Gene Therapy Might Prove a Cure for 'Bubble Boy' Disease
They were once imprisoned in plastic bubbles that cut them off from the dangerous, infectious world.
But now, children born with a disease that robs them of a functioning immune system may have gained a new lease on life.
Researchers say gene therapy may be a cure for X-linked severe combined immune deficiency (SCID-X1), widely known as "bubble boy disease."
Ten infants have successfully received the experimental therapy, which involves collecting their bone marrow and exposing it to a virus that inserts a corrected copy of the defective gene into their stem cells, say researchers at St. Jude Children's Research Hospital in Memphis, Tenn.
"These patients are toddlers now who are responding to vaccination and have immune systems that produce all immune cells they need for protection from infections as they explore the world and live normal lives," said lead researcher Dr. Ewelina Mamcarz, a doctor with St. Jude's Department of Bone Marrow Transplantation and Cellular Therapy.
The gene therapy appears to have fully restored the immune system in the toddlers, something that hasn't been possible before, said Dr. James Downing, president and CEO of St. Jude Children's Research Hospital.
There's also no indication that the children might develop leukemia, which has been a side effect of previous efforts to treat "bubble boy" disease using gene therapy, Mamcarz said.
Because of this, Downing has declared the therapy a "cure" for the disorder.
New hope for a grim disease
SCID-X1 is caused by a mutation in a gene called IL2RG that produces a protein essential for normal immune function.
About 1 in every 200,000 infants are born with SCID-X1, and their outlook has not been good, Mamcarz said.
"Because infants with the disorder have no functioning immune system, without treatment a diagnosis of SCID is a true death sentence," Mamcarz said. "A simple infection like the common cold could be fatal."
Perhaps the most famous case involved a boy named David Vetter, who lived in a sterile, plastic bubble in the 1970s until he died at the age of 12. His struggle inspired a TV movie about the disease.
The best treatment for the disease so far had been a bone marrow transplant from a matched sibling donor, but more than 4 of 5 babies with SCID-X1 lack such donors, Mamcarz said.
Even those lucky enough to receive a bone marrow transplant often see it fail later on, or must rely on regular infusions of immunoglobulin to support their struggling immune systems, the researchers said.
Gene therapy fixes immune cells
This new therapy uses a genetically altered virus to infect stem cells in bone marrow collected from the babies. The virus inserts an undamaged copy of the IL2RG gene into the cells.
Importantly, the virus also included "insulators" to block activation of genes adjacent to the location where IL2RG is inserted into patient's DNA, the researchers said. This, they hoped, would stop the treatment from inadvertently causing leukemia by stumbling across a cancer-causing gene and activating it.
The babies are treated with chemotherapy to "make space in the marrow for the stem cells to grow," and then the genetically corrected stem cells are placed back into their bone marrow, Mamcarz said.
The study, published April 18 in the New England Journal of Medicine, reports on the condition of the first eight infants treated with this new procedure. All were treated between the ages of 2 months and 14 months, and all lacked a genetically matched sibling donor.
Seven of the eight infants responded immediately to the therapy, growing a full range of immune cells three to four months after receiving their corrected stem cells. The eighth infant also responded after receiving a booster shot of gene-corrected stem cells.
Most patients were discharged from the hospital within one month, and all are developing and growing normally, the researchers said.
Gael Jesus Pino Alva was one of the first infants to get the therapy, and he now has a fully functioning immune system at the age of 2. He is "mixing with people and living like a normal toddler," St. Jude's officials said.
Experts excited by the findings
John Boyle, president and CEO of the Immune Deficiency Foundation, said the initial results are "wildly encouraging."
"There is a lot of reason to be excited and hopeful for the future," Boyle said. "The preliminary data is showing a much more complete reconstitution of the immune system than we've had with bone marrow transplantation. They are getting closer to that 'holy grail' of reconstitution for someone who has SCID."
However, these patients will need to be tracked to make sure side effects don't crop up, Boyle added.
Dr. Michael Grosso, chair of pediatrics and chief medical officer at Northwell Health's Huntington Hospital in Huntington, N.Y., agreed that the therapy needs to be tested on more people longer-term.
"Replicating this work in larger numbers of subjects will be necessary for identifying a true success rate and for ferreting out the risks and side effects," Grosso said. "But every great journey begins with a first step."
Treating these children was a "very logical next step" for this research team, which had successfully used the gene therapy to treat young adults in their 20s with SCID-X1, said Dr. Charlotte Cunningham-Rundles, a professor of immunology at the Mount Sinai School of Medicine in New York City.
"In this study they said, that worked pretty nice in these really challenging cases, how about we move over to these kids who are a couple of months old? We'll probably do even better," Cunningham-Rundles said.
Research has shown it's probably best to treat babies born with SCID-X1 as quickly after birth as possible, Cunningham-Rundles said.
"Everyone likes the idea of something you can do extremely early, to get the angst over with," she said.
The U.S. National Institutes of Health provides more about SCID.
SOURCES: Ewelina Mamcarz, M.D., assistant faculty member, St. Jude Department of Bone Marrow Transplantation and Cellular Therapy, Memphis, Tenn.; James Downing, M.D., president and CEO, St. Jude Children's Research Hospital, Memphis, Tenn.; John Boyle, president and CEO, Immune Deficiency Foundation; Michael Grosso, M.D., chair, pediatrics, and chief medical officer, Northwell Health's Huntington Hospital, Huntington, N.Y.; Charlotte Cunningham-Rundles, M.D., Ph.D., professor, immunology, Mount Sinai School of Medicine, New York City; April 18, 2019, New England Journal of Medicine