BOSTON – Helen Obando, a shy slip of a girl, lay curled in a hospital bed in June waiting for a bag of stem cells from her bone marrow, modified by gene therapy, to start dripping into her chest.
The hope was that the treatment would cure her of sickle cell disease, an inherited blood disorder that can cause excruciating pain, organ damage and early death. Helen, who at 16 was the youngest person to undergo the therapy, was sound asleep for the critical moment in medical science.
For more than a half-century, scientists have known the cause of sickle cell disease: A single mutation in a gene turns red blood cells into rigid crescent or sickle shapes instead of soft discs. These misshapen cells get stuck in veins and arteries, blocking the flow of blood that carries oxygen to the body.
Millions of people globally suffer from the disease. Researchers have worked for decades on improving treatment and finding a cure, but experts said the effort has been hindered by chronic underfunding, in part because most of the estimated 100,000 patients in the U.S. are black. The disease also affects people with southern European, Middle Eastern or Asian backgrounds, or those who are Hispanic, like Helen.
This is the story of two quests for a sickle cell cure — one by the Obando family and one by a determined scientist, Dr. Stuart Orkin, 73, who has labored against the disease since he was a medical resident in the 1970s.
Like many others affected by sickle cell, the Obando family faced a double whammy: not one but two children with the disease, Helen and her older sister, Haylee. They lived with one hope for a cure, a dangerous and sometimes fatal bone marrow transplant.
But then they heard about a potential breakthrough: a complex procedure to flip a genetic switch so the body produces healthy blood. It will be years before scientists know whether the new procedure is effective in the long term. If it is, sickle cell disease could be the first common genetic disorder to be cured by manipulating human DNA.
In 2001, Sheila Cintron, 35, and Byron Obando, 40, had their first child, Haylee, who they discovered had the disease in a newborn screening. Doctors warned them that the odds were 1 in 4 that any future children would have sickle cell, too. They decided to take the chance, and less than two years later, Helen was born. Her disease was even worse.
The couple Obando decided not to have more children. But four years later, Cintron discovered she was pregnant. But they were lucky. Ryan did not inherit the mutation.
When he was 9, doctors suggested that his bone marrow might cure Helen. As it turned out, he matched not Helen but Haylee. The transplant succeeded for Haylee; Helen continued to worsen.
Nothing had prepared Orkin for the suffering he witnessed in his 30s as a resident in the pediatric hematology ward at Boston Children’s Hospital, where children with sickle cell cried in pain.
Fetuses make hemoglobin — the oxygen-carrying molecules in blood cells — with a different gene. But the fetal gene is turned off after birth, and an adult hemoglobin gene takes over. If the adult gene is mutated, red cells sickle.
Researchers had to figure out how to switch hemoglobin production to the fetal form. No one knew how to do that. But Orkin kept looking.
The breakthrough came in 2008. With the cost of gene sequencing plummeting, researchers found a promising lead: a gene called BCL11A.
In a lab experiment, researchers blocked this gene and discovered that the blood cells started making fetal instead of adult hemoglobin.
Next they tried blocking the gene in mice. Again, it worked.
Patients came next, in the gene therapy trial at Boston Children’s that began in 2018.
The trial — run by Dr. David Williams and Dr. Erica Esrick — has a straightforward goal: “We’re going to re-educate the blood cells and make them think they are still in the fetus,” Williams said.
Doctors gave adult patients a drug that loosened stem cells — immature cells that can turn into red blood cells — from the bone marrow, their normal home, so they floated free in the bloodstream. Then they extracted those stem cells from whole blood drawn from the patient.
The researchers used a disabled genetically engineered AIDS virus to carry information into the stem cells, flipping on the fetal hemoglobin gene and turning off the adult gene. Then they infused the treated stem cells into patients’ veins. From there, the treated cells migrated into bone marrow, where they began making healthy blood cells.
With the success in adults, the Food and Drug Administration said Boston Children’s could move on to teenagers.
In the months after Helen’s gene therapy infusion, her symptoms have disappeared. She had her six-month checkup Dec. 16. She had no signs of sickle cell disease.