Scientists have long known what causes sickle-cell disease and its devastating effects: a single mutation in one errant gene. But for decades, there has been only modest progress against an inherited condition that mainly afflicts people of African descent.
With advances in gene therapy, that is quickly changing — so much so that scientists have begun to talk of a cure.
In a half-dozen clinical trials planned or underway, researchers are testing strategies for correcting the problem at the genetic level. Already a handful of the enrolled patients, who have endured an illness that causes excruciating bouts of pain, strokes, and early death, no longer show signs of the disease.
Among them is Brandon Williams, 21, who lives with his mother in Chicago. Because of his sickle-cell disease, he had suffered four strokes by age 18. The damage makes it hard for him to speak. His older sister died of the disease.
Following an experimental gene therapy, his symptoms have vanished. Life has taken a sharp turn for the better: no more transfusions, no more pain, no more fear.
“He said, ‘Mom, I think I want to get me a job,’ ” said his mother, Leuteresa Roberts.
It is still early in the course of these experimental treatments, and it is likely to be at least three years before one is approved. Researchers hope the effects will last, but they cannot be certain.
“We are in uncharted territory,” said Dr. David A. Williams, chief scientific officer at Boston Children’s Hospital.
At the moment, the only remedy for sickle-cell disease is a dangerous and expensive bone marrow transplant, an option rarely used. An effective gene therapy would not be simple or inexpensive, but it could change the lives of tens of thousands of people.
“This would be the first genetic cure of a common genetic disease,” said Dr. Edward Benz, professor of medicine at Harvard Medical School.
It also would mark a turning point for a large community of underserved patients. Most of them have African ancestry, but Hispanics and those with southern European, Middle Eastern, or Asian backgrounds are also affected.
Experts have long maintained that advances in treatment have been limited partly because sickle-cell disease is concentrated in less affluent minority communities.
“Having tried for a number of years to raise philanthropic money, I can tell you it’s really hard,” said David Williams.
An estimated 100,000 people in the United States have sickle cell disease. Worldwide, about 300,000 infants are born with the condition each year, a figure projected to grow to more than 400,000 by 2050.
The disorder is most common in sub-Saharan Africa, where an estimated 70 percent of children with it die before adulthood.
In sickle-cell disease, blood cells stuffed with hemoglobin are distorted into sickle shapes. The misshapen cells get stuck in blood vessels, causing strokes, organ damage, and episodes of agonizing pain — called crises — as muscles are starved of oxygen. Children usually return to normal between crises, but teenagers and adults may suffer chronic pain.
Treating the disease, with its complications, is expensive: Annual costs per patient are estimated at $10,000 a year for children and $30,000 for adults. Those with the disorder go in and out of hospitals.
Roberts knows this cycle all too well.
Her daughter, Britney Williams, had sickle-cell disease. At 22, she went into the hospital during a crisis and died, leaving behind a baby daughter.
Roberts’s son, Brandon Williams, was devastated and terrified. He told her he had suffered too much, and his big sister’s death brought home to him the fact that his life, too, could end at any moment. He wanted to stop the monthly blood transfusions that were easing his symptoms. He wanted to go ahead and die.
Then Dr. Alexis Thompson, a sickle-cell specialist at Northwestern University, told Williams that he could join a new study of gene therapy that might help. There were no guarantees, and there was a chance Williams could die from the treatment.
Williams was enthusiastic, but his mother was filled with trepidation. In the end, she decided “we’ve got to try something,” she recalled.
In the new trials, subjects must have immature blood cells — stem cells — removed from their bone marrow. The stem cells are genetically modified, and then infused back into the patient’s bloodstream. The goal is for the modified cells to take up residence in the bone marrow and form healthy red blood cells.
Scientists are testing three methods for modifying stem cells. In the first, a form of gene therapy, a virus is used to insert a viable copy of the hemoglobin gene into the stem cells.
Until recently, the viruses had a limited capacity to carry genes, and the hemoglobin gene simply would not fit. Only recently have scientists found viruses that can do the job.
The second approach starts with the fact that the human genome can make two kinds of hemoglobin: fetal, active in the fetus but shut off after birth, and adult hemoglobin.
Some researchers are trying to block the gene that turns off fetal hemoglobin and turns on adult hemoglobin, allowing patients with sickle-cell disease to produce fetal hemoglobin instead.
A third strategy depends on gene editing with CRISPR, a tool that lets scientists snip out parts of genes and paste in new sections. Several groups are doing early studies with CRISPR.
Farthest along is a new iteration of gene therapy to produce fetal hemoglobin, currently in trials conducted by Bluebird Bio, a biotech company in Cambridge.
Williams wound up in the gene therapy trial run by Bluebird.
His mother will never forget the call she got from Thompson, saying her son was producing enough normal blood cells.
“I was like, yes, yes, thank you Lord,” Roberts said.