In June 2019, Helen Obando, a fragile young woman, lay curled up in a hospital bed waiting for a bag of stem cells from her bone marrow, which had been modified through gene therapy, to be administered in the chest intravenously.
They hoped that this treatment was the cure for their sickle cell anemia, an inherited blood disease that can cause unbearable pain, organ damage and premature death.
Helen, who at 16 was the youngest person to receive this therapy, was deeply asleep before the big moment.
It was a crucial moment for medicine.
For more than half a century, scientists have known what causes sickle cell anemia: a single mutation of a gene that causes red blood cells to become stiff and curved in the shape of a crescent, or sickle, instead of Be soft disk-shaped. These deformed cells get stuck in the veins and arteries obstructing the blood flow that carries vital oxygen to the body and causing what distinguishes this terrible disease: episodes of acute pain that begin in childhood.
Globally, millions of people, mostly Africans, suffer from sickle cell anemia. Researchers have worked for decades to improve treatment and find a cure, but experts said their work has been hampered by poor funding, due in part to the fact that most of the approximately 100,000 people suffering from the disease in the United States They are African-American, usually poor or poor.
The disease also affects people who come from southern Europe, the Middle East or Asia, and also those of Hispanic origin, such as Helen.
This is the story of two searches to find a cure for sickle cell anemia: one, that of the Obando family and another, that of a tenacious scientist at Boston Children’s Hospital, Stuart Orkin, 73, who has worked to combat this disease since he was a resident physician in the 1970s.
Like many other people with sickle cell problems, the Obando family suffered a double setback: not only one daughter was born with that disease, but two, Helen and her older sister Haylee Obando. They hoped to get a cure: a dangerous, and sometimes deadly, bone marrow transplant that usually goes to those patients who have a healthy brother who is compatible. But then they heard about the possibilities of a discovery: a complex procedure that reverses a genetic switch in order for the body to produce healthy blood.
Scientists have been experimenting with gene therapies for two decades, with different levels of success. And it will be years before they know if this new procedure is effective in the long term. But if it is, sickle cell anemia could be the first common genetic disease to be cured with human DNA manipulation.
Four weeks after the injection of stem cells, Helen was strong enough to be discharged. At his home in Lawrence, Massachusetts, sitting on a sofa with his mother aside, he put a hand over his eyes and began to sob. She and her family wondered if it would work, if her suffering was really going to end.
A family’s nightmare
Sheila Cintron, 35, and Byron Obando, 40, met when she was in eighth grade and he was in the last year of high school. They fell in love and Haylee, their first daughter, was born in 2001, when Cintron was 17 years old.
When the test they did at birth revealed that Haylee had that disease, her father asked what sickle cell anemia was.
Soon they knew.
On the occasion when the family gathered to celebrate their first birthday, Haylee began screaming without comfort. They took her immediately to the hospital. It was the first of many pain crises.
The doctors warned their parents that if they had another child, the chances of having the same disease were one in four. But they decided to take the risk.
Helen was born less than two years later. But although the illness was severe in Haylee, in Helen it was much worse. When he was nine months old, a serious blockage of blood flow in his pelvis destroyed his bone. At 2 years, his spleen, the organ that helps fight bacterial infections, enlarged dangerously due to another obstruction of blood flow. The doctors removed it through surgery.
After Helen was born, her parents decided not to have any more children. But four years later, Cintron realized that she was pregnant again.
However, they were lucky. His third son, Ryan Obando, did not inherit the sickle cell mutation.
As Ryan grew, Helen’s health worsened. When he was 9 years old, Helen’s doctors suggested a drastic solution: if Ryan was compatible with her, maybe he could help heal her by giving him part of her bone marrow, although there would also be significant risks for her, which included death caused by serious infections or major damage to his organs if his brother’s immune system attacked Helen’s body.
It turned out that Ryan was not compatible with Helen, but with Haylee.
The transplant was successful, but her parents wondered how they could allow one of their daughters to be cured while the sickest continued to suffer.
There was only one way to get a donor for Helen: to have another child. In 2017, the couple embarked on another strenuous medical journey.
Obando had had a vasectomy, so doctors had to extract sperm from the testicles through an operation. Cintron had 75 ovules removed from the ovaries and fertilized with her husband’s sperm. This produced 30 embryos.
All embryos had the sickle cell gene and none was compatible with Helen.
So the family decided to move from Lawrence, where Helen couldn’t go out all winter due to the cold that triggered her pain crises, to Mesa, Arizona. The family had already sold their home when they learned that the doctors at the Boston Children’s Hospital were working on a sickle cell gene therapy.
Cintron contacted Erica Esrick, the principal investigator of the tests. But those trials were not yet available for children.
Scientific research
Nothing had prepared Orkin for the suffering he witnessed when he was in his late thirties and was a resident physician in the pediatric hematology ward at Boston Children’s Hospital. It was the 1970s and in the beds there were many children with sickle cell anemia who cried in pain.
Orkin knew that, at least in theory, there was a solution to the riddle of sickle cells: fetuses produce hemoglobin – the molecules in the blood cells that carry oxygen – with a different gene. Blood cells filled with fetal hemoglobin do not deform. But the fetal gene is turned off after the baby is born, and replaced by an adult hemoglobin gene. If the adult gene mutates, the red blood cells become sickle.
The researchers had to figure out how to change hemoglobin production to the fetal form. No one knew how to do it.
Orkin needed ideas. Thanks to the support of the National Institutes of Health and the Howard Hughes Medical Institute, he was able to continue investigating.
The discovery came in 2008. The cost of DNA sequencing was decreasing greatly, and scientists were finding millions of genetic indicators in human DNA, which allowed them to focus on small genetic differences between people. The researchers began doing large-scale population DNA analysis to look for small, but important, changes in genes. They wondered if there was a molecular switch that could be reversed to make the cells stop producing fetal hemoglobin and start producing adult hemoglobin. And if it existed, could that switch be reversed again?
They discovered a promising clue: a common gene called BCL11A.
In a laboratory experiment, the researchers inhibited this gene and discovered that blood cells that were in Petri dishes began to produce fetal and non-adult hemoglobin.
They then tried to inhibit the gene in mice that were genetically modified to suffer from sickle cell anemia. It worked one more time.
Later, in 2018, they worked with patients in the gene therapy trial of the Boston Children’s Hospital.
This essay – directed by David Williams, an expert in the biology of blood-forming stem cells and working at Boston Children’s Hospital, and Esrick – has a clear objective: “We are going to re-educate blood cells and make them believe that are still in the fetus, ”said Williams.
Doctors gave adult patients a drug that released stem cells – immature cells that can become red blood cells – from the bone marrow, where they normally lodge, to float in the bloodstream. Then they extracted these stem cells from all the blood obtained from the patient.
The researchers used a genetically engineered AIDS virus designed to carry information to stem cells, reversed the fetal hemoglobin gene and deactivated the adult gene. The patients were injected intravenously with the treated stem cells. Hence, the treated cells migrated to the bone marrow of the patients, where they began to produce healthy blood cells.
Seeing success in adult patients, the Food and Drug Administration said Boston Children’s Hospital could already work with teenagers.
When his mother told him about the gene therapy trial, Helen got scared. But the more he thought about it, the more prepared he felt to take the risk.
His symptoms disappeared in the months after the application of gene therapy at Boston Children’s Hospital.
Helen had an appointment scheduled for a semi-annual review on December 16. His total hemoglobin level was so high that he was almost at normal levels, which he had never experienced even with blood transfusions. He had no sign of sickle cell anemia.
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