Ten newborns with the rare genetic disorder known as bubble boy disease were cured with gene therapy, researchers revealed Wednesday.
The treatment appears to have completely rid the babies of their immune disorder with no side effects or complications – a result scientists have sought for decades through painstaking research and heartbreaking setbacks.
An earlier attempt to use gene therapy to treat severe combined immunodeficiency disease, or SCID, was halted in 2003 after researchers realized the therapy was giving the children cancer.
The treatment unveiled Wednesday does not appear to carry such calamitous side effects, and experts hope it could help advance cures for other rare genetic disorders such as sickle cell disease.
"It's a game changer," said Jennifer Hemall, a pediatric immunologist at Children's Hospital of Philadelphia, who was not involved in the study.
"For immunologists following this disease, gene therapy has always been out there as the hope of the future. It's exciting to see this wave of treatments actually becoming a reality."
Infants with SCID are essentially born without a functioning immune system. Without treatment, they rarely survive past their first birthday and can be killed by infections as innocuous as the common cold.
Such children were once kept isolated in sterile environments, giving rise to the term 'bubble boy'. Their unusual predicament has caught national attention and been featured in movies and TV shows.
The survival rate in recent years has soared with the advent of widespread screening tests and refinement of life-saving procedures such as bone marrow transplants.
But such treatments have come with complications, often leaving children dependent on regular infusions of immunoglobulin or causing their new immune systems to attack their own body.
The new gene therapy - developed by St. Jude Children's Research Hospital and UCSF Benioff Children's Hospital in San Francisco and published in the New England Journal of Medicine – corrects the genetic defect in the DNA of babies soon after they're born, prompting their bodies to generate missing parts of their immune system.
In interviews, the researchers said they first extracted blood stem cells from the infants' bone marrow. They used a modified virus as a vehicle to deliver the correct copy of a defective gene into those patients' stem cells.
Those corrected cells were then reinfused back into the patient, where they proliferated and created healthy immune cells.
To avoid accidentally turning on cancer-causing genes as previous gene therapies did, the researchers built "insulators" into the virus so that neighboring genes wouldn't be affected when the virus made its insertion into the DNA.
In another innovation, the researchers gave their infant patients a tiny amount of chemotherapy to clear existing cells from the bone marrow before they reinfused the treated cells, giving the corrected cells a better chance to take hold.
The announcement was bittersweet for many at St. Jude Children's Research Hospital. Their team leader and senior author on the paper, Brian Sorrentino, spent the final months of his life racing against a fatal cancer to finish his work on the experimental treatment.
Sorrentino was diagnosed at a young age with Hodgkin's lymphoma, said his widow, Suzanne Sorrentino.
"The loss of hair, the pain and agony of the treatment, it's what made him determined to find new treatments for other diseases in kids," his wife said in an interview.
Sorrentino had been working since the 1990s, alongside other immunologists, on gene therapy for SCID, but his work took on new urgency in the final year and half of his life after his cancer diagnosis, Suzanne said.
When he could no longer get to the hospital, St. Jude colleagues started arranging conference calls and setting up shop at Sorrentino's home dining table. By then, it was apparent the experimental procedure was succeeding. Several of their infant patients had grown into toddlers with fully normal immune systems.
"He told me he thought he was saved as a kid from Hodgkin's because there was something he thought he should be doing with his life," said Suzanne, her voice cracking as she recalled one of her last conversations with her husband.
"With the trial working, and the children doing so well, he felt it was a sign that he achieved what he was supposed to. That it was time for him to go."
In recent years, as newborn screening for SCID has become mandatory across the country, experts have found the disease to be more common than previously thought - occurring in as many as one in 50,000 infants.
There are several forms of SCID. Gene therapy for a variant called ADA-SCIDS is available in Europe. But a cure for the most common form – X-linked SCID, which is only found in boys – had remained elusive until now.
The disease drew national attention in the 1970s with the case of David Vetter. News outlets chronicled his life as he grew up cocooned in plastic. His story spawned the 1976 John Travolta movie The Boy In the Plastic Bubble.
And even after Vetter's death, something about the disease's vulnerable isolating effects kept it in the national consciousness, making a famous cameo in a Seinfeld episode and becoming the panned premise of a Jake Gyllenhaal movie Bubble Boy.
Until now, the most effective therapy for SCID had been transplanting blood-forming stem cells from a tissue-matched sibling donor, but most patients lack such donors.
Half-matched and unrelated donors have also proven life-saving but often resulted in complications.
The first successful gene therapy trial in 2000 by French doctors gave many researchers and patients hope that they could fix the molecular underpinnings of the disease instead of simply treating its symptoms. But when leukemia was found in some of those patients, it temporarily halted gene therapy trials in America and much of the world and sent dispirited researchers searching for answers.
"The leukemia stopped the field for a long time and rightfully so, because people had to figure out what went wrong," said Jordan Orange, a pediatric immunologist at Columbia University, who was not involved in the St. Jude study but helped develop a gene therapy for another immunodeficiency disease called Wiskott-Aldrich.
"But that led us to the point now where we're finally beginning to see actual cures to incurable conditions."
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