Dr. Peter Mundel, Kidney Disease Researcher May 31, 2017 by Lauren Eva Why I Do What I Do: Spotlight on Dr. Peter Mundel, Kidney Disease Researcher Dr. Peter Mundel is a physician-scientist who has spent the past 30 years studying kidney cells called podocytes, which are specialized cells with a central role in glomerular diseases like FSGS. Dr. Mundel has been an esteemed member of NephCure’s Scientific Advisory Board since 2007, and in 2011, NephCure helped fund his work by providing him with a bridge grant. A major focus of his work has been the development of new, targeted treatments for patients with FSGS and other glomerular diseases. Last year, he left his professorship at Harvard Medical School/Massachusetts General Hospital to lead the research of a new start-up company called Goldfinch Bio, a biotechnology company that is singularly focused on discovering and developing precision therapies for kidney disease. We spoke with Dr. Mundel about his work and what inspired him to leave academia to create new treatments for people living with FSGS and Nephrotic Syndrome. NKI: How did you first become interested in studying the kidney? What is it about glomerular diseases specifically that interests you? Dr. Peter Mundel Dr. Mundel: I first became interested in studying the kidney when I was in medical school, back in Germany in the late ‘80’s. I had joined the laboratory of Dr. Wilhelm Kriz, who was one of the leading investigators in the field. At that time, there was nothing known about podocytes. They were considered passive bystanders. Everybody was thinking about mesangial cells and their role in the pathogenesis of kidney disease. So, I saw an opportunity and I entered the field and started to work on podocytes, and that’s what I focused on for 30 years since then: I got into the biology of these cells, learned about their function in health and disease, and then later of course I was trying to find podocyte-targeted therapies. But it all started 30 years ago in medical school in Germany. I still remember how I would sit with Professor Kriz in his office and we would say “one day we should develop podocyte protective medicines.” That’s what we said, and 30 years later, we’re doing it! NKI: Could you tell us about your discovery process of deciding to study a new drug? I am thinking specifically of abatacept because many people in our community are familiar with it, and I know you were instrumental in discovering its use in treating Nephrotic Syndrome. Dr. Mundel: We can definitely talk about the abatacept story, because it has good parallels, and it also helps explain what brought me to Goldfinch Bio. We identified B7-1/CD80 in podocytes, way back at my lab in Heidelberg, using differential Display PCR, a technique that allows you to monitor changes in gene expression between normal and diseased cells. We had our first paper on B7-1 in 2004 in The Journal of Clinical Investigation, where we showed that B7-1/CD80 has a role in podocytes in proteinuria, in addition to its role in the immune system. We studied the role of B7-1/CD80 in podocytes for another for 10 years, and then we began studying the use of abatacept [which targets CD80/B-71] in patients. What’s interesting with abatacept is that we now know that there is a subgroup of patients that respond well to this drug. Going forward, the challenge will be in identifying with precision who are these patients for whom it will work. There is no silver bullet: not every patient with Nephrotic Syndrome and FSGS will respond to the same drug. Some people will respond to abatacept and some people will respond to some as-yet-unidentified new drug. We will need to take a precision medicine approach. Knowing this, we will now need to define patients molecularly—not by saying they have FSGS or proteinuria, but by saying they have proteinuria driven by CD80/B7-1, or by protein ‘X’ or protein ‘Y’. That is exactly what our colleagues in oncology do: when you have a mutation in BRAF [which causes, for example, skin cancer or melanoma], you get a BRAF blocker for your melanoma. At Goldfinch, we are basically bringing the oncology playbook to the kidney space. We need to figure out who will respond to which drug, and we will need to use people’s genetics to identify targets for new, specific drugs. I think abatacept was the first stop at personalized medicine. When our paper [on abatacept] came out, there was an accompanying editorial by Börje Harraldsson that said exactly that—“A New Era of Podocyte-Targeted Therapy.” There is a trial going on with abatacept right now. I’m very pleased about that, because if you see in our original New England Journal of Medicine (NEJM) paper, patient number 5, this woman was on and off all kinds of drugs. But abatacept works so well for her that she is now in complete remission. And now, in her late 20’s, for the first time she has a good life; she enjoys her life. She doesn’t go from medicines with side effects to being hospitalized as she used to. I think this is a great success, because this is an idea that started in my lab almost 20 years ago. Because of this work, there is someone who really feels good and has a good life. And so as I said, the challenge now is to find all those patients who will respond to each of our precision treatments. NKI: Wow. That must make you feel incredible to know that years and years of your research led to this woman finally feeling like she could have a good life. Dr. Mundel: It’s a humbling experience. It’s very humbling that I had the privilege to have an impact on someone’s life. Because you see, I’m an MD by training, but after medical school I have only done research. But indirectly I act like a physician—I don’t treat her myself, but because of my work, she now has a better life, and I’m very happy for her. For all of our patients at NephCure that we care about with FSGS and Nephrotic Syndrome, I think this is a beacon of hope. For some of them [abatacept] will work too, and for others we will now find new drugs. But it clearly shows that the overall idea of finding podocyte protective drugs is a good idea, and it can work. NKI: So in the future, how would what you’re describing work? Would patients come in to their clinician and have gene mapping done, and when the results come in, their clinician would know exactly how to treat them? Dr. Mundel: That is basically the end goal. At Goldfinch, we are building a patient registry where we will sequence thousands of patients with FSGS. This will allow us to stratify patients, so when we have a drug that we know will work for a certain pathway or mutation, we will be able to select patients who can benefit from this drug. We will be able to say, “You have a mutation in protein ‘X’, so we are giving you a drug correcting the effects of protein ‘X’ mutation.” That’s the targeted approach that we’re talking about when we refer to precision medicine. At the same time, we need to identify more causes of FSGS. The work done by Dr. Martin Pollak and Dr. Friedhelm Hildebrandt has identified a lot of these genes, and there are even more to be found. What their work shows is that there is a genetic underpinning of FSGS. At Goldfinch, we will continue that work and work closely with many academic collaborators. So to answer your question more directly, down the road what you described is exactly what we are going to bring to patients with kidney diseases. At some point, the patient comes in and they have proteinuria, and their doctor will do a genetic test. Right now, we can do it for about 70 or 80 genes [that are associated with FSGS and Nephrotic Syndrome], somewhere in that ballpark. Down the road, there may be hundreds, and patients will be tested for them. And we will have different medicines, so based on the patient’s mutation, we will be able to give them a specific treatment. We will no longer give patients nonspecific steroids or cyclosporine, but instead give them a targeted medicine because we will understand exactly what’s causing the disease. That’s what we want to do at Goldfinch—bring this personalized medicine to patients with FSGS. NKI: Right, and that way they’re not wasting time cycling through drugs that aren’t working, and in the meantime, not just not having a very great life, but also heading towards end stage kidney disease. That will save a lot of time. Dr. Mundel: Exactly. That’s the other goal—we want to prevent patients with FSGS to progress to end stage kidney disease and from going on to dialysis. At Goldfinch, our goal is to prevent people from going on to dialysis or needing a transplant—to stop the disease in a specific way by addressing the root cause. NKI: This is fascinating. And before you mentioned Dr. Pollak and Dr. Hildebrandt’s work, which has been funded in part by NephCure, I was going to refer to it and say, it’s really interesting from an outsider’s view how all this research is culminating: the genetic research, and drug discovery research, and podocyte research. It seems like it’s finally all coming together. Dr. Mundel: Oh, absolutely. Let me give you a prime example. My own work has been focused on the podocyte actin cytoskeleton. Independently, over the last five or six years, geneticists identified several FSGS causing mutations affecting the podocyte cytoskeleton. We now understand the genetics of the podocyte cytoskeleton, and this dovetails with what we understand about the biology. We are living in a time when genetics and biology are coming together. When you have both, then you can have the precision and the tools to make a targeted therapy. NKI: Wow, what an exciting time to be a glomerular disease researcher. That excitement and that feeling of being just around the corner, that must have been part of what led you to leave academia. You had a very distinguished position at Harvard, and you left it to join Goldfinch Bio. That speaks volumes of your confidence in it. Dr. Mundel: It does, and I believe that what we’re doing is the right thing. I’ll tell you, when I first came to Harvard in 2010, I thought I would continue doing academic research until I die in my office. And then this amazing opportunity came. As we discussed, it’s the dovetailing of the biology and the genetics, but also the work done by Dr. Melissa Little and by Dr. Joseph Bonventre, who’s one of our founders. They showed that it is possible to make kidney organoids, which are “kidneys in a dish”. So now we have the ability to study human kidney disease, if you will, in a dish. There’s also been an explosion of technical data, where analyzing the genetic data is becoming cheaper and cheaper. And cloud computing has arrived, which we didn’t have five years ago. Now we have all the computational tools, the biological tools, the genetic tools to bring such a push to this field. It’s absolutely exciting. In 2008 we had a manuscript where we showed how cyclosporine, which is clinically used to treat NS, works on podocytes. Then we had the NEJM paper where we repurposed the drug abatacept from Rheumatoid Arthritis to patients with FSGS. Joining Goldfinch was the next logical step. I want to make new drugs targeting the causes of the diseases, and I think Goldfinch is the perfect place to do it. And as you said my confidence is reflected in the fact that I have left Harvard. I’m not on a leave of absence, I have not kept my professorship; I have shut down my laboratory and returned all my grants and funding. I want to focus on Goldfinch now, because by focusing on it we can do our best. I wholeheartedly believe in what we are doing here, and I wholeheartedly believe that we will be successful in helping our patients. They really need new treatments. There are no drugs approved in the US to treat FSGS, and the last approved therapy to treat proteinuric kidney disease occurred over 20 years ago. It is pretty much the same since I graduated from medical school in 1991 . It’s time to bring a renaissance and provide new therapies for our patients. For me there is no better mission than doing that. The goldfinch was a prominent symbol during the Renaissance, and signified hope and a new beginning. We chose to name our company Goldfinch Bio because we feel that the vision of our company is to lead a renaissance in developing new therapies for patients with kidney disease. I think it’s a sign of hope and optimism that there’s a new chapter, a new age that we are ushering in and that we want to lead. Because the patients deserve that we find good therapies for them. I’m proud to be part of the team here at Goldfinch that will do exactly that: find new therapies for patients with kidney disease. For me there’s nothing better that I can think of doing with my time. We were thrilled to speak with Dr. Mundel and learn more about his latest venture. Researchers like Dr. Mundel and many others provide us with real hope and conviction that we will one day find a cure for the diseases that cause FSGS and Nephrotic Syndrome. Since 1999, NephCure has helped provide funding for more than 50 research projects to learn more about causes and potential cures for the diseases that cause Nephrotic Syndrome. Today, these researchers are closer than ever to moving new treatments from the laboratory to the pharmacy shelf. Thank you for your commitment to this work, Dr. Mundel, and all who have dedicated their lives to eliminating these rare and chronic diseases! Dr. Peter Mundel is a past awardee of the esteemed American Society of Nephrology Young Investigator Award and a distinguished investigator who lead the Mundel Laboratory at Massachusetts General Hospital and Harvard Medical School from 2010 to 2016. In April 2014, Dr. Mundel received, jointly with Dr. Anna Greka, Renal Division, Brigham and Women’s Hospital, a 2014 Top 10 Clinical Research Outstanding Achievement Award from the Clinical Research Forum. In 2013, he and distinguished colleagues published the first targeted treatment for proteinuric kidney disease in the New England Journal of Medicine. (Abatacept in B-71; N Engl J Med 2013; 369:2416-2423). The associated editorial in the NEJM describes their discovery as a “New Era of Podocyte-Targeted Therapy for Proteinuric Kidney Disease.” Dr. Mundel attended medical school at the University of Heidelberg, Germany. He completed a Postdoctoral Research Fellowship in the program “Experimental Kidney and Circulation Research” at the University of Heidelberg, which was funded by the German Research Foundation. He is also the author or co-author of over 86 original research articles. Dr. Mundel’s research focus has been on the makeup and function of podocytes, key cells found in each of the one million separate filtration units packed into a single human kidney.
Sandra Vargo says June 22, 2017 at 3:22 pm Thank you for your work and dedication to kidney disease. Are there any studies or research being conducted on c3 nephropathy that you are aware of? If not, do you think the information gained from your current work translates to c3?
Michael Ochs says July 2, 2017 at 8:45 pm July 3rd 2017 – E-mail from Michael Ochs – Germany Dear Dr. Mundel, Thank you for all your research and work on kidney diseases. It is very promising and encouraging reading this article and the objectives of your work at Goldfinch Bio. We are regularly following the news at nephcure.org. Our son Johannes (born 10/2013) got steroid resistent NS with primary FSGS, discovered 01/2016. We have been through lot’s of different therapies (Cortison, Prograf and others) but never went into remission for longer than ca. 14 days. All known genetic tests have been made at BIOSCIENCIA (Ingelheim, Germany) with Johannes, myself and my wife during 2016, but no genetic error or defect could be found. They advised us to wait for ca. 2-3 years (while hopefully new genetic mutations related to FSGS will be identified) before continuoing with new genetic tests on Johannes. In January and May this year Johannes got a RITUXIMAB therapy, which each led shortly to full remisson, but after max. 2 weeks proteinuria was back again, however on a lower level with generally improved blood values. Nevertheless, where we are is not satisfying and we fight with the known side effects of the drugs he has to take. Question 1: Are there more genetic mutations related to FSGS know in the US which might be unknown in Germany and therefore would it be worth to continue genetic tests with Johannes in the US? Question 2: Which therapie after RITUXIMAP we gonna apply next? Question 3: Do you want us to share our experiences and medical results (therapies, success, genetic results, medical reports, etc.)? Thank you very much indeed. Best Regards, Michael Ochs
Lauren Lee says July 21, 2017 at 12:37 pm Hi Michael, Thank you for reaching out to us. I am sorry to hear about Johannes and hope he is doing well these days and enjoying a nice summer. It sounds like you are well informed and staying on top of research in the field. I applaud you for being such an awesome advocate for your son. I wonder if anyone has directed you to the work on genetics in kids with Nephrotic Syndrome that is coming out of Dr. Friedhelm Hildebrandt’s lab in Boston? More information can be found here https://vector.childrenshospital.org/2014/09/a-28-gene-test-for-kidney-disease/. Johannes can certainly participate in this study by having your pediatric nephrologist reach out directly to Dr. Hildebrandt’s lab. If you are interested in having additional genetic testing done with a counselor assisting you with the read-out, I can introduce you to a doctor who offers this through his institution. As far a therapies go, I would encourage you to maintain an ongoing discussion with your physician about next steps. If you are interested in seeking a second opinion, we can also suggest some physicians you may want to reach out to in your area or who are available to do phone consults. In addition to participating in Dr. Hildebrandt’s study, there are several other study opportunities you may want to consider. Please visit our clinical trial finder on this site. Simply click on ‘Get Involved’ and follow the link at ‘Participate in Research.’ Thsi will take you to our trial finder tool. I suggest searching Nephrotic Syndrome rather than just FSGS. If there are no studies local to you, you may still be eligible to participate from afar. Lastly, I encourage you to stay connected to us and reach out to me at llee@nephcure.org at anytime. We are interested in helping in any way we can and love your proactive willingness to learn more! Thank you, again, for your thoughtful questions. Take care and all my best to Johannes. Lauren Lee
Caren singer says August 30, 2017 at 10:48 pm I have been diagnosed with FSGS. I am female, I am 71. Other than this frightening diagnosis, I am in good health. Are there any trials that I could possibly be apart of? I have been a dialysis patient for the sat 6 months. Thank you,
Chelsey Fix says September 1, 2017 at 10:02 am Hi Caren, Thanks for your interest in clinical trials! To find opportunities near you, you can try our clinical trial finder, available here – https://nephcure.org/research/participate-in-research/. Doing a quick search, I found some opportunities for FSGS patients, and you can see that list here – http://bit.ly/2epLkb3 I hope you continue to be in good health. Best of luck looking for clinical trials – please keep us updated with your progress. Thank you! Chelsey Fix cfix@nephcure.org