Kidney Disease

In a study of a rare disorder called MUC1 kidney disease (MKD); which the researchers showed stems from the harmful build-up of a misfolded version of a protein called MUC1 in kidney cells. Moreover, the researchers found that the cell’s failure to remove the misfolded protein; could be traced to a specific molecular step in the secretory pathway; and remarkably, that a compound called BRD4780 could clear the traffic jam.

The compound worked in human kidney cells and kidney organoids (miniature kidneys-in-a-dish engineered from patient cells); and in an animal model of MKD. BRD4780 could be a starting point for developing new medicines for MKD; and several other toxic proteinopathies, for which no treatments are currently available.

“What blew my mind is that, in the process of studying the mechanism behind MKD; we have uncovered fascinating new biology about how cells handle misfolded proteins, and these key insights may help us address several devastating diseases,” said study senior author Anna Greka, an institute member and director of the Broad’s Kidney Disease Initiative (KDI); an associate professor at Harvard Medical School, and a kidney specialist at BWH. “The team is working around the clock to translate these discoveries into a new therapy we can bring to patients as quickly as possible.”

Clear MUC1-fs from cells

MKD is a rare, inherited disease that leads to kidney failure. In 2013, a team led by Broad president and founding director Eric Lander and institute member and Program in Medical; and Population Genetics co-director Mark Daly tracked down the genetic root of MKD (previously called medullary cystic kidney disease, or MCKD): the addition of a single letter in the gene mucin 1 (MUC1).

The mutation results in the production of a truncated; misfolded protein dubbed MUC1-fs that collects in patients’ kidney cells. As MUC1-fs accumulates, kidney cells die, eventually leading to kidney failure. To find drug-like compounds that might help clear MUC1-fs from cells; first author and postdoctoral fellow Moran Dvela-Levitt of the KDI, Greka and their colleagues turned to the Broad Drug Repurposing Hub a collection of more than 3,700 compounds at different stages of the drug development process; maintained by the institute’s Center for the Development of Therapeutics.

Their search turned up BRD4780, a compound that never made it to the clinic; cast aside when it proved to be unsuccessful as a blood pressure drug. Greka, Dvela-Levitt, and their colleagues found that BRD4780 eliminated MUC1-fs; left normal MUC1 untouched, and prevented kidney cells with the MKD mutation from dying.

UMOD-associated kidney disease

When the researchers looked closely; they surprised to find that BRD4780 does not bind to MUC1-fs. Rather, it latches onto TMED9, a so-called ‘cargo receptor’ that carries protein cargo along the secretory pathway. This keeps the misfolded protein from reaching the lysosome; (an organelle whose job is to chew up unwanted proteins), causing MUC1-fs to rise to dangerous levels in kidney cells.

The researchers noted that when BRD4780 bound to TMED9, the cargo receptor released its hold on MUC1-fs; allowing the cell to degrade the misfolded protein. Knocking out the gene for TMED9 using CRISPR had the same effect. “This is completely new biology,” Greka said. “We did not know that a cargo receptor like TMED9 could block; and ultimately interfere with the destruction of a misfolded protein. And the question became, is the same biology at work in other conditions cause by a build-up of misfolded proteins?”

More than 50 diseases are considered toxic proteinopathies, including retinitis pigmentosa; (RP, an inherit form of blindness where the retina degenerates) and UMOD-associated kidney disease (UKD, another rare genetic kidney disorder). Greka and her colleagues reasoned that similar problems with the secretory pathway might be to blame in at least a few of these diseases.