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.
NephCure Funded Research: Dr. Alessia Fornoni May 27, 2017 by Lauren Eva NephCure Funded Research: Dr. Alessia Fornoni Dr. Alessia Fornoni is a physician scientist focused on better treating and one day, curing individuals with FSGS and other diseases that cause Nephrotic Syndrome. Early in her research career, she received a grant from NephCure, which enabled her to identify a new gene that plays a role in Nephrotic Syndrome. Her breakthroughs in research today could lead directly to a cure for FSGS. Recently, she shared with us her recollections of that experience and what receiving that grant meant for her work. -NKI I grew up on a goat farm in Italy. When I was 8, a local physician buying cheese at our farm encouraged my parents to send me to school in a nearby city. It was there that I first set my sights on becoming a doctor. Medical school brought me to the United States where, after several years in research, I became a nephrologist. Early in my nephrology training, I was fortunate to receive funding from NephCure. The grant I received from NephCure truly catapulted my career and solidified my interest in glomerular diseases like FSGS. In 2008, as a young investigator at the University of Miami, my NIH-funded research was focused on diabetic kidney disease. One day, I was approached by the Chief of Kidney and Pancreas transplantation, Dr. George W. Burke, who shared with me interesting results he gathered when utilizing rituximab in patients with post-transplant proteinuria. His findings sparked my interest—Why did a drug that was used primarily to treat cancer by depleting immune cells also seem to improve these patients’ kidney disease? I decided to investigate this phenomenon further. Dr. Alessia Fornoni With my team, I studied 27 individuals with primary FSGS who received kidney transplants. We were able to prove that preventive treatment with rituximab can reduce the chance of recurrence of proteinuria in patients with FSGS after their kidney transplant. This was groundbreaking. We hoped that our data could help patients with kidney failure due to FSGS, who are tragically at a 30-80% risk of redeveloping the disease after a kidney transplant. At this point, I knew that a new study was needed to confirm my findings and to demonstrate the direct mechanisms by which rituximab may protect the kidney. I had more questions and knew that there was more to learn. But without additional funding, I would not have been able to continue. I turned to NephCure Kidney International. Supporters like you have helped NKI create a research award program, open exclusively to glomerular disease researchers who have a focus on finding a cure for affected families and patients. Through this program, I applied for and received a Bridge Grant that allowed me to continue my work on rituximab. Because of this funding from NephCure, we made significant advancements in the field.We created a screening that enabled us to predict which patients would develop recurrent FSGS after their transplant. We also identified a new gene (SMPDL3b) that plays a role in Nephrotic Syndrome. This gene can now be targeted and used to help create new drug treatments. These discoveries give other researchers in this field building blocks to learn more about FSGS, potentially leading to additional breakthroughs. Before our discoveries with rituximab, I was primarily focused on diabetic kidney disease. Today, due in part to funding from NephCure which advanced my work, I have developed a strong interest in studying rare glomerular diseases, like FSGS. And like me, when you look at a list of the top glomerular disease researchers in this field, many of them received funding or other support from NephCure at some point in their career. Your donation to NephCure makes a difference. For me personally, you have allowed me to reach breakthroughs in my work on FSGS and other glomerular diseases. Can you make a donation today to ensure that research into Nephrotic Syndrome and FSGS can continue? Your gift can help support scientists early in their career, as I once was, who need additional support to study these rare kidney diseases. My battle to find a cure for patients with glomerular disease continues today. Recently, I discovered that a compound called hydroxypropyl beta cyclodextrin (HPβCD) may have benefits in the treatment of certain types of kidney disease. HPβCD has already shown promising pre-clinical results and is now being developed by Variant Pharmaceuticals to treat FSGS. I am hopeful about its potential to delay the progression of this chronic and often times debilitating disease. Thank you for your support thus far in our journey, and thank you for working alongside me in our joint effort to eliminate FSGS and other diseases that cause Nephrotic Syndrome. Together, I know that one day soon, we will find a way to eliminate the suffering caused by this condition. With gratitude, and with the commitment to work with you in finding a cure and training the next generation of physician scientists, Alessia Fornoni, MD, PhD Alessia Fornoni, MD, PhD, is a professor of medicine at the University of Miami Miller School of Medicine, the Peggy and Harold Katz Family Chair, the Director of the Peggy and Harold Katz Family Drug Discovery Center, and the newly named chief of The Katz Family Division of Nephrology and Hypertension. Dr. Fornoni’s research, which has been NIH-funded for the past 10 years, focuses on podocytes and mechanisms of proteinuria, lipid biology, insulin signaling, drug development, and target identification. Her clinical interests are in the area of diabetic kidney disease and of rare glomerular disorders, such as focal and segmental glomerulosclerosis, and Alport syndrome. As a mentor, Dr. Fornoni has trained more than 20 pre- and postdoctoral research fellows, several of whom have gone on to faculty or academic/research positions. She has published more than 90 original articles and is an internationally known lecturer.
Advocacy Alert! Ask Your Senator to Support FSGS Research Funding May 12, 2017 by Kylie Karley Advocacy Alert! Ask Your Senator to Support FSGS Research Funding Ask your Senator to to sign on to Senator Stabenow’s letter requesting that FSGS be eligible for research funding under the Department of Defense’s Peer Reviewed Medical Research Program for fiscal year 2018 Background Each year, the United States Senate crafts an annual Department of Defense (DoD) appropriations bill, which includes a list of conditions that are deemed “eligible for study” through the Peer-Reviewed Medical Research Program (PRMRP). In order for a condition to be included, Senators need to support the condition and officially ask for its inclusion. Senators have many competing appropriations priorities and in order for them to support a condition-specific request, they need to be educated and asked to do so by their constituents. (You) As a result of grassroots outreach, the Senate has recognized FSGS as a condition eligible for study annually for a number of years. This support allows FSGS researchers to compete for nearly $278 million in federal research funding each year. You can read about FSGS researchers that received funding for projects through this program here. Take Action Secure the contact information for your Senator by visiting www.Senate.gov and using the “Find Your Senator” query tool in the upper left corner of the page. Call the office and ask for the Health Legislative Assistant. You can either leave a voicemail or request their e-mail address and send them a message using the template below. If you call, you can use the template as a guide in your conversation. Politely and occasionally follow up on the request. You should have an expectation that the office will respond to your specific concerns. Email Template Dear _______, My name is _________ and I am a constituent from _________. I am also an advocate for the Focal Segmental Glomerulosclerosis (FSGS) community. FSGS is a rare and devastating disease that attacks the kidney’s filtering units (glomeruli), causing serious scarring, which often leads to permanent kidney damage and even failure. FSGS is a leading cause of end-stage renal disease (ESRD), kidney dialysis, and transplantation. FSGS is disabling, potentially fatal, and treatment options remain limited for affected individuals. Please join Senator Debbie Stabenow in requesting that Focal Segmental Glomerulosclerosis (FSGS) be listed as a condition eligible for study through the Department of Defense’s Peer- Reviewed Medical Research Program, and encouraging continued research at the National Institutes of Health (NIH) during consideration of fiscal year (FY) 2018 appropriations through important report language. FSGS is also a leading cause of end-stage renal disease (ESRD), which nearly 30,000 veterans suffer from nationwide. An additional 3,000 veterans are expected to reach ESRD each year with significant disparities among African Americans. In addition, researchers suggest that environmental exposures have yielded new opportunities for investigating FSGS in the military population. More needs to be done to improve our understanding of the impact of FSGS among our military personnel and veterans. Please consider adding your name to the letter by contacting Lorenzo Rubalcava in Senator Debbie Stabenow’s office at Lorenzo_Rubalcava@stabenow.senate.gov or 4-4822. This letter will close on May 18th, 2017. Thank you for your time and your consideration of this letter. Sincerely, [Name] [Address]