Masanobu Komatsu, PhD, Associate Professor, Vascular Biology and Cardiovascular Metabolism, Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute, talks about the study of blood vessels, how they form, and how this process could be applied to help patients with arteries that are defective, clogged, blocked etc.
Interview conducted by Ivanhoe Broadcast News in November 2017.
I want to start by asking you a little bit about your research? What is it that you’re looking at in terms of vascular system?
Komatsu: We study biology of blood vessels and how blood vessels form through a process called angiogenesis.
And what are you looking to do? Are you looking at how they could possibly reform in the human system?
Komatsu: So blood vessels have a tubular-like structure, it’s like a pipe; it’s hollow so that the blood can go through. But the initial sprout doesn’t have this kind of structure, no hollow structure, no tubing structure. The vessels form with sprouting and branching, but that has to be followed by the maturation process. Without the maturation process, you cannot have functional blood vessels. So, what we are doing in our lab is studying how the blood vessel maturation process is regulated at the molecular level and how this process failed in the disease situation. Blood vessels are formed with specialized cells called endothelial cells; it’s a lining inside the lumen of blood vessels, kind of like tiles on the wall. These tiles need to be very tightly sealed so that the blood doesn’t leak. Without maturation you don’t have that tightness of the seal.
Down the road, how would this work in the human body? You talked about the stems and branches and maturation process. What is your thought of how this could work way down the road?
Komatsu: Abnormal blood vessels and defective blood vessels are associated with many human diseases, disorders and medical conditions ranging from cancer to cardiovascular diseases, and to complications in diabetes. Even Alzheimer’s disease is thought to be facilitated by vascular defects or defective small blood vessels in the brain. For example, in Alzheimer’s disease, the small blood vessels in the brain start becoming leaky in elderly people. The brain cells are very sensitive, so the blood leakage is going to damage the cells and those cells start dying eventually. Over time, you lose a lot of brain cells so that the brain shrinks in Alzheimer’s. Also eye diseases, like macular degeneration in older people and diabetic retinal disease, are also blood vessel leakage problems. Leaky blood vessels cause damage to the retina nerve so that you lose the nerve cells and you go blind.
So the stroke and macular degeneration, anything with heart?
Komatsu: The ischemic heart and ischemic limbs are related to atherosclerosis problems. You don’t have sufficient blood supply because the arteries are clogged. So, naturally, your tissues start making new blood vessels through the endogenous process. That process is very important for those patients. Doctors tried to enhance this angiogenesis process in the ischemic heart and ischemic limbs to recover blood flow to the tissues. But, that kind of clinical trial didn’t really work. Actually, all of them failed. We believe it’s because you can grow new sprouts and branches, but that treatment doesn’t necessarily promote the vessel maturation process. We study the maturation process so that we can overcome that problem.
What have you found so far, are you to the point where you think you have come close to finding something that might work?
Komatsu: Yes. We found the molecule that is very important for the maturation of blood vessels. It’s a cellular protein found in normal blood vessels. In the diseased tissues this protein level is very low. We also found that when you force an increase to this protein level in the endothelial cells that line the blood vessels, you can repair the defective blood vessels. The next goal is to find out how to increase this protein level.
If you’re talking about finding something down the road that might work in people, the maturation process, what’s your next step in getting this to work in humans?
Komatsu: We already found this protein, like I said. So, the next question is how to boost the production of this protein. We could do this in two different ways; one is to find a pharmacological method, like a drug to increase this protein production in endothelial cells. The other potential way is to use gene therapy to increase the protein level.
Could you explain how that would work with gene therapy?
Komatsu: Gene therapy would most likely be used systemically, or locally in terms of ischemic leg or even ischemic heart disease. Definitely, for ischemic legs you can directly apply or inject gene therapy particles so that you can locally treat the maturation of new blood vessels. But we will need to collaborate with other people who are developing a gene therapy vector because that’s not what we do. So we would collaborate with experts who develop gene therapy vectors.
What are the implications down the road for this kind of research, how does this fit in to their lives years down the road potentially? How long will it take before we see it in humans?
Komatsu: The functionality of blood vessels is important in many areas of human disease and in various clinical conditions. In some areas, we may start having an impact of our application relatively soon, maybe within ten years or so. For other clinical conditions, application is going to take longer, even another generation. So, it depends.
The impact on tissues again down the road how much of a difference would this make in people’s lives?
Komatsu: For people with an ischemic heart, a heart attack is really a life-threatening situation. If you can successfully build functional blood vessels to bypass the clogged arteries, you can supply fresh blood to the tissue. That will definitely save lives. And people with severe peripheral arterial disease, PAD – a lot of diabetic patients have this –, risk leg amputation when it’s really bad. But if the vessel maturation treatment works, then you can save the legs.
These are some applications you could envision within ten years?
Komatsu: Ischemic heart disease and ischemic legs are conditions that we may be able to make an impact sooner. Those problems could potentially be treated locally. Gene therapy is good for local treatment. So, that’s the one area that you could have a relatively quick effect of our study.
I might be asking your colleague about cancer, is this also an appropriate application with your study? If so could you tell me why?
Komatsu: Yes, so the application in cancer is a little bit complicated. The cancer tissues produce a lot of blood vessels. But, interestingly, these blood vessels are quite dysfunctional and chaotic. A lot of vessel sprouts are formed that don’t follow the maturation process. The problem is that when cancer patients take a drug, blood vessels must deliver the drug to the tissue. The blood vessels are the supply lines of the drug. So if the blood vessels are no good, then you don’t get the drug compound to the tumor. There is now a lot of study going on in my lab, as well as other labs in the world, trying to repair those blood vessels so that you can enhance the drug efficacy in cancer.
END OF INTERVIEW
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Masanobu Komatsu, PhD
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