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. 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.

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.

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.

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. 

Why I Do What I Do: Spotlight On Susan Madigan, CureMaker

We were thrilled to chat recently with Susan Madigan, a longtime supporter of NephCure and grandmother to a young granddaughter who has Minimal Change Disease. Susan has been involved with NephCure in many ways over the years, and we talked with her about the different events and programs she’s contributed to. One of the programs that Susan has been a member of is the CureMakers recurring monthly giving program—meaning she has signed on to contribute to NephCure on a regular monthly basis! Her support has truly made a difference in our work, and we’re pleased and delighted to have her as a member of our community and to share her story with you today.

NKI: How long have you been involved with NephCure, and how did you first become involved?

Susan: My involvement with NephCure revolves around my concern for my granddaughter. She was diagnosed with Nephrotic Syndrome when she was four, and she’s now almost ten. I didn’t get involved right away in the beginning, not knowing much about it. And then I did, in 2012 I became more involved, and then I think I became a CureMaker. I’ve been coming to your Countdown to a Cure gala in New York and supporting my daughter’s walks in Los Angeles for a few years. And I’ve been to a couple of other things here in New York.

I’ve been to the Countdown to a Cure gala two or three times now. One time I had a conflict, but from then on I’ve always blocked that whole period off. I know it’s in November, so I make sure I’ll be around for it.

When my granddaughter was first diagnosed, she was swollen, and my daughter and son-in-law thought she had a bee bite or something. They hadn’t a clue what it was all about; no one did. She woke up swollen and they took her to the pediatrician who said “No, it’s not a bite.” They were able to figure out her diagnosis right away. She now has a wonderful nephrology support team in LA, including her long-time nephrologist, Dr. Elaine Kamil [who serves on the NKI board] as well as Dr. Dechu Puliyanda, her current day-to-day nephrologist.

I don’t talk to my granddaughter much about it; we don’t hide it, but it’s not a constant topic of our conversation. At this point, she’s doing alright. Certain things could still be in the future for her that obviously, we can’t know, or that she can’t comprehend yet.

We’re all very committed and we all try to stay on top of it, but some of it is still a big mystery in my life. But if there’s anything I can do to help, I’m thrilled to do so.

NKI: You’ve been involved with so many activities with NephCure—what’s been your favorite thing so far?

Susan: I love the walks—my daughter’s walk involves a lot of children. Her support group is full of children, and she has t-shirts made for everybody, so we all wear the same shirt. The kids have a banner that they carry. And I like that, because I think it involves the patient—the child—as well as his or her friends, so that they’re aware that something is happening there. I like that a lot.

To me, the gala is also very special, because it gets everybody there and involved. You get all these great people there, and it’s pretty and a lot of fun. I think the auction is great because it raises money for NephCure. The last time I went, I didn’t realize my paddle was in my hand and I kept raising it, (laughs) and finally I thought, after the third time, you’ve got to put this on your lap!

NKI: I know that you and your granddaughter live on opposite coasts. Does donating monthly to NephCure as a CureMaker help you feel connected to her?

Susan: I think to contribute to an organization on a sustaining level is A. easier for the person who donates, and B. you always feel connected, not just at the end of the year, if you choose to donate then. I think it offers security for the organization to know that you have “X” number of people who will be contributing on a monthly basis. And for the people who donate, it’s a very convenient, painless way of doing it! It’s an easy way to contribute for people who want to give, but who may sometimes forget at the end of the year. I love it, I think it’s just wonderful. I also tell my granddaughter about it so that she knows I’m supporting her on a monthly basis.

I really think NephCure is doing an incredible job—as someone said, it’s a disease without a cure, which is rather a disheartening way to put it, but certainly at this point there’s no cure for it. And anything I can to do help, I’d be thrilled to.

NephCure would like to thank Susan for her unwavering and touching support in honor of her granddaughter. Without dedicated people like Susan, the work that we do at NephCure to provide support and education for people living with Nephrotic Syndrome and fund research to find better treatments and a cure would not be possible. Thank you, Susan!

To learn more about the CureMakers monthly giving program, visit our donation page here or give us a call at 610-540-0186 x10. To hear more about a local walk in your area or our Countdown to a Cure gala in NYC, send us an email at events@nephcure.org to get connected with your regional manager.

In 2015, Dr. Evren Azeloglu, a biomedical engineer and an Assistant Professor at the Icahn School of Medicine at Mount Sinai, was awarded the NephCure Kidney International-ASN Foundation for Kidney Research Grant. He planned to use this grant to explore how kidney cells retain their structural integrity against mechanical injury.

Much of the work done in Dr. Azeloglu’s lab involves the podocyte, the specialized kidney cell that is affected by glomerular diseases like FSGS. Podocytes play an important role in glomerular function. Together with other cells, they help form a filtration barrier in the kidney, and they cooperate with other cells to support the structure and function of the glomerulus.

Below, we discuss Dr. Azeloglu’s latest research and what it means for people living with glomerular kidney diseases in our search for better treatments and a cure.

NKI: You’ve recently released two articles (here and here), both from research funded in part by NephCure. Can you tell us about your latest research?

Dr. Azeloglu: Well, podocytes have a very beautiful structure, and we used cutting-edge imaging technology to capture the three-dimensional geometry of these cells. This paper is essentially about how the podocyte shape is not just pretty and sophisticated, but also very necessary for their function. And their shape has certain consequences for disease: some of the glomerular diseases may be directly borne out of the fact that these cells are shaped this way. If you look at the below gif, you will see how these cells look in the body. This is the first time anyone has ever visualized them with this kind of precision.

NKI: Can you elaborate on what you mean when you say that their form suits the function?

Dr. Azeloglu: Well let’s say that you want to build a drawbridge, and you want to be able to have tall ships travel below or through it. So you can either spend a lot of money and build a very tall bridge that is stationary, or you can build one that opens and closes. Basically, you are proposing a “functional upgrade” to a regular bridge. Unfortunately, that comes at a cost. The bridge needs to be able to separate in the middle.

Following that analogy, podocytes have this special shape that allows them to do something that no other cell can do. What we are showing in our paper is that this special shape also comes with a price: incredible fragility. This works in the same way that a drawbridge has less stability than a regular arched bridge and would not be able to sustain the same level of, for example, an earthquake. You sacrifice that stability because you want to be able to open it up. In the same way, podocytes have incredible surface area; they have this amazing structure that allows them to filter blood plasma into urine, but what we’re showing is that only at this shape, the cells start showing this incredibly fragile behavior, and even a little change of their chemistry leads to disease.

This ties in very well with the current knowledge that the podocytes are sort of the first guys to fail, if you will. This is one of the reasons why, for example, diabetic patients, whose cells are under constant stress because of insulin spikes, high levels of glucose, and all sorts of other oxidizing agents, are much more likely to develop nephropathy. So, what we are trying to show here is that these cells are incredibly fragile compared to most other cells in our body.

NKI: What does it mean to be a biomedical engineer studying podocytes, and from a larger perspective, kidney disease?

Dr. Azeloglu: I approach kidney research from an engineer’s perspective: the same way we study machines, buildings, and structures that have to withstand physical stress, which is exactly what podocytes have to do day in and day out. What we’re looking for, and what most of the projects in my lab focus around is: can we understand what makes these cells more susceptible to physical damage, and perhaps reinforce their structure? When all’s said and done, podocytes form a filter, which has a biological function, but to achieve that function, the podocyte uses a very simple physical mechanism: forming a sieve. So we ask, can we come up with therapeutic strategies that can make the podocytes stronger and more resilient? Or can we identify how specific chemical and biomechanical assaults weaken them?

NKI: So is your lab directly looking at ways to fortify the cell? Or is that something you’re laying the groundwork for, for someone else to build from.

Dr. Azeloglu: To be able to fortify something, you want to be able to understand it first. There’s been a lot of science over the last two decades showing that a lot of what these cells do is basically prepare for constant physical abuse, for lack of a better word. It’s just not very pleasant to be a podocyte. It’s biologically expensive to try to maintain physical integrity. So “Part One” of my lab’s research program is: to try to understand what makes these cells unique and special, what is the repertoire of these cells for withstanding physical stress. And “Part Two” is: if we can understand it, can we eventually fortify it? Can we prevent this structure from failing under disease conditions? These cells are very fragile, and they need all the help they can get. We’re expecting them to stick around for 80 years — that’s a long time to be under constant physical abuse.

NKI: The podocyte is such a specific cell—how did you become interested in studying it exclusively?

Dr. Azeloglu: Partly because of the video that you’re looking at—they’re really unique. They’re also almost a poster child of physical cellular stamina. They’re a great example of a microscopic structure that has evolved to do a very specialized physical task and do it for an extended period of time. It’s sort of a dream come true for an engineer.

NKI: What stage were you at in your research when you received this award? Did it have a big impact on what you were able to do?

Dr. Azeloglu: Oh, absolutely! I had just received my appointment as an Assistant Professor, and I had just started setting up my own lab. Without this, I basically wouldn’t have been able to do that.

I come from a cardiac background—as a biomedical engineer, I trained in a cardiac biomechanics lab. And the heart, being a mechanical pump, is another example of a living tissue that’s doing a physically demanding job. I studied that for ten years and as I was transitioning into nephrology, the NephCure-ASN Award was critical. It helped me establish myself as an expert in this field as well. It’s sort of a rite of passage—a lot of the fellows who’ve received this award have moved on to successful careers, so it’s almost expected for you to have one to establish yourself in the field.

I also think my goals and the goals of the NephCure-ASN Award align very well. I want to understand these cells from an engineer’s perspective, which I think is very relevant to their function, and if we can understand it, I think we’ll be able to cure diseases like FSGS. We’ll be able to not only help patients in terms of their symptoms, but also actually cure the disease. I’m in a pharmacology department, so I know that our standard methods can only help us so far; hopefully, this new, fresh perspective will be able to take us to the next level: instead of just dealing with the symptoms, we’ll be able to cure kidney disease. Hopefully.

We were delighted to speak with Dr. Azeloglu on the results of his current research. If you want to stay updated on his work, you can follow him on Twitter (@azeloglu) or visit his lab’s website at http://labs.icahn.mssm.edu/azeloglulab. Thank you for your dedication to this work, Dr. Azeloglu and team!

Dr. Evren U. Azeloglu is an Assistant Professor in the Department of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. He was originally trained as a mechanical engineer, but later went on to receive his Ph.D. in biomedical engineering from Columbia University. In 2010, Dr. Azeloglu was awarded the Howard Hughes Medical Institute Fellowship from the Life Sciences Research Foundation. His background in biomechanics and systems biology is uniquely positioned to study complex diseases such as hypertension and diabetic nephropathy. He aspires to design transformative therapeutic tools using nanotechnology and tissue engineering.

Through generous donations from the NephCure Kidney International community, NephCure has been able to support Dr. Martin Pollak’s kidney disease research at Beth Israel Deaconess Medical Center (a Harvard Medical School teaching hospital) since 2007. Dr. Pollak’s lab works on identifying genetic causes of kidney diseases, like FSGS. They have made some very exciting progress over the past few years, leading to Dr. Pollak’s election into the prestigious National Academy of Sciences in 2014.

Dr. Pollak’s research has identified that two common variations in the apolipoprotein L1 (APOL1) gene impart up to a ten-fold increased susceptibility to FSGS among African Americans. African Americans and others of recent African ancestry suffer disproportionately from chronic kidney disease: although they make up 13% of the U.S. population, they represent 35% of all individuals on dialysis. Other researchers have calculated that 1 in 8 African Americans are at risk for developing kidney disease due to APOL1—stark numbers that may indicate that some forms are FSGS would not be classified as a “rare disease.”

But the research being done at Dr. Pollak’s lab may one day help prevent treat—and prevent—this disease from occurring. Dr. Pollak was recently featured in an article on SFGate.com as saying that “We want to put our own [kidney disease research] division out of business by preventing this disease to begin with.”

We are thrilled to offer a “progress report” on this work directly from Dr. Pollak’s lab. We spoke recently with Andrea Knob, a genetic counselor, clinical research coordinator, and key player in Dr. Pollak’s study, who gave us some background on the work the study is doing, what we can expect from this lab in the future, and how you can get involved in this research yourself.

Q: What is the goal of the research being done in Dr. Pollak’s lab?
Andrea: The purpose of our study is to learn more about the causes of kidney conditions including FSGS, Nephrotic syndrome, unexplained proteinuria, and renal failure by studying genetics. We identify and study genetic factors that may contribute to the development of these conditions. We hope that this will further the knowledge required for scientists to develop better treatments in the future.

Q: What is your role at Dr. Pollak’s lab?
Andrea: I am the clinical research coordinator for Dr. Pollak’s lab. With my background in genetic counseling, I help patients and families navigate the research process, assist them in documenting their personal and family health histories, and serve as a resource for any questions surrounding genetics and research. I am the liaison between our patients/families and our physicians/scientists.

Q: What do you enjoy about CKD research?
Andrea: Every person and family has a story to share, and this information is so valuable and so important. It is amazing to witness this generosity, and to be a part of a team that is so dedicated to making progress in this field. Research answers the questions that otherwise would be left unknown, and that in turn provides hope.

Q: What is APOL1?
Andrea: APOL1 is one of several genes that we study in the Pollak lab. Variations in this gene have been found to confer resistance to trypanosomiasis, a serious disease in some African regions, and as such these variations have risen in frequency in parts of Africa. We are investigating how these gene variants contribute to kidney disease in persons of African ancestry.

Q: Why did the lab decide to focus on APOL1?
Andrea: APOL1 is one of several genes that we study as we try to learn more about the causes of FSGS, Nephrotic syndrome, and related conditions in patients and families. Our lab’s interest in the genetics of FSGS led us to explore the basis of the high rate of FSGS in persons of African ancestry. Certain specific variations in the APOL1 gene contribute to this disparity.

Q: What impact can diagnosing an APOL1 mutation have on treatments for patients?
Andrea: We need to learn more about genes, including APOL1, that may contribute to the development of kidney disease. (We also think there are more to be discovered!) Diagnosing a gene mutation helps doctors determine who might be at increased risk of developing kidney disease. While it may not affect the treatment for patients at this time, the goal is to acquire the information we need about these gene variations in order to develop better treatments in the future.

Q: What is involved for patients in this study?

Andrea: Participation involves a questionnaire, a saliva sample, and a urine sample (if possible) that can be given from home. (If participants prefer to give a blood sample instead of a saliva sample we can help arrange this.)

Q: Who can participate in this study?
Andrea:
• Anyone with FSGS, Nephrotic syndrome, or unexplained proteinuria
• Anyone with a family member who has FSGS, Nephrotic syndrome, or unexplained proteinuria
• Anyone with African ethnicity with non diabetic kidney failure
• Any healthy individual without kidney disease

Q: How do I get more information about the study?
Contact Andrea Knob with any study related questions by phone at 617-667-0467 or by email at aknob@bidmc.harvard.edu. You can also read more about the research study by clicking here. 

In early January, President Obama honored 102 early career scientists with a Presidential Early Career Award for Science and Engineering. It is considered the highest honor for scientists that are in the dawn of their career—the award is given to federally funded researchers that have done exceptional work in advancing their field.

Dr. Anna Greka, long-time friend of NephCure and kidney disease researcher at Harvard University, was a recipient of this award.  Pres. Obama praised Greka and the other recipients, saying, “These innovators are working to help keep the United States on the cutting edge, showing that Federal investments in science lead to advancements that expand our knowledge of the world around us and contribute to our economy.”

Dr. Greka received a Young Investigator Grant from NephCure in 2008, and has continued to support NS patients and families with her hard work and dedication to research. Her research lab focuses on the development of targeted therapies to treat kidney diseases like FSGS and MCD. Dr. Greka also founded the Glom-NExT conference to bring brilliant minds together and focus exclusively on finding therapies for these kidney diseases. She will also be collaborating with NephCure to host a Regional Symposium in the spring. You can read more about Dr. Greka’s lab and her work here – http://grekalab.bwh.harvard.edu

You can read the full statement from the White House about the PECASE awards here. 

Late last year, ChemoCentryx announced plans to launch a clinical trial in 2017 to evaluate a potential treatment option for FSGS patients. The treatment option, known as CCX140, successfully completed a Phase 2 trial (testing for safety and effectiveness) that included patients with diabetic nephropathy. ChemoCentryx is hoping that success indicates that CCX140 will be beneficial to FSGS patients. Currently, there are no FDA approved treatments for FSGS. 

NephCure is dedicated to supporting research efforts that would result in approved treatment options for FSGS patients, and we are excited about the potential of CCX140 to help the patient community.

Please make sure to “like” us on Facebook and check our website regularly for updates on this development.