Scientists have long known what causes sickle cell disease and its devastating consequences: a mutation in a gene that falls apart. But for decades, there has been little progress against an inherited condition that primarily affects people of African descent. With advances in gene therapy, this quickly changes – so much that scientists have begun talking about treatment. In the planned or conducted half dozen clinical trials, researchers are testing strategies to correct the problem at the genetic level. Already several of the enrolled patients who have suffered a disease that causes painful attacks of pain, strokes and early death no longer show signs of the disease.
After experimental gene therapy, his symptoms disappeared. Life has turned to better: no more transfusions, no more pain, no more fear.
"He said," Mum, I think I want to find a job, "says his mother, Leuteresa Roberts.
It is still early in the course of these experimental treatments and probably at least three years before being approved. Although researchers hope that the effects will continue, they can not be sure.
"We are in unexplored territory," said Dr. David Williams, Chief Scientific Officer at Boston Children's Hospital. Currently the only drug for sickle cell disease is a dangerous and expensive bone marrow transplant, which is rarely used. Effective gene therapy would not be simple or cheap, but could change the lives of tens of thousands of people. "This would be the first genetic treatment of common genetic disease," says Dr. Edward Benz, professor of medicine at Harvard Medical School. It will also mark a turning point for a large community of patients who are under-served. Most of them have African descent, but Latin Americans as well as those with southern Europe, the Middle East or Asia are affected. Experts have long argued that progress in treatment is limited, partly because sickle cell disease is concentrated in less wealthy minority communities. "Having tried for many years to raise charity money, I can tell you that it is very difficult," said Dr. Williams. Around 100,000 people in the United States have a sickle-cell cage. disease. Globally, about 300,000 babies are born with this condition every year, with the figure expected to grow to over 400,000 by 2050
The disorder is most common in Sub-Saharan Africa, where about 70 % of children with it dies before maturity. In sickle cell disease, blood cells filled with hemoglobin are distorted in sickle-shaped forms. Deformed cells get stuck in the blood vessels, causing strokes, organ damage, and episodes of agonizing pain – called crises – because the muscles are burned by oxygen. Children usually return to normal between crises, but teenagers and adults may suffer from 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 susceptible to infections.
Everyday life can be challenging. Many adults with sickle cell disease do not have health insurance, especially in countries that have not expanded Medicaid, says Dr. John Tisdale, senior researcher at the National Institutes of Health.
Employment can be difficult because the disease is exhausting. However, many people who apply for social security damage are denied, said Dr. Tisdale. They find themselves in emergency wards when they are in crisis.
The treatment of the disease, with its complications, is expensive: Annual cost per patient is estimated at $ 10,000 per year for children and $ 30,000 per adult. People with this disorder enter and leave hospitals. Roberts knows this cycle very well.
Her daughter, Britney Williams, had a sickle cellular disease. At age 22 she went to the hospital during a crisis and died, leaving behind a baby daughter. Roberts' son, Mr. Williams, was devastated and terrified. He told her that he had survived too much, and the death of his great sister led him to the fact that his life could end at any given time. He wanted to stop the monthly blood transfusions that relieved his symptoms. He wanted to go ahead and die.
Then Dr. Alexis Thompson, a sickle cell specialist at the Northwest University, told Mr. Williams that he could get involved in a new gene therapy study that could help. There was no guarantee, and Mr. Williams was likely to die from the treatment. Williams was enthusiastic, but his mother was full of trembling. In the end, she decided: "We have to try something," she remembers. Williams is among the first to receive one of the experimental gene therapies in which researchers have tried to give his immature blood cells a new and functional gene . Roberts and the family pastor watched how the treated cells dripped back into his veins.
"I was so overwhelmed," recalls Ms. Roberts. "I cried tears of joy."
In the 1980s, when researchers first began thinking about gene therapy to correct genetic diseases, sickle cell disease was at the top of the list
In theory, it looked easy – only a small change in one gene led to life in misery and early death.
Each patient has exactly the same genetic mutation. To cure the disease, all scientists had to correct this genetic error.
But it was not that easy. Among the many problems that have plagued gene therapy studies, there were those that are specific for sickle cell disease. Genogenin genes are only active in red blood cell precursors that are derived from bone marrow stem cells and the genes are only active for about four or five days until mature red blood cells are formed, said Dr Benz.
But when they are active, the genes direct cells to make huge amounts of hemoglobin, so much that red blood cells resemble a gelatin bag. , "How is a gene being manipulated, or a gene is placed in it, so that it is expressed only in these cells and in high levels?", Asked Benz.
In new studies participants should have immature blood cells – stem cells – removed from their bone marrow. Stem cells are genetically modified and then infused back into the patient's bloodstream. The goal is that the modified cells reside in the bone marrow and form healthy red blood cells.
Scientists have three methods for modifying stem cells. In the first form of gene therapy, a virus is used to insert a viable copy of the hemoglobin gene into the stem cells. Until recently, viruses had limited capacities to carry genes, and the hemoglobin gene would simply not fit. It is only recently that scientists have discovered viruses that can do the job. The second approach begins with the fact that the human genome can create two types of hemoglobin: fetal hemoglobin, active in the fetus but discontinued after birth, and adult hemoglobin. Some researchers are trying to block the gene that excludes fetal hemoglobin and becomes adult hemoglobin, allowing patients with sickle cell disease to produce fetal hemoglobin. "For decades now, we know that hemoglobin is different in the fetus – it is not a sickle, and it works like adult hemoglobin," says Dr. Stuart Orkin, a Harvard University researcher who found a hemoglobin breaker. ,
A third strategy depends on editing a gene with a Crispr tool that allows scientists to cut out parts of genes and put them in new sections. Several groups do early studies with Crispr.
With the latest achievements, all three approaches now seem feasible. A further iteration of gene therapy for the production of fetal hemoglobin is currently being conducted by Bluebird Bio, a biotech company in Cambridge, Massachusetts.
The company reported results for four patients out of nine in the study who were treated six months ago. All four produce enough normal hemoglobin that they no longer had symptoms of sickle cell disease.
Bluebird plans a larger study, in consultation with the Food and Drug Administration, which will include 41 patients, all of whom will receive gene therapy. The company hopes to complete the study and obtain approval in 2022.
Following recent scientific advances, N.I.H. launched an initiative called Cure Sickle Cell to speed up progress. This will bring "significant new money," said Dr. Keith Houts, director of divisions at the institutes, although the overall amount has not yet been determined.
For many pioneering patients in these studies, the results are remarkable.
Carmen Duncan, 20, from Charleston, CA, was removed from her spleen when she was 2 years old as a result of complications of sickle-cell disease. She spends much of her childhood in and out of hospitals.
"I would have stayed for two weeks," she said. Her hands and legs would hurt from clogged blood vessels. "One simple touch really hurts."
Monthly blood spills helped, she said, but they were heavy. Then she entered the Bluebird gene therapy test.
Today, doctors say there are no signs of sickle cell disease anymore. He longed to join the military, but was broken because of his condition. Now she plans to sign up. Manny Hernandez, 20, is the first patient in a study at the Boston Children's Hospital, where researchers are trying to resume fetal hemoglobin production. He works: Doctors say he no longer has the disease.
And Mr. Williams? He found himself in the gene therapy study led by Bluebird. His mother will never forget the call she received from Dr. Thompson, saying her son produces enough normal blood cells. For him, sickle-cell disease has also disappeared.
"I was like, yes, yes, thank you, Lord," said Mrs. Roberts.