Scientists have long known what sickle cell disease causes and what devastating effects they have: a single mutation in a missing gene. For decades, only modest progress has been made against an inherited disease affecting mainly people of African descent.
With advances in gene therapy, this is changing rapidly – so much so that scientists are talking about a cure.
In half a dozen planned or ongoing clinical trials, researchers are testing strategies to address the problem at the genetic level. Already a handful of enrolled patients suffering from a disease that causes painful pain, strokes and early death no longer show signs of the disease.
After experimental gene therapy, his symptoms have disappeared. Life has changed for the better: no more transfusions, no more pain, no more fear.
"He said," Mom, I think I want to get a job, "said his mother, Leuteresa Roberts.
In the course of these experimental treatments, it's still early, and it's likely to take at least three years until one is admitted, although the researchers hope the effects will continue, they can not be sure.
"We're on unfamiliar territory," said Dr. David A. Williams, Chief Scientific Officer of the Boston Children & # 39 ; s Hospital.
Currently the only remedy for sickle cell disease is a dangerous and expensive bone marrow transplant, a rarely used option Effective gene therapy would not be easy or inexpensive, but could change the lives of tens of thousands of people
"That would be The first genetic cure for a common genetic disease, "said Dr. Medicine at Harvard Medical School.
This would also be a turning point for a big one e community of underserved patients. Most of them have African ancestors, but also Hispanic and those with southern European, Middle Eastern or Asian background are affected.
Experts have long claimed that progress in treatment is limited, in part because sickle cell disease is concentrated in less affluent minority communities.
"After years of trying to raise philanthropic money, I can tell you it's really hard," Dr. Williams.
A difficult life
An estimated 100,000 people in the United States have sickle cell disease. Every year, around 300,000 babies are born with this condition worldwide, a figure that will increase to more than 400,000 by 2050.
The disease most commonly occurs in sub-Saharan Africa, where an estimated 70 percent of children are affected by it dies before adulthood.
In sickle cell disease, blood cells filled with hemoglobin are distorted into sickle shapes. The malformed cells remain in blood vessels and cause strokes, organ damage and painful episodes – so-called crises – because the muscles are suffering from oxygen. Normally, children return to normalcy between crises. Teenagers and adults, however, suffer from chronic pain.
The malformed 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 infection.
Daily life can be a challenge. Many adults with sickle cell disease are not covered by health insurance, especially in states where Medicaid was not expanded, according to Drs. John Tisdale, lead investigator at the National Institutes of Health.
Employment can be difficult because the disease weakens. However, many who apply for a social security disability are rejected. Tisdale. They end up in emergency rooms when they are in crisis.
The treatment of the disease with its complications is expensive: The annual cost per patient is estimated at $ 10,000 a year for children and $ 30,000 for adults. Those with the disorder go in and out of hospitals.
wife. Roberts knows this cycle only too well.
Her daughter Britney Williams had a sickle cell disease (19459011). At 22 she went to hospital during a crisis and died, leaving a small daughter behind.
wife. Roberts & # 39; s son, Mr. Williams, was devastated and scared. He told her he had suffered too much, and the death of his big sister made him realize that his life could end anytime. He wanted to stop the monthly blood transfusions that relieve his symptoms. He wanted to go on and die.
Then Dr. Alexis Thompson, a sickle cell specialist at Northwestern University, told Mr Williams that he could participate in a new gene therapy study that could help. There were no guarantees and there was a possibility that Mr. Williams died of the treatment.
Mr. Williams was thrilled, but his mother was terrified. In the end, she decided, "we have to try something," she recalls.
Williams was among the first to receive one of the experimental gene therapies in which researchers attempted to give his immature blood cells a new and functional gene . Roberts and the family pastor watched as the treated cells dripped back into his veins.
"I was so overwhelmed," remembers Mrs. Roberts. "I cried tears of joy."
In the 1980s, when researchers began to think about gene therapy to correct genetic disorders, sickle cell disease was high on the list.
Theoretically, it seemed uncomplicated – only a tiny change in a single gene led to misery in life and early death.
Each patient had exactly the same genetic mutation. To cure the disease, all scientists had to fix only one genetic error.
But it was not so easy. Among the many problems plaguing gene therapy research, there were problems specific to sickle cell disease.
Hemoglobin genes are only active in the precursors of red blood cells derived from bone marrow stem cells, and there are only genes active for about four or five days until mature red blood cells form. Benz.
However, when active, the genes instruct the cells to produce enormous amounts of hemoglobin, so much so that the red blood cell is like a bag holding gelatin.
The researchers had a problem. "How do you manipulate a gene or insert a gene so that it is only expressed in these cells and at a high level?" Benz.
In the new studies subjects must have immature blood cells – stem cells – taken from their bone marrow. The stem cells are genetically modified and subsequently infused back into the patient's bloodstream. The aim is that the modified cells stay in the bone marrow and form healthy red blood cells.
Scientists are testing three methods for modifying stem cells. In the first form of gene therapy, a virus is used to introduce a viable copy of the hemoglobin gene into the stem cells.
Until recently, viruses had limited ability to transport genes, and the hemoglobin gene simply would not work. Only recently scientists have found viruses that can fulfill this task.
The second approach begins with the fact that the human genome can produce two types of hemoglobin: fetal hemoglobin, which is active in the fetus but is turned off after birth, and adult hemoglobin.
Some researchers are trying to block the gene that activates fetal hemoglobin and adult hemoglobin, so patients with sickle cell disease can produce fetal hemoglobin instead.
"We have known for decades that hemoglobin is different in a fetus – it does not swell and it works the same way as adult hemoglobin," Dr. Stuart Orkin, a researcher at Harvard University who found hemoglobin change.
A third strategy hinges on gene manipulation with Crispr (19459011), a tool that allows scientists to excise and insert parts of genes into new sections. Several groups are doing early studies with Crispr.
With the recent progress, all three approaches are now feasible. Most advanced is a new iteration of gene therapy for the production of fetal hemoglobin, which is currently being conducted in studies conducted by Bluebird Bio, a biotech company based in Cambridge, Massachusetts.
The company reported results from four patients out of nine in the study who were treated at least six months earlier. All four produced so much normal hemoglobin that they no longer had symptoms of sickle cell disease.
Bluebird is now planning a larger study in consultation with the Food and Drug Administration, which will involve 41 patients receiving gene therapy. The company hopes to complete the study and obtain regulatory approval in 2022.
Following recent scientific advances, N.I.H. has launched an initiative called Cure Sickle Cell to accelerate progress.
It will bring "significant new money," Dr. Keith Hoots, departmental director at the institutes, although the sum has not yet been determined.
The results were remarkable for many of the pioneering patients in these studies.
Carmen Duncan, 20, of Charleston, SC, had removed her spleen at the age of 2, a complication of sickle cell disease complications. She spent much of her childhood in and out of hospitals.
"Sometimes I stayed two weeks," she said. Her arms and legs would hurt from clogged blood vessels. "A simple touch really hurt."
Monthly blood transfusions helped, she said, but they were distressing. Then she participated in the gene therapy study of Bluebird.
Today, doctors say, she has no signs of sickle cell disease anymore. She had longed to go to the military, but was banned because of her condition. Now she wants to get in touch.
Manny Hernandez, 20, was the first patient in a study at Boston Children's Hospital, where researchers are trying to resume production of fetal hemoglobin. It worked: doctors say he does not have the disease anymore.
And Mr. Williams? He ended up in the gene therapy study by Bluebird.
His mother gets the call from dr. Never forgive Thompson, who states that her son produces enough normal blood cells. For him, the sickle cell disease has disappeared.
"I was like, yes, yes, thank you, sir," said Mrs. Roberts.