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Scientists have known for a long time what causes sickle cell disease and its devastating effects: a single mutation in a stray gene. But for decades, there has been only modest progress against a hereditary disease that primarily affects people of African descent.
The progress of gene therapy is evolving rapidly, so much so that scientists have started talking about curative treatment.
In half a dozen clinical trials planned or underway, researchers are testing strategies to correct the problem at the genetic level. Already a handful of registered patients, who have endured a disease that causes excruciating pain, stroke and early death, no longer show any sign of the disease.
Among them is Brandon Williams, 21, who lives with his mother in Chicago. Because of his sickle cell disease, he had already had four strokes at the age of 18 years. The damage makes it difficult for him to speak. Her older sister died of the disease.
After an experimental gene therapy, her symptoms disappeared. Life has improved for the better: more transfusions, more pain, more fear.
"He said," Mom, I think I want to find a job, "said his mother, Leuteresa Roberts.
It is still early in these experimental treatments and it will probably take at least three years for one to be approved. The researchers hope the effects will last, but they can not be sure.
"We are in unknown territory," said Dr. David A. Williams, chief scientist at Boston Children's Hospital.
At present, the only cure for sickle cell disease is a dangerous and expensive bone marrow transplant, a rarely used option. Effective gene therapy would be neither simple nor cheap, but it could change the lives of tens of thousands of people.
"This would be the first genetic cure for a common genetic disease," said Dr. Edward Benz, a professor of medicine at Harvard Medical School.
It would also mark a turning point for a large community of underserved patients. Most of them have African origins, but Hispanics and those of South European, Middle Eastern or Asian origin are also affected.
Experts have long argued that progress on treatment has been limited, in part because sickle cell disease is concentrated in less affluent minority communities.
"After trying for several years to raise philanthropic funds, I can tell you that it's really difficult," said Dr. Williams.
A difficult life
In the United States, about 100,000 people have sickle cell disease. Worldwide, about 300,000 infants are born with this disease every year, a number should reach more than 400,000 by 2050.
This disorder is particularly prevalent in sub-Saharan Africa, where about 70% of children with this condition die before adulthood.
In sickle cell disease, blood cells packed with hemoglobin are deformed sickle-shaped. Deformed cells get stuck in the blood vessels, causing strokes, organic lesions and excruciating pain episodes – called seizures – while muscles lack oxygen. Children usually return to normal between seizures, but adolescents and adults may experience chronic pain.
Deformed cells do not survive long in the blood – 10 to 20 days, compared to the usual 120 days. Patients may be severely anemic and prone to infection.
Daily life can be a challenge. Many adults with sickle cell disease do not have health insurance, especially in states that have not expanded Medicaid, said Dr. John Tisdale, senior researcher at the National Institutes of Health.
The job can be difficult because the illness is debilitating. Still, many who apply for Social Security disability are denied, said Dr. Tisdale. They find themselves in emergencies in times of crisis.
And treating the disease, with its complications, is expensive: annual costs per patient are estimated at $ 10,000 per year for children and $ 30,000 for adults. Those who suffer from disorder come in and out of hospitals.
Ms. Roberts knows this cycle too well.
His daughter, Britney Williams, had the sicklecell disease. At 22, she went to the hospital during a crisis and died, leaving behind a little girl.
Mrs. Roberts' son, Mr. Williams, was devastated and terrified. He told her that he had suffered too much and that the death of his older sister had made him realize that his life too could end at any time. He wanted to stop the monthly blood transfusions that alleviated his symptoms. He wanted to go ahead and die.
Next, Dr. Alexis Thompson, a specialist in sickle cell disease at Northwestern University, told Williams that he could participate in a new study on gene therapy that could help him. There was no guarantee, and there was a chance that Mr. Williams could die of the treatment.
Mr. Williams was enthusiastic, but his mother was worried. In the end, she decided "we have to try something," she said.
Dr. Williams was one of the first to obtain one of the experimental gene therapies, in which researchers have attempted its immature blood cells a new and functional gene.
Mrs. Roberts and the pastor of the family saw the treated cells fall back into his veins.
"I was so overwhelmed," Roberts recalls. "I cried tears of joy."
Enticing science
In the 1980s, when researchers began to think of gene therapy to correct genetic disorders, sickle cell disease was at the top of the list.
In theory, it seemed simple: a single, minimal change in a single gene led to a life of misery and early death.
Each patient had exactly the same genetic mutation. To cure the disease, it was enough for scientists to correct this genetic error.
But it was not so easy. Among the many problems that tainted gene therapy research, there were some that were specific to sickle cell disease.
Hemoglobin genes are active only in the precursors of red blood cells, derived from bone marrow stem cells, and are active only for about four or five days until the formation of mature red blood cells, said Dr. Benz.
Yet, when they are active, genes direct cells to produce huge amounts of hemoglobin, so much so that the red blood cell is like a bag containing gelatin.
This left the researchers with a problem. "How do you handle a gene or do you introduce a gene so that it is only expressed in those cells and at high levels?" Asked Dr. Benz.
In the new tests, subjects must have immature blood cells – stem cells – extracted from their bone marrow. The stem cells are genetically modified and then reinjected into the patient's bloodstream. The goal is that the modified cells install in the bone marrow and form healthy red blood cells.
Scientists are testing three methods to modify stem cells. In the first, a form of gene therapy, a virus is used to insert a viable copy of the hemoglobin gene into stem cells.
Until recently, viruses had a limited capacity for gene transport and the hemoglobin gene just did not fit. It is only recently that scientists have discovered viruses capable of doing the job.
The second approach starts from the fact that the human genome can produce two types of hemoglobin: fetal hemoglobin, active in the fetus but closed after birth, and adult hemoglobin.
Some researchers are trying to block the gene that disables fetal hemoglobin and activates adult hemoglobin, thus allowing patients with sickle cell disease to produce fetal hemoglobin.
"We've known for decades that hemoglobin is different in the fetus: it does not cause the sickle and works as well as adult hemoglobin," said Dr. Stuart Orkin, a researcher at Harvard University, who said discovered the hemoglobin switch.
A third strategy depends on gene editing with CRISPR, a tool that allows scientists to extract parts of genes and paste them into new sections. Several groups are doing preliminary studies on Crispr.
With recent progress, the three approaches now seem achievable. The furthest is a new iteration of gene therapy to produce fetal hemoglobin, currently being tested by Bluebird Bio, a biotechnology company based in Cambridge, Mbadachusetts.
The company reported the results of four out of nine patients in the study who had been treated at least six months earlier. All four have produced enough normal hemoglobin to no longer show symptoms of sickle cell disease.
Bluebird is currently preparing a larger study, in consultation with the Food and Drug Administration, which will include 41 patients, all of whom will benefit from gene therapy. The company hopes to complete the study and obtain approval in 2022.
Following recent scientific advances, the N.I.H. launched an initiative called Cure Sickle Cell to accelerate progress.
This will bring "significant new funding," said Dr. Keith Hoots, Institute Division Director, although the total has not yet been determined.
For many pioneering patients in these trials, the results have been remarkable.
Carmen Duncan, age 20, of Charleston, SC, had the spleen extracted at 2 years of age, as a result of complications from sickle cell disease. She spent much of her childhood in hospitals.
"Sometimes I stayed for two weeks," she says. His arms and legs would hurt him because of the blocked blood vessels. "A simple touch really hurts."
Monthly blood transfusions helped, she said, but they were heavy. She then entered Bluebird's gene therapy trial.
Today, doctors say, she has no signs of sickle cell disease anymore. She wanted to join the army, but had been banned because of her condition. She is now planning to enlist.
Manny Hernandez, 20, was the first patient in a Boston Children's Hospital trial in which researchers were trying to restart fetal hemoglobin production. It worked: the doctors say that he no longer has the disease.
And Mr. Williams? He was found in the Bluebird-led gene therapy trial.
Her mother will never forget the call she received from Dr. Thompson, claiming that her son was producing enough normal blood cells. For him too, sickle cell disease has disappeared.
"I was like, yes, yes, thank you Lord," said Ms. Roberts.
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