Tracing the arc of precision therapies for kidney disease

Physician-scientist Anna Greka, MD, PhD, associate professor at Harvard Medical School, founding director of Kidney NExT at Brigham and Women’s Hospital and director of the Broad Institute Kidney Disease Initiative, discusses groundbreaking work on a rare kidney disease, prospects for new therapeutics and collaborating on drug development.

Illustration of kidneys on the left, DNA helix in the middle, and female doctor on the right.

Chronic kidney disease affects an estimated 850 million people worldwide, exacting a terrible toll on patients and their families. In the U.S. alone, Medicare spends more than $110 billion on kidney disease annually. Frustratingly, there have been no new drug discoveries for decades, partly because so many complex genetic and environmental factors twine together to create a spectrum of kidney disease. That’s why some scientists focus on rare disease driven by a single gene mutation, like MUC1 kidney disease (MKD), a heritable disorder that gradually causes kidney failure. The Greka Lab at Brigham and Women’s Hospital (BWH) and the Broad Institute of MIT and Harvard did groundbreaking work illuminating the MUC1 mechanism, then identified a small molecule compound that showed merit in MUC1 cells, an MKD mouse model and even in kidney organoids created from patient-derived stem cells. Of course, misfolded proteins cause many diseases, including ALS, Alzheimer’s disease, and retinitis pigmentosa. So, a compound useful for MKD may have far wider implications.

Physician-scientist Anna Greka, MD, PhD, is an associate professor at Harvard Medical School, founding director of Kidney NExT at BWH and Harvard Medical School and director of the Broad Institute Kidney Disease Initiative. Dr. Greka answers questions about her work on MUC1, prospects for new therapeutic strategies and gathering patient groups and industry groups to collaborate on the arc of new therapies.

Interview edited and condensed for clarity


Your research on the rare MUC1 kidney disease uncovered a new disease mechanism involving the secretory pathway. Can you tell us about this work and its implications for both rare and common diseases?

A mutation in the mucin 1 gene generates a misfolded protein — one could call it a nonsense protein. Kidney cells have to do something with this misfolded protein, and the preferred action would be to send it into a cellular trash can called a lysosome. However, in many cases, cells are overwhelmed by the accumulation of this toxic protein and are unable to get rid of it. We discovered this was the case with MUC1. Then, we discovered that the misfolded protein gets trapped in the early part of the secretory pathway where cells package proteins to send them different places to perform their function. This happens because the protein is bound by a cargo receptor called TMED-9.

We decided to screen a small molecule library that might give us a drug with the ability to degrade and remove this misfolded protein. We discovered one single compound — out of about 4,000 compounds — which we called BRD4780. It has the remarkable property of taking this misfolded protein and driving it to be degraded in the lysosome. The drug appears to bind the TMED-9 cargo receptor and tells it, “Release your cargo and allow it to go to the lysosome.”

We had already developed a mouse model for MUC1 kidney disease by removing the mouse gene for MUC1 and replacing it with the human mutated version of the MUC1 gene. One obvious question was, if we feed this drug to mice, can we get the human protein piling up in mouse kidneys to be removed? After a week of treatment, we were able to do just that — a wonderful proof of concept for this approach.

Of course, mice are not humans, so we turned blood cells from MUC1 patients and unaffected sibling controls into pluripotent stem cells, then turned the stem cells into human kidney organoids — mini-kidneys-in-a-dish, if you will. We found the misfolded protein accumulated in the patient organoid kidney cells. Within three days of treating the organoids with the drug, we were able to clear out the mutant protein, offering an additional layer of proof of concept, this time in human cells!

Kidney failure and dialysis exert a huge clinical, human and economic burden. Your work uncovered a potential therapeutic target in the kidney. Can you discuss the prospects for new therapeutic strategies and the potential of your research approach for kidney failure in general?

It is hard to develop therapies for kidney disease, probably because in reality it is not a single disease but rather a collection of several diseases that we have not yet fully understood. We’re just beginning to unravel how genetics might contribute to our susceptibility to progressive kidney diseases, scratching the surface of what that looks like. Several of these diseases might be caused by many genes acting together in conjunction with other factors like diet, obesity and diabetes, which are major drivers of kidney failure in the world today.

A mutation in a single gene, MUC1, is sufficient to drive kidney disease progression in some patients. It’s my belief that if we focus on rare diseases, we can ultimately put the pieces of the puzzle together to treat the more common, more complex diseases as well. Careful, mechanistic work can lead to transformative discoveries down the road. The arc of discovery from gene to mechanism to therapy might help us build therapies that alone, or in combination, will lead to treatments for more complex diseases, or diseases currently not well understood. With this strategy in mind, I think we’ve been richly rewarded so far in this project. It has potential to help not only people with kidney diseases but also many others affected by toxic proteinopathies outside the kidney, including diseases of the eye, brain, lung and liver, such as retinitis pigmentosa, or even Alzheimer’s disease.

In the service of finding solutions for rare diseases you have brought together patient groups and biotech/pharma companies. What critical trends do you see in how these communities can advance the development of new therapies?

All the entities you mention are very important in moving from a discovery in the lab all the way to a drug you can give to patients in clinical trials. I’m a professor, and I run an academic research lab. I must talk to colleagues in the biotechnology and pharmaceutical world to let them know about discoveries we’re making in our lab. It’s important that a bridge between academic groups and industry is in place, in a healthy way, to translate our discoveries to the clinic. Investment is needed for a compound explored in the lab to be made into a real drug that goes into clinical trials.

And, of course, the main stakeholder in everything I do as a physician-scientist is the patient. It’s important to have the patients’ voices at every step, for them to tell us what they care most about. Patients and their families can be tremendous advocates for increased investment in a particular disease, or for attention from the FDA. In the case of MUC1 kidney disease, we need patients to participate in our registry. We need them to provide samples, so we can develop biomarkers that will tell us how we’re doing in treating this disease when we have a drug that goes into clinical trials. So it’s very important that patients become our partners in this journey from the laboratory all the way to the clinic and to approval.

Join Anna Greka at our upcoming program "Accelerating Biotech and Pharmaceutical R&D through Genomics," June 2-3, 2020. Continue the conversation with us @HMS_ExecEd or with Dr. Greka @AnnaGreka

— Francesca Coltrera