Abstract: FR-OR061
A Novel Therapeutic Strategy for Autosomal Dominant Tubulointerstitial Kidney Disease
Session Information
- Genetic Diseases and the Kidneys
November 08, 2019 | Location: 144, Walter E. Washington Convention Center
Abstract Time: 04:30 PM - 04:42 PM
Category: Genetic Diseases of the Kidneys
- 1002 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Dvela levitt, Moran, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
- Alimova, Maria, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
- Emani, Maheswarareddy, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
- Kohnert, Eva, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
- Thompson, Rebecca L., Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
- Sidhom, Eriene-Heidi, Harvard Medical School, Brookline, Massachusetts, United States
- Rivadeneira, Ana, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
- Roignot, Julie, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States
- Papagregoriou, Gregory, University of Cyprus, Nicosia, Cyprus
- Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
- Kmoch, Stanislav, Institute of Inherited Metabolic Disorders, Prague, Czechia
- Alper, Seth L., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Weins, Astrid, Brigham & Women's Hospital, Boston, Massachusetts, United States
- Greka, Anna, Harvard Medical School, Brookline, Massachusetts, United States
Background
MUC1 kidney disease (MKD) is an autosomal dominant tubulo-interstitial kidney disease caused by a frame-shift mutation in the MUC1 gene (MUC1-fs). The disease is characterized by slowly progressive tubulo-interstitial damage that leads to end-stage renal disease. No treatment is currently available. Affected individuals require dialysis or kidney transplantation in the third to seventh decade of life. The main goal of this study was to investigate the cellular and molecular mechanisms by which MUC1-fs causes alteration in epithelial cell function, and to develop a mechanism-based therapy for this disease.
Methods
To investigate the biological mechanism responsible for MKD, three different model systems were developed: a patient-derived cell line, a knock-in mouse model and patient iPSC-derived kidney organoids.
In order to identify a possible treatment for MKD, a high content screen (HCS) composed of 4,000 compounds was developed to detect the removal of mutant MUC1-fs protein from kidney epithelial cells.
Results
Immunofluorescence studies indicated that while MUC1-wt was located at the cell surface, the mutated protein MUC1-fs was accumulated intracellularly, where it induced ER stress by activation of the unfolded protein response (UPR).
The HCS identified BRD, a small molecule that cleared MUC1-fs not only from patient cells, but also from kidneys of knock-in mice and from patient kidney organoids. Importantly, BRD showed no overt toxicity at any concentration tested, and in fact, it rescued cells from ER stress-induced cell death.
Conclusion
These results indicate that intracellular accumulation of MUC1-fs induces ER stress- related cell toxicity, a pathologic mechanism likely responsible for the progressive renal damage associated with the MUC1 mutation. Our findings reveal BRD as a promising lead for the treatment of MKD.
Funding
- Private Foundation Support