
Kidney / metabolism
Mice
Mice, Knockout
Polycystic Kidney, Autosomal Dominant* / drug therapy
Polycystic Kidney, Autosomal Dominant* / genetics
Polycystic Kidney, Autosomal Dominant* / metabolism
Renal Insufficiency* / metabolism
TRPP Cation Channels / genetics
TRPP Cation Channels / metabolism

Substances

Adenosine Monophosphate
AMP-Activated Protein Kinases
2-chloro-3-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-6-oxo-5-phenyl-7H-thieno)(2,3-b)pyridin-4-olate potassium
TRPP Cation Channels