Hakon Hakonarson, MD, PhD, Director of Center for Applied Genomics at the Children’s Hospital of Philadelphia talks about lymphatic issues and how testing can help resolve them.
Interview conducted by Ivanhoe Broadcast News in September 2019.
Give us if you will a timeline of where you are in this particular research.
HAKONARSON: It was actually interesting that there was a faculty person here at children’s hospital Philadelphia who came to me one day because her family had a lymphatic condition, and no one knew what caused it or how to treat it or deal with it. And she basically asked me if she would be able to provide some funding, could we work on this condition and try to resolve it? And this was probably six years ago or so, five, six years ago. And I said, of course, we would be happy to help. And so we ended up collecting samples from her family. It was actually a four generation family that we have samples from. And we found a new mutation. So we were able to for the soul of this family and help them with respect to therapy. This sort of sparked interest in lymphatic conditions because we had found a brand new mutation that no one knew about from before. So we reached out to the lymphatic sort of consortium or the association because they had patient registry all over the country. These are rare conditions, but obviously the U.S. has 350 million people so these patients do exist. We managed to begin recruiting patients from all over the U.S. We recruited patients here to CHOP and CHOP had actually very recently founded a lymphatic center which is led by Dr. Yoa Dory who was my co-author with this manuscript. We started recruiting those patients and genotyping them, and then we encountered a patient who was about eleven, twelve years old at the time. And he had been tried on this medication that, you know, we and others had sort of shown worked for some patients and had absolutely no effect. So Dr. Dory was having difficulties with them because he had such an overgrowth of the lymphatic vessels – that he was leaking fluid into the pericardium, which is the membrane around the heart, so that constricts and prevents the heart from beating normally. He was leaking fluid into his lungs, so his lung capacity was shrinking and shrinking and shrinking, was down to twenty three percent, which is barely compatible with life. And he was leaking fluid in his belly. His extremities to the extent that he couldn’t stand up from a chair. So it was a really, really severe condition. I’m a pulmonologist. I’m a lung specialist myself. And I just happened to be on the patient service and saw the patient and discussed this study that we are doing on the gene chart. This was maybe about four years ago, and the family got interested because there was really nothing that was available to help him other than sort of palliative surgery that still led to the condition getting worse and worse and worse over time. And then we end up finding a brand new gene and mutation in a gene that had never been described for this condition before. And this led to the observation that there were actually cancer medications that could potentially benefit if you had a mutation in this particular gene.
So the leap to thinking that you have a cancer medication that might impact the lymphatic overgrowth.
HAKONARSON: Yeah, that came because we found a mutation that we tested in cells and some functional assays. And we showed that the mutation led to this sort of signaling pathway that that regulates cell growth and proliferation or multiplication of the cells was just on all the time. And that is very, very abnormal. And this is sort of what happens with cancer cells. I mean, they take control and they grow without any anything being able to block it or stop it. And the same thing was happening here with the lymphatic cells except that these are not cancer cells. But they just had this stimulus to grow because there was a mutation in an enzyme gene, which is called a kinase, but it’s just sort of a regulator of this proliferated sort of phase in the cells. And so that pointed to, ah-ha, I mean, now we may be able to test this medication. So we started some cell based assays. We took lymphatic cells and we grew them. And what we saw is that these lymphatic cells when they had the mutations – we basically just put the mutation into the cells – we use a method which is called crisper cass, which you’ve probably heard about. And the cells – they just start proliferating out of control. And we looked at the medications that we you know was previously shown to work for some patients, had no effects on the cells. Absolutely none. And then we took the cancer medication that we had predicted may show benefit, and it basically totally normalized the growth of the cells. Now, that’s a cell culture. So you don’t know if that’s going to translate into an organism. And so the next thing we did was to take zebra fish. And the reason we picked zebra fish model is just because they mature so rapidly that if we put the mutation in the fish we only have to wait a few days and then we can see that there are lymphatic vessels developing and they just develop out of control.
Are those fish translucent?
HAKONARSON: Yeah you can see through them.
So when you guys went into the lab and saw this, what was your reaction?
HAKONARSON: Well the reaction was wow. I mean, that is impressive, but, I mean, we were hoping that this would happen because if this happened, we would then be able to see if we took a medication, could we treat it? Could we reverse it or rescue it, as we call it? And that exactly was the case. So we put the medication – this cancer medication into the fish, so basically you can’t give the fish a pill or an injection. You just put it into the water so it diffuses all over the fish. All the lymphatic overgrowth reversed and became normal. And this was sort of ah-ha. Because the patient was basically dying in front of our eyes, so we put together an application. We went to the IRB and requested what’s called sort of a compassionate use IND with the FDA. And all of that in light of reviewing all of the data on what the patient had been through, they approved us to use this cancer medication to treat the patient. So we started with a very, very low dose. We recruited one of our colleagues from the from the Oncology Group, Jean Belasco, and she led the treatment phase of the patient, started with a very low dose, and we thought that that’s going to be least sort of concerning with respect to side effects, and we can always go up on the dose if needed. And that dose, which was maybe about a quarter of the dose that you use for treating cancer patients because those cells are so resistant and aggressive – they just melted away. And the whole overgrowth stopped and his entire lymphatic system normalized. It’s like wheat that you give a poison to – the wheat just goes away and the normal grass grows up. And that’s exactly what happened. And now he has essentially a normal lymphatic system, and the child basically came off oxygen, started walking, started running, started biking. And he is essentially with normal daily activities today. So it’s a fascinating story.
So you had a stimulus, and the stimulus was your colleague who had a family history of the disorder. And it seems to me like, and correct me if I’m wrong, the child became the catalyst for further experimentation.
HAKONARSON: Yes. That’s a great summary of what happened next because this obviously was essentially like a miracle because we did not expect to see such a dramatic response. So we have now continued recruitment, not just at CHOP but from all over the U.S. And we have now found many, many more patients with mutations in these genes and in other genes that do the same thing. They respond to the same medication. We have now a couple of other patients who have already been treated, and they responded really, really well as well. And we have now established – CHOP has a mechanism which is called the Frontier program. The Frontier program is sort of a program set to do innovative, novel therapies that may be difficult to get funding from the NIH or from other sources because they are deemed to be too risky or too – or maybe not necessarily likely to yield results because there is high risk. CHOP funds these type of programs and has several such programs, and we are one of them. And our program is now just starting. So we are basically going to set up a – you can call it the world’s center for lymphatic disorders hoping that patients who have these disorders – they can take a cheek swab, send it to us, we can diagnose the problem, and if they have this condition that is treatable, they can come here or we can guide their physicians treating these conditions essentially anywhere in the world.
First of all how would you even know you had a lymphatic issue. And number two, what would you say to them on how they might secure treatment through this center or program?
HAKONARSON: The lymphatic condition – you always develop swelling. So you develop dema and the swelling is typical. The central duct is most likely to begin leaking fluid into the chest, but then it goes into the abdomen and into the heart and into the extremities, or there’s gravity so you have more on the lower extremities than you have on the upper. But essentially anywhere in the body because the lymphatic system is all over the body, there’s this sort of fluid leak happen, so patients who have the DMA – they should be checked out to see if they have a lymphatic condition. Sometimes it’s the venous system – varicose veins and problems with the venous system – but sometimes it’s the lymphatic system. And you know family physicians – they can do a simple imaging study to differentiate between the two. And if a lymphatic condition is established, then the individual can basically have a cheek swab done. So you know the company called 23 and Me – they do these type of things. We have this ability to send out kits. They could for example come to our website and basically say they are so-and-so, they have a lymphatic condition. They would want to be tested. And we would send them a kit. We would test them. And if they have a mutation, we would have the ability to offer them therapy that they could either come here for treatment or we could guide. If they have a center that is capable of delivering that type of therapy, we could guide that locally.
END OF INTERVIEW
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If you would like more information, please contact:
John Ascenzi
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