Astrid Weins, MD, PhD, is an Associate Pathologist at Brigham and Women’s Hospital in Boston, MA, and an Assistant Professor of Pathology at Harvard Medical School. Her research focuses on understanding acute Nephrotic Syndrome and podocyte injury. She does this by combining observations with state-of-the-art imaging and tissue interrogation techniques. Learn more about her work on Minimal Change Disease (MCD) and about the TRACTION-2 trial, Goldfinch Bio’s clinical research trial investigating GFB-887 with the hope of preventing the progression of kidney disease in patients with treatment-resistant Minimal Change Disease, FSGS, and Diabetic Nephropathy. The TRACTION-2 trial is the first large-scale clinical trial opportunity for Minimal Change Disease patients, and is also available for patients with FSGS and Diabetic Nephropathy.
- Why are you interested in Minimal Change Disease (MCD)?
I have studied kidney, and specifically, podocyte biology for many years. The podocyte is a unique and fascinating cell with a critical function in regulating urine filtration. It is the main target of injury in MCD. As a kidney pathologist, I love scientific investigation, and my strong belief is that knowing the cause of a disease is the key to its cure.
Minimal Change Disease deserves so much more attention than is has received in the past. People often refer to it as a “benign” condition, because in many cases it responds well and fast to steroids. However, there are some children, and even more adults that don’t respond to this therapy, and we have currently no way of predicting who will respond and who won’t. Once we understand what causes a disease, we can develop rationales for choosing and developing specific, targeted therapies.
- What makes MCD different from other protein-spilling kidney diseases?
First, it’s of rapid onset and in most cases also shows a rapid response to therapy. Second, we have had no idea what causes it, other than that we presume it’s caused by a circulating factor. Third, in contrast to most other protein-spilling diseases, it is more common in children than in adults. Fourth, the kidney biopsy shows no significant changes by light microscopy, although the ultrastructural changes to the podocytes are widespread and severe. Hence, the term “minimal change” disease (which refers to its unremarkable light microscopy appearance) is really a misnomer.
- Can you summarize your research on MCD and its significance?
In our clinical practice, my colleagues and I came to recognize a unique feature in biopsies from patients with MCD, which suggested that the injury might be caused by an autoantibody against podocytes. An autoantibody-mediated cause would make sense, since antibodies are circulating in the blood, are filtered by the kidney and can access the podocytes.
We hypothesized that the target of such an autoantibody would have to be an exposed podocyte protein, which led us to test for autoantibodies against nephrin, an essential component of the filtration barrier. Indeed, we identified anti-nephrin autoantibodies in a subset of adults and children with MCD both circulating in their blood and bound to nephrin in their kidney biopsy. This is a huge breakthrough in our understanding of this condition, as we can now define a subset of patients as suffering from an autoimmune disease.
- What are you looking at in your NephCure-funded grant, “Autoimmunity in Primary or Recurrent Podocytopathies – Clinicopathologic correlation and mechanistic studies”?
In this grant, we are now extending our studies to patients with primary FSGS and recurrent FSGS after transplant. Since the changes to the podocytes in MCD and primary and recurrent FSGS are virtually indistinguishable, we hypothesized that a subset of patients with primary and recurrent FSGS also have circulating antibodies that target nephrin. Our preliminary findings demonstrate that this is indeed the case in a subset of patients from our own institution. Now we need to expand our studies to more samples.
- Can you tell us about treatment-resistant MCD versus steroid-sensitive MCD?
The vast majority of MCD is steroid-sensitive, meaning that these patients will respond well to steroids. A small subset of these patients, however, will remain steroid-dependent, meaning they cannot come off this therapy or their Nephrotic Syndrome will relapse.
This is not a good thing because 1) steroids have harsh side effects, especially during long-term use, and 2) often additional immunosuppressive agents are given that may add even worse side effects. Treatment-resistant patients never fully respond to steroids, and often receive a long list of unsuccessful immunosuppressive therapies, and despite all efforts may continue to spill protein and experience ongoing podocyte damage.
- Why do you think so many people are diagnosed with MCD to later be re-diagnosed with FSGS?
Two possible reasons: 1) Sampling: With exception of the scarring, both MCD and Primary FSGS are indistinguishable on biopsy. Since we only look at a tiny sample of biopsied kidney tissue, and early FSGS can be very focal, we may miss scarring already present in your kidney. 2) Disease progression: A disease does not start out with scarring. Being diagnosed with MCD in your first and with FSGS in a later biopsy does not mean you were re-diagnosed; it just means that the initial injury was severe enough to have led to scarring during the course of the disease.
Based on my experience, I believe that MCD and Primary FSGS are related and can represent expressions of the same initial disease process. This means that understanding one could enhance our understanding of the other.
- Why do you think there have not been trials for Minimal Change Disease patients until now?
MCD has been generally perceived as a rather “benign” condition. Many patients respond well to a limited course of steroids, and complications remain rare, so there was no perceived acuity to start trials.
We also haven’t had sufficient molecular understanding of this disease to provide a rationale for trying new or different treatments. Our studies may change how clinicians view this disease and may initiate such trials.
Goldfinch Bio is a biotechnology company based in Cambridge, MA which focuses on advancing kidney precision medicine. Its mission is to deliver disease-modifying precision medicine that brings hope and renewed quality of life to people living with kidney diseases. Goldfinch Bio’s TRACTION-2 clinical research trial is evaluating an investigational precision medicine, GFB-887, for the potential treatment of treatment-resistant Minimal Change Disease, FSGS, and Diabetic Nephropathy. The purpose of the trial is to determine if GFB-887 is safe and may help people who have high levels of protein in their urine due to kidney diseases caused by podocyte injury.
This article was developed in partnership with Goldfinch Bio, Inc.