Sickle-cell anemia was the first disease to have its genetic cause identified, in the 1950s — a milestone in human genetics. Yet today, there’s just one FDA-approved drug, hydroxyurea, developed 20 years ago at Children’s. Though it’s a mainstay of treatment, reducing the frequency of severe pain, acute chest syndrome and the need for blood transfusions, it can cause toxicity, and about half of patients aren’t helped by it. Only a hematopoietic stem-cell transplant is curative.
Research on sickle-cell disease has generally been underfunded compared with other genetic diseases like cystic fibrosis that aren’t as common. But Children’s has been exploring new treatment approaches for decades, and two exciting possibilities have emerged.
A quick tutorial: In sickle-cell disease, the hemoglobin molecules in red blood cells have a mistake in their amino acid sequence, causing them to assume a rod-like shape. This distorts the cells and makes them sticky. The cells clump together and stick to the linings of the blood capillaries, creating a blockage that deprives tissues of oxygen, leading to severe pain and ultimately organ damage.
But there’s more to the story, and that’s what the first new approach is about.
A decade ago, Orah Platt, chief of laboratory medicine at Children’s, proposed that sickle-cell is really an inflammatory disease. In an attempt to heal the injured, oxygen-deprived tissues, white blood cells come to the area of blockage. But instead of helping, they literally inflame the situation, exacerbating the crisis and causing more sickling.
Breaking the cycle
Some years later, at a cancer conference, David Nathan, former physician-in-chief at Children’s and president emeritus of the Dana-Farber Cancer Institute, heard about a potential cancer treatment that would inhibit adenosine receptors. He knew adenosine is a natural brake on inflammation, and got an idea.
“I went to the web and typed in ‘sickle cell’ and ‘adenosine’ to see if anyone else was thinking about it,” Nathan says.
One person was: Joel Linden of the La Jolla Institute of Allergy & Immunology. He’d found, in mouse models of sickle cell disease, that activating a certain adenosine receptor inhibited inflammation and tissue injury. He’d also zeroed in on the main inflammatory culprits in humans, white blood cells known as iNKT cells, and showed them to be loaded with these adenosine receptors.
A drug stimulating the receptors was already available: Lexiscan (regadenoson), used in cardiac stress testing. “We started talking, and said, ‘gee, we should do a clinical trial,’” says Nathan.
That trial, with 80-year-old Nathan at the helm, got NIH stimulus funding. So far, it’s shown that Lexiscan is safe and that it “disarms” iNKT cells in sickle-cell patients who haven’t yet had an acute crisis, Nathan says. Next is a dose-seeking study, in adults and children 14 and older, and then a placebo-controlled trial of Lexiscan in 96 patients with acute pain crisis or acute chest syndrome, at Children’s and eight other institutions.
Making sickle-cell benign
But Nathan is equally excited about the second approach, which could prevent sickle-cell crises from occurring at all.
It’s long been known that certain people with the sickle-cell mutation have few or very mild symptoms. They carry high levels of a fetal form of hemoglobin that normally stops being made after birth. For decades, researchers have tried to figure out why.
In collaboration with the Broad Institute of Harvard and MIT, Children’s researchers Stuart Orkin and Vijay Sankaran compared patients with mild versus severe sickle cell disease, surveyed their genomes, and found five genetic variants that correlated with fetal hemoglobin levels. They eventually homed in on a single gene: BCL11A. When they suppressed BCL11A in human cells and in mice, red blood cells began making fetal hemoglobin in large amounts.
“If you can get fetal hemoglobin up high enough, sickle cells will not sickle,” says Nathan. “This is going to be the ultimate answer that will put me out of business.”
In their latest work, Sankaran, Children’s trustee Harvey Lodish, and their colleagues followed up on an early clue. Back in the 1960s, the renowned Children’s hematologist Louis Diamond and his fellow Park Gerald noted increased fetal hemoglobin in infants with trisomy 13, a syndrome in which an extra chromosome 13 leads to mental retardation, heart defects, eye problems and other anomalies.
“People put this observation aside,” says Sankaran, “but since we now know every gene that’s on chromosome 13, we decided to ask whether we could home in on the genes of importance in fetal hemoglobin production.”
Their analysis, published this month, found some promising candidates – a pair of microRNAs, and a protein whose activity they regulate, known as MYB. When MYB is suppressed, fetal hemoglobin production increases.
Both BCL11A and MYB have other important functions, so caution would be needed in trying to block them with drugs. But even suppressing them a little could have a large effect on fetal hemoglobin production.
“If we just slightly knock down activity, we may not have any side effects,” Sankaran says. “We know there are people with variations of levels of these, without any repercussions. Rather than having nonspecific therapies for sickle-cell disease that work to a limited extent, we might have more effective and targeted therapies.”
That would be the answer to many people’s dreams.