The Future Is Now: Rare Diseases in a Dish

Marshall L. Summar, MD


November 17, 2015

Editorial Collaboration

Medscape &

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Editor's Note : Brian Wamhoff, PhD, is the Cofounder and Vice President of Research and Development, for HemoShear Therapeutics Charlottesville, Virginia

Marshall L. Summar, MD: Hi. I'm Dr Marshall Summar. I'm here at the NORD Summit in Washington, DC, and I have the great privilege of speaking with my friend, Brian Wamhoff, from HemoShear Therapeutics. It's a biotechnology company in Charlottesville, Virginia. We are going to have a conversation today about some new technology developments in the field of rare diseases.

Brian, thanks for taking the time to be here today.

Brian Wamhoff, PhD: Thanks, Marshall.

Challenges to Understanding Rare Diseases

Dr Summar: We've been working together for about a year on a joint project between Children's National Medical Center and HemoShear on rare diseases. Do you want to describe what we've got going on?

Dr Wamhoff: It's pretty exciting. We're developing therapeutics right now for children with organic acidemias. One of the challenges is how to get cells from kids who are alive, particularly from their liver, so that we can understand the biology. As you know, very rarely do mouse models mimic rare human genetic diseases. The bigger challenge is that once you get the cells out of a patient, they do weird things. They don't behave like they do in the body, and it's very difficult to understand the fundamental biology in these kids, particularly the disease.

Dr Summar: When I previously worked with liver cells that we got from patients or animals, within 24-48 hours, they started sort of turning into skin cells and losing their biology.

Dr Wamhoff: It's a great analogy. A liver cell literally looks like a cube, and then when you put it in plastic, it starts to spread out. If that's what were happening in our bodies, neither you nor I would be sitting here right now. They lose their function almost within 24 hours, and that's the biology that you're trying to develop a drug for. It can be very misleading and take you down a pathway where you're almost doomed to failure.

Dr Summar: Most of my work has been around intermediary metabolism, which is what we call "small molecule biochemistry." We've always had problems building mouse models because mice just run at a much faster rate metabolically, so any changes tend to kill the mice off and we can never really study what's going on. We built some very sophisticated methods, but they don't work very well when we want to study these.

Recreating the Rare Disease Outside of the Body

For our audience here, one of the things we've been doing is liver transplants for many of the inborn errors that we study, because that's about the best therapy that we have. The livers that are taken out of the patients, we can't currently do anything with them, so we discard them. When we started working with you guys, we found ways to take those cells and really dive deep into the biology. Tell me what the limits are and what we can do with that. What do you think we're going to be getting out of that?

Dr Wamhoff: Not to geek out too much on what we actually do—

Dr Summar: Oh, geek out a little bit.

Dr Wamhoff: The platform is pretty powerful. Let's take the patient back in July from whom we received a liver. You normally would have discarded it. That's biowaste at the end of the day. It turned out that her liver was pretty healthy. It just couldn't metabolize amino acids, so there was a buildup of ammonia in her blood and that's why she needed a new liver. We are able to take that discarded liver and isolate the cells out, but once you do that, you've taken a cell out of its environment. It's no longer near its neighbors, there's no blood flow, and it's in a state of shock.

At HemoShear, we figured out a way to take those cells, bring their neighbors back, and put them in an environment that makes them think that they're back in the liver. This is cutting-edge in terms of interfacing mechanical engineering with biological materials. We literally recreate a three-dimensional structure for the cells and then restore blood flow and transport to those cells. That's very important because, as we were talking about earlier, when you take a cell and put it in a Petri dish to study it in your lab, it becomes like a skin cell. When we restore blood flow, transport, and the neighbors, and make them think that they're back home, these cells wake up.

With her cells in particular, we were literally able to recreate her rare disease outside of her body and show all of the disease pathology that you saw in her when she was your patient. It was amazing. They're making ammonia. We could challenge them with a high-protein diet, and we could play with the urea cycle, things that you could never do before. You definitely couldn't do it in a human, but you couldn't even do it on the laboratory bench. This is the case for many rare diseases.

Dr Summar: One of the problems that we have with clinical trials is that these patients are fragile, so trying to perform medical manipulations and trying new therapies is always fairly dangerous. My hope for the technology and this idea of working with differentiated cells is that we have a safe test bed where we can try some of these ideas. When we actually took a liver from a patient and saw that it responded the same way as the patient did, from what we knew historically, that was pretty exciting.

Hunting for New Therapeutic Targets

Dr Summar: Where do you see this leading us in the future?

Dr Wamhoff: I think the future is now. We're already learning things about her disease that we never knew before. We typically know the primary mutation, the cause of the disease. It's very difficult to treat the primary mutation. Sometimes the protein degrades, so you can't even go in and try to fix it genetically. Adenoviral therapies still have their challenges. Because we recreated her disease, we now know all the biology around the primary mutation. What we're seeing are potential therapeutic targets arise.

It's no different from atherosclerosis or diabetes, where we know so much about those diseases and the National Institutes of Health (NIH) has dumped funding into them. We know the pathways to hit. We are sort of on the frontier of knowing the disease biology, and I think we are going to unmask new therapeutic targets. Hopefully, with that patient's case, we can be back in the clinic with a drug someday.

Dr Summar: I viewed it as a way to accelerate the process, too, because the mouse models were not working quite as well as we'd like. They work great for some, don't get me wrong. For some of them, they're great, but for some of the really high-profile metabolic diseases, they're very tough to recreate. This is a tool that I think will prove very useful. I'm excited about hunting for targets and hunting for therapeutic avenues. I think it's going to be fun to watch how this technology develops.

Do you see any other uses coming? Obviously, I love intermediary metabolism and rare things. Where do you think we can use this outside of my limited field?

Dr Wamhoff: What we're doing now is very important, in that we are focusing in on a specific disease to prove that we can be successful. Sometimes, we want to do everything. You get this platform that, at any point in time, can recreate a rare vascular disease, a rare liver disease, and even rare tumors. We're working with the National Cancer Institute (NCI) to come up with a tumor platform.

As I go through those diseases, success opens up other things. For example, in Marfan syndrome, a vascular disorder, we understand the mutation, but it's very challenging to do science in a human. We need to recreate it outside the human. When we think about rare cancers, for example, we can use the same fundamental principles that we used to create a liver within the lab to create a tumor microenvironment. We can take tumor cells from the patient and really understand for the first time what they are doing and what we need to be targeting.

There is a lot of promise. We need to be successful now and in the near future. I think that with a little success in some of the initiatives going on at the National Center for Advancing Translational Sciences (NCATS) and expanding out these organ systems, this could be the future of how we go after these rare diseases.

Dr Summar: This has been fun to talk about. We get to talk about this a lot, and it's a lot of fun.

Dr Wamhoff: We can travel the world together talking about it.

Dr Summar: We appreciate Medscape Rare Diseases for giving us a chance to bring this to you. Thank you very much.


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