Tuesday, September 16, 2014

Researchers work to block kidney, lung damage and pain in sickle cell disease

KutlarMeilerandPollockwebfront[1]Restoring a balance of the most powerful dilator and the most potent constrictor of blood vessels in the body could help patients with sickle cell disease avoid kidney and lung damage as well as pain, researchers say.

They believe drugs already on the market for pulmonary hypertension can turn down the inflammation and blood vessel constriction that results from the imbalance of nitric oxide and endothelin, said Dr. Abdullah Kutlar, Director of the Sickle Cell Center at Georgia Regents University.

Kutlar; Dr. Steffen E. Meiler, Vice Chairman of Research in the Medical College of Georgia Department of Anesthesiology at GRU; and Dr. David Pollock, Chief of the MCG Section of Experimental Medicine, are co-principal investigators on a $8.8 million National Heart, Lung and Blood Institute-funded study that will explore the therapeutic possibilities.

They say the problem is the pro-relaxation, anti-inflammation molecule nitric oxide has a tough time surviving in sickle cell disease while its nemesis, the protein endothelin, appears to thrive. As fragile red blood cells break apart in these patients, they release hemoglobin into the blood, which scarfs up nitric oxide. “Hemoglobin acts like a sink for nitric oxide,” Meiler said.

To make matters worse, sickle cell disease increases the level of free radicals, which also tie up nitric oxide. One question they want answered is whether sickle cell disease further compounds the problem by reducing nitric oxide production, possibly because of endothelin dysfunction. “You could have a minimum of three mechanisms that affect the overall availability of nitric oxide,” Meiler said.

“You have this reduced nitric oxide system and we think endothelin is promoting all the inflammation that causes a lot of the bad things to happen, including pain,” added Kutlar.

Pollock and others already know from their studies of endothelin’s effect on blood pressure that endothelin’s  A receptor – which causes constriction, inflammation and sodium retention – becomes more active when its B receptor – which makes nitric oxide and helps eliminate salt – becomes inactive for any reason.

Whether or not endothelin is a cause, the problems are clear: kidney disease, acute chest syndrome and unrelenting pain – in addition to episodic pain crises – are hallmarks of the genetic disease affecting 1 in 500 blacks in the United States.

While patients with sickle cell disease are living longer, Kutlar and his colleagues expect that without new strategies, the incidence of these related chronic problems also will increase.

Current therapy includes hydroxyurea, the only Food and Drug Administration-approved drug for sickle cell disease, which increases the level of fetal hemoglobin, which cannot sickle. Patients also get nonsteroidal anti-inflammatory agents and narcotics for pain. The researchers think endothelin antagonists could be a strong addition.

“There is not enough proof of concept data out there to convince physicians to prescribe it for their patients as an off-label use,” Pollock said.  So they’ll be looking at ambrisentan, which selectively blocks the endothelin A receptor, and bosentan, which blocks both A and B
receptors in sickle cell disease. “We want to decrease the predominance of endothelin over nitric oxide and see what happens,” Pollock said.

The five-year study will start in animal models of sickle cell and progress to clinical trials of these drugs, Kutlar said. The many questions the researchers hope to answer include whether there is any benefit to blocking only the A receptor versus both. They’ll measure key health indicators, such as how much protein is spilling into the urine and whether pressure inside the lung’s arteries is reduced.

The new NHLBI grant also includes a program to inspire and prepare the next generation of sickle cell researchers. Dr. Betty S. Pace, MCG’s Tedesco Distinguished Chair in Pediatric Hematology/Oncology and Interim Section Chief, will lead the related initiative that will help launch the independent research careers of junior faculty at GRU and from across the country. The two-year program includes mentorship by an MCG sickle cell researcher as the scholars pursue their own research ideas. They’ll also complete a master of clinical and translational science degree while in Augusta. Pace will initiate a national search next month for the first two to three trainees who should start in February.

She is looking for “someone who is really on fire” about a career that will move the sickle cell field forward. Pace, who treats patients and pursues better methods for enhancing fetal hemoglobin expression, had very early and personal inspiration: one of her best friends in junior high school had a stroke and died in her teens from sickle cell disease.

“We must recruit young scientists into the field, not only for clinical care, but to carry on the research,” said Pace, who additionally heads one of six national programs, also funded by the NHLBI and geared at improving diversity among researchers studying non-malignant blood diseases. “It’s exciting.”

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