NephCure Supported Research: Gary W. Liu February 1, 2018 by Lauren Eva Gary W. Liu was diagnosed with Minimal Change Disease as a child. Today, he is investigating new ways to deliver drugs directly to the kidney in the hopes of one day providing a cure for diseases that cause Nephrotic Syndrome. Gary W. Liu Gary Liu is a fifth-year graduate student and National Science Foundation Graduate Research Fellow in University of Washington Bioengineering Professor Dr. Suzie Pun’s lab and collaborator with University of Washington Nephrology chair and clinician Dr. Stuart Shankland. We spoke with him recently to learn more about his unique story and personal approach to his bioengineering work. NephCure: Can you tell us about your diagnosis and experience with kidney disease? Gary Liu: I was diagnosed with Minimal Change Disease (MCD) when I was five. I remember that I was really thirsty and kept drinking water, but none of it was coming out. One night, I was in so much pain that I couldn’t move. All the water I’d been drinking didn’t have anywhere to go but up and out, and I vomited. I was taken to the ER and put on the typical treatments—immunosuppressants and glucocorticoid steroids. As I was a kid, I was constantly told that I would get over this, because MCD is a disease that is supposed to resolve itself. But as I entered middle school and high school and when I started going into undergrad, the disease was always in the background. There were periods when I was in remission, in which I was otherwise healthy, but then I would have a disease flare whenever we had to increase the dosage. These drugs had a lot of side effects that were particularly difficult to deal with as a kid. They made you gain a lot of weight, and on the playground kids were not very nice. Over time, as I lived with the disease and experienced firsthand as a patient the limitations of the available treatments, I was curious as to why there were not more effective treatments and a definitive cure. In undergrad, I looked into the literature and observed that there were not “engineered” treatments for diseases like mine—glomerular kidney diseases. When I applied to graduate school, I realized that I wanted to learn ways to apply bio-engineering to kidney diseases. I wanted to then take that training and one day start my own lab to engineer new treatments that can hopefully cure kidney disease. I draw upon a lot of the emotions and feelings that I had as a patient to try to remind myself everyday why I go to work: so that people and patients like myself don’t have to go through what they’re currently going through with the disease. Gary working in the lab. NephCure: Could you describe, for a layperson, your current projects in this area? Liu: In glomerular kidney diseases, there are cells that are very important for kidney function called podocytes. When podocytes are healthy and functioning, they look like octopuses. They have these “feet” that form a zipper with their neighbor. This zipper is really important for how the kidney is able to filter the blood—you can imagine that together the zippers form a nice filter. In a lot of kidney diseases, these podocytes are injured, or they undergo what’s called “effacement,” where the foot processes retract. If you have effacement or if you have a podocyte that dies off, your kidneys are now more leaky. They start leaking what normally stays in your blood into your urine. If that podocyte death or injury continues, that leads to irreversible kidney scarring and eventual kidney failure. When we look at what the current clinical standard for treatment is—immunosuppressants, the anti-hypertensives—they do work for some forms of kidney disease, but they don’t address this fundamental problem of podocyte dysfunction or podocyte loss. One of the projects that we’re looking into is how we can take advantage of natural stem, or progenitor, cells in the kidney and then engineer them so that they can regenerate these podocytes that are lost. Image borrowed with permission from Gary Liu’s presentation, “From patient to researcher: Transforming kidney disease treatment” There’s been a lot of exciting findings in this area. The Romagnani group in Italy found that if you collect urine from kidney disease patients, you’ll see that they lose progenitor cells into their urine. They’ve shown that if you take these cells from kidney disease patients and then inject them into mice with kidney disease, these cells actually go into the mouse kidney and start regenerating new functional podocytes. If we can collect urine from people with kidney disease, grow these progenitor cells, and then inject them back into the patient, this could be a new way of treating patients with their own progenitor cells. What we’re trying to do is better engineer them so this can be a more effective clinical therapy. We’re looking at two different routes to go about this. One way is to graft nanoparticle “backpacks” onto the stem cells. One of the challenges whenever you inject cells into the body is that you lose a lot of them, because they have to be able to circulate for a long time; they have to be able to survive before they can actually get to the kidney. If we have nanoparticles that are loaded with the drugs, the cells could survive better. It’s kind of like these cells are hikers, and we’re giving them backpacks with food and a map so they know where they’re going. These drugs can enhance their proliferation and survival once they’re injected into the body. We think that these will be able to help these cells survive longer, so that they can go into the kidney and actually differentiate into functional podocytes. Image borrowed with permission from Gary Liu’s presentation, “From patient to researcher: Transforming kidney disease treatment” The other route we’re considering is a non-viral means of genetically engineering these cells. In viral genetic engineering, there’s always a risk of oncogenesis, or causing cancer, because viruses inset DNA randomly within the host DNA. If we can do this non-virally, we increase the safety profile so that the DNA does not necessarily insert randomly. We then provide a means of genetically editing these cells, which means that in patients with genetic causes of kidney disease, this might be a curative therapy for them. Through our work with nano-sized materials, we are beginning to understand that the charge (neutral, positive, or negative) of these materials influences where these materials go in the body. Our recent work has shown that materials that are very negative in charge home into the kidneys more than other organs. We’re very excited about this data, as this knowledge can lead to improved drug carriers that better deliver drugs to the kidneys for kidney disease, and hopefully improve the side effect profile of those drugs. Since receiving the grant, we’ve been able to make great progress isolating and growing renal progenitors from patients’ urine, and in initial animal experiments, these cells seem to decrease proteinuria and regenerate lost podocytes. We’re excited about these preliminary data, and are continuing with our “backpack” formulations. NephCure: You were able to receive funding for this project in a very particular way. Could you describe the grant you received and how it’s different? Liu: I received this grant through the Department of Defense’s Peer Reviewed Medical Research Program. Typically, for this kind of work we would have applied for funding through the National Institutes of Health (NIH). But we didn’t have that option because the National Institute of Diabetes and Digestive and Kidney Diseases (which funds kidney research as part of the NIH) didn’t have a way to fund early-stage projects without significant established preliminary data. We needed a funding mechanism for this project that encouraged high risk, high potential impact work. The Department of Defense route for funding had not been done before, because kidney diseases such as FSGS were not listed as an option to study until 2016. [Editor’s note: the Department of Defense Peer Reviewed Medical Research Program designates a list of conditions each year that researchers can select from to apply for funding to study. NephCure volunteer advocates have so far successfully gotten FSGS on the list of designated diseases each year since 2016.] NephCure did a lot of great advocacy work on Capitol Hill to get FSGS on the list as one of the diseases that researchers can receive grants to study. Because of NephCure’s hard work with the Department of Defense, we were able to get these new and exciting ideas funded. The Department of Defense grant allows us to try to generate the preliminary data that may enable us to get more grants, or even perhaps entice biotech companies to get on board. We are incredibly grateful for NephCure’s great advocacy work. Through this route, our lab was able to secure much-needed research funds to support our work. Thank you to all of the patients, doctors, and activists who made the work I’m doing possible.