Stem Cell Research for Treatment of Critical Limb Ischemia with Dr. Michael R. Go, Ohio State University Medical Center
Listen to the full podcast of this interview at http://vasculardiseasemanagement.com/content/stem-cell-research-treatmen....
How prevalent is critical limb ischemia now?
Critical limb ischemia is, unfortunately, quite prevalent. There are about 1,000 cases of critical limb ischemia per 1 million in the U.S. population. That’s somewhere between 50,000 and 75,000 patients a year that are affected.
What are the current treatments for critical limb ischemia and why are they not always successful for patients diagnosed with it?
Standard treatment for critical limb ischemia right now involves revascularization. This can happen either via bypass surgery or via a percutaneous intervention such as angioplasty and stenting. The problem is that these patients have blockages in the arteries that feed blood to the leg and currently, treatment revolves around getting around or eliminating those blockages. That treatment is fairly successful but the problem is that rerouting the plumbing so to speak doesn’t treat the underlying disease, which is atherosclerosis. It simply reroutes blood around the blockage so one can imagine in that situation that if there’s progression of the disease, there can be redevelopment of blockage in the future and furthermore, the conduits that we use for bypass or the stents that we use when we do percutaneous treatments are not always durable. They can thrombose, clot off, and redevelop blockages within them.
Why are some patients completely ineligible for bypass surgery at all?
That’s really the Achilles heel of treating the whole disease. The fact of the matter is that when a patient comes to you with critical limb ischemia, there’s a 50% chance that that patient is not even eligible for any kind of treatment and the reasons are varied. Most commonly is that the degree of atherosclerosis is such that there is nothing that we can reconstruct. If a blockage is present in the middle of a thigh or at the knee, it’s easy for us to do a bypass around that blockage down to a healthy artery below the blockage, but in patients with very extensive disease, even very low in the foot, below the knee, into the foot, the blockages persist and there is no target blood vessel to which we can route the bypass. That’s a common reason why patients are not candidates for surgery.
Other patients, who may be a candidate for anatomic reasons are not because they have significant comorbidities, severe coronary artery disease, severe pulmonary disease that precludes putting the patient to sleep under anesthesia. Other patients are so debilitated by the time they see us with their limb ischemia that they don’t really have rehabilitation potential after you subject them to a pretty major operation such as bypass surgery.
Other patients are ineligible because right now as far as bypass surgery is concerned, the only reasonable way to do bypass surgery to the small vessels below the knee is to use the patient’s own vein. Many patients, for a variety of reasons, don’t have an available vein to harvest.
Patients come to us with disease that is so far advanced that there is no way we can save their leg and we end up having to do what is called a primary amputation.
When these treatments are unsuccessful, patients generally lose a limb. Does that often result in death also?
It does result in death. The outcome for these patients when we meet them, if they are not eligible for any treatment or revascularization, is very dismal. If you take that whole group of patients, half of them end up with an amputation within 6 months and 20% of them end up dying within 6 months and the overall 5-year mortality for critical limb ischemia is 70%, which rivals that of many cancers.
What is the study that you’re currently working on for Ohio State University that would possibly help these patients who are ineligible or for whom the treatments are unsuccessful?
One of the things that all vascular surgeons have learned over the last several decades is that some patients come in with blockages in their artery and they compensate fairly well and aren’t affected very severely. Some patients come in with blockages in their artery and are affected very severely to the point of getting gangrene of their feet or developing critical limb ischemia. The difference between those 2 groups of patients is that the group that does better is able to mount a very nice collateralization response; the body forms new channels, new pathways, new blood vessels by which blood can be routed around the blockage and still feed the tissues below the area of the blockage. That’s an autologous response, but in the folks who have very severe critical limb ischemia, that response can be impaired and what we are seeking to do is augment that natural response to the point that patients get enough collateral blood flow that we can hopefully prevent amputations for them.
How do you plan to augment that natural response?
One of the stimuli that has been identified as contributing to this collateralization are stem cells, which retain an innate ability to differentiate or at least stimulate differentiation of other cells into new vascular structures. Stem cells are found all over the body. The highest concentrations of what are called hematopoetic cells, or stem cells related to vascular function, in an individual are found in the bone marrow. The way our hypothesis works is that we harvest bone marrow from a patient with limb ischemia; we isolate and concentrate the hematopoetic stem cells and then deliver these cells into the ischemic leg with the hope that it might create what we call a proangiogenic milieu in the ischemic leg and help stimulate the proliferation of these collateral vessels in the area where the main vessel is blocked.
How do you deliver the stem cells to the ischemic limb?
There are a variety of approaches to this. In the particular study that we’re talking about, we inject them intramuscularly into the angiosome where there is an axial vessel occlusion. If the patient has a tibial artery occlusion, for example, below the knee, we’ll inject the stem cell IM into the specific group of muscles that are fed by that blocked artery.
How often will patients come in for follow-up visits after you deliver the stem cells?
I’ll continue to follow the patients as I would any of my limb ischemia patients at about every 3 months. I think it’s too early to know when we might see a response but one might imagine, based on how native collateralization works, that response might occur over weeks to months after treatment and that’s what we’re looking for.
How will you be able to tell that the treatment is working? Do you use a certain kind of imaging equipment?
There are a variety of endpoints that we’re going to look at. First and foremost is, have we salvaged the patient from an amputation? Have we helped that patient avoid the amputation and if so, that’s really the biggest indicator of success. Many times, patients will also have wounds or ulcers on the foot from poor blood flow. Having helped those ulcers to heal is another way to tell. We also have a variety of testing to do; measuring blood pressure at the level of the arteries in the ankle, measuring blood pressure at the level of the capillaries in the skin, we also use questionnaires, evaluate patients’ level of pain, how far they can walk, and then finally, we also evaluate our success with imaging, doing angiograms or cat scans to see if we have increased the density of these capillaries or collateral blood vessels.
What do you hope to achieve in terms of your conclusions and results within the next year?
Right now, we’re in the middle of a phase 1 study so this is a safety study. We have a limited number of patients that we are going to treat and follow for the next year to make sure that the treatment is safe and doesn’t have any unwanted side effects. I think we all believe that’s not the case but of course, we need to prove that and as soon as that’s done, we hope to expand to a phase 2 trial where we will probably involve several other medical centers and then we’ll really start to study if these treatments are helping these patients as far as treating their limb ischemia. It’s an exciting time.
Do you know of any other institutions currently studying stem cell therapy for critical limb ischemia patients?
There are actually several other places and several other vascular doctors interested in a similar field. There are a lot of unanswered questions: What is the best type of stem cell to use? Where is the best place to harvest these stem cells from? Is it from the patient’s bone marrow? Is it from their peripheral blood, where stem cells also exist? Would it be better to use umbilical cord blood or even fetal tissue? Those are questions that are valid scientifically and also get into some ethical questions.
What is the best way to deliver these cells? The way we’re doing it is with intramuscular injection, but I don’t think that it has been established as the best way. It may be intra-arterial injection or periwound injection are better ways to deliver these cells. There are lots of folks around the country looking at all of these questions and hopefully together, we can come up with some answers for these folks who don’t really have any answers right now.
Dr. Go is a vascular surgeon at the Ohio State University Medical Center. He is also assistant professor of vascular surgery at the Ohio State University College of Medicine.