During his residency, Ken Ataga, M.D., was distressed by the poor treatment given to some of the people that came into his hospital. Those patients – who had the blood disorder sickle cell disease -- would show up in excruciating pain, get pain meds and IV fluids, and then be on their way. There was nothing to shorten their pain episodes or prevent them from happening in the first place. What’s worse, many of Ataga’s fellow physicians assumed that because these sick patients kept showing up on their doorstep they must be addicts jonesing for more drugs.

“It became clear to me that someone had to do something,” said Ataga, who is now an associate professor of medicine and director of the Sickle Cell Program at UNC-Chapel Hill.

Ataga was still in his medical training when hydroxyurea, the only drug available for these episodes, entered the scene. Because the drug was previously used as a chemotherapy agent it came with its own set of risks, but it was the only option available for desperate patients. Ataga wanted to provide other options. When he voiced his interest to sickle cell researcher Gene Orringer, M.D., he was met with unbridled enthusiasm.

“He went out of his way to encourage me to pursue this as my focus, and because he was so enthusiastic about it I actually found his enthusiasm infectious,” said Ataga, who later was mentored by Orringer on his path to clinical research through the NC Translational and Clinical Sciences (NC TraCS) Institute K30 program. “I decided it would be a good goal to pursue, to explore the disease and see if I could develop new treatments. It is not like I grew up saying I wanted to work on the disease, but looking back I am glad I did that because it has been a real eye opener.”

Ataga is originally from Nigeria, where as many as one to two percent of its population of 250 million are afflicted with the disease. In Nigeria, sickle cell disease is a common health problem; if you don’t have it yourself, you have a friend or relative that does. In the United States, it is a different story; the number of people with sickle cell is below 200,000. Ataga thinks this difference is to blame for what he has seen as a general disinterest of pharmaceutical companies to pursue research on sickle cell disease. If drug discovery is a numbers game, Ataga says that money makers like diabetes and hypertension will win out over what is seen in the Western world as a rare blood disorder.

In sickle cell disease -- as the name suggests -- the body’s red blood cells assume an abnormal, rigid, sickle shape. The sickling is caused by a defect in the gene for hemoglobin, the molecule responsible for carrying oxygen in the blood. Normally red blood cells are very supple and move easily through veins and arteries, but the abnormally shaped cells of sickle cell disease can get stuck in small blood vessels and block blood flow and oxygen to parts of the body.

“You can imagine if the blood vessel is a pipe with cells flowing through it and blood cells are sticking to the side of the wall, the cells get stuck to the blood vessel wall and cause an obstruction of blood flow,” said Ataga. “This decreased blood flow to organs and tissues can cause patients to develop pain. And because blood flows to every part of the body, sickle cell disease can affect just about every organ of the body. For a clinician that can make it an interesting disease to study, but for a patient that is obviously not interesting at all.”

One of the aspects of sickle cell disease that has piqued Ataga’s interest has to do with another type of blood cell, the platelet. When a wound suddenly appears, platelets are the first group of cells that are activated and form clots to stop the bleeding. But platelets are also very active in people with sickle cell disease, though no one knows exactly why. So Ataga joined forces with Leslie Parise, Ph.D., professor and chair of biochemistry at UNC, to look more closely at the molecular players responsible for turning on platelets. They focused on a compound called CD40 ligand that first pops up on the surface of activated platelets and then gets chopped by enzymes into a substance that circulates in the blood.

Ataga and Parise, as well as Sheritha Lee, a former graduate student in the laboratory of Parise, looked at the levels of CD40 ligand on the platelets and in the blood of sickle cell patients when they were healthy and when they were in crisis, and then compared those levels to people without sickle cell disease. They found that the patients had lower levels of this compound in their platelets and higher levels in their blood than did healthy controls. The differences became even more pronounced when the patients were having a painful crisis. So Ataga wondered if keeping the platelets from releasing this compound into the blood could temper these painful episodes in sickle cell patients.

“The treatment we give patients in 2011 in the U.S. is the same treatment they have received for the last fifty years,” said Ataga. “We simply don’t have any treatment that can shorten or terminate these pain episodes [which can last from hours to days]. Let’s compare that to treatments for heart attacks: if a patient comes in with chest pain and is having a heart attack, you give them medicine or do an angioplasty to bust up the clot and minimize that episode. We don’t have a similar approach for sickle cell disease – which is not to say that people haven’t tried; it is just that nothing has worked so far. So what I am trying to do is to test a drug that potentially could either terminate or reduce the duration of the pain episode.”

That drug is called eptifibatide, which is already in use for acute coronary syndrome. It also happens to block the release of CD40 ligand from platelets, decreasing the stickiness of platelets so they don’t aggregate as much during a crisis. Right now Ataga is using the Clinical and Translational Research Center (CTRC), the clinical unit of NC TraCS Institute, to conduct a double-blinded placebo-controlled study assessing the effects of eptifibatide on patients. Ataga hopes that the drug will help decrease the vicious cycle that occurs during the painful crisis, potentially reducing the amount of time his patients are in pain. So far, the treatment appears to be well- tolerated, but Ataga will not know until the end of the study whether it has made the crisis period shorter and more tolerable.

Ataga has been through the clinical trial rigamorole before. He helped take one drug, senicapoc -- designed to hydrate red blood cells and make them sickle less -- through phase I, II, and III trials. Then the trials stopped when the UNC Data and Safety Monitoring Board found that the drug did not decrease the frequency of painful crises. Because sickle cell is a complicated disease, Ataga says, no one knows what is going to work and what is not going to work until it goes through trials. And those trials take funding, something that is in short supply when dealing with a “rare” disease and a tough economic climate.

“I get frustrated, but I can’t change the system all by myself,” said Ataga. “I am a physician so I feel like my primary responsibility is to take care of patients the best I can, meaning that research is often secondary. But that doesn’t mean I have given up hope that one of the new approaches I am trying will work.”