Abstract: SA-PO135
A Selective USP30 Inhibitor Attenuates Progressive Fibrosis in Ischemia-Induced CKD
Session Information
- AKI: Mechanisms - AKI-CKD Transition
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Bedford, David C., Mission Therapeutics Ltd, Cambridge, United Kingdom
- Wright, Jamie A., Mission Therapeutics Ltd, Cambridge, United Kingdom
- Knights, Charlotte, Mission Therapeutics Ltd, Cambridge, United Kingdom
- Rong, Song, Phenos GmbH, Hannover, Germany
- Shushakova, Nelli, Phenos GmbH, Hannover, Germany
- Schmidt, Sonja, Phenos GmbH, Hannover, Germany
- Gueler, Faikah, Phenos GmbH, Hannover, Germany
- Molnar, Judit, Mission Therapeutics Ltd, Cambridge, United Kingdom
Background
Much literature evidence points towards an essential role of mitochondrial quality control mechanisms in acute kidney injury progression. Ischemic-reperfusion injury (IRI) results in metabolic adaptation of Proximal Tubule Epithelial Cells (PTECs), a site of high mitochondrial turnover (1). Moreover, exacerbation of renal injury has been demonstrated following IRI in both PINK1 KO and PARK2 KO mice (2).
USP30 is a mitochondrial associated deubiquitylating enzyme and represses PINK1/PARKIN-mediated mitophagy (3). Within the kidney, USP30 expression is predominantly tubular and accordingly, USP30 inhibition may provide a mechanism to protect against IR-induced tubular injury. Here we present data on MTX008, a selective small molecule inhibitor of USP30 in a mouse model of IRI induced kidney fibrosis.
Methods
MTX008 was administered to C57BL/6 mice 15 mg/kg (p.o.) and compared to vehicle treatment from Day -1 through to Day +21. On Day 0, mice were anaesthetized, and their left renal pedicle clamped for 45 min, then released to induce IRI. Mice were monitored and urinary kidney injury biomarkers (KIM-1 and NGAL) were measured on Day +1 and +7. On Day +14 and Day +21 kidneys were harvested. Morphology, fibrosis and immune cell infiltration were assessed.
Results
Body weight was similar between groups and remained constant throughout the observation periods. MTX008 appeared to limit urinary kidney injury biomarkers, KIM1 and NGAL on Day +1. There were large interindividual variations and the differences did not reach significance. Macrophage infiltration was significantly reduced on Day +21. Masson trichome stain revealed significantly less tubular atrophy in MTX008 treated animals on Day +14 and Day +21. Fibronectin expression in the cortex was significantly reduced in MTX008 treated mice on Day +14 and +21.
Conclusion
MTX008, a novel selective small molecule inhibitor of USP30 has shown efficacy in a model of IR-induced CKD. Daily treatment has shown significant benefits towards attenuated tubular atrophy and reduced cortical fibrosis. Mission Therapeutics is investigating MTX008 in a variety of preclinical renal injury models with a view to developing this novel molecule towards the clinic.
1 McWilliams, et al. 2017
2 Tang, et al. 2018
3 Bingol, et al. 2014
Funding
- Commercial Support –