Gene Therapy Breakthrough Helps Children Born Without Immune System
Ten children with an especially rare and hard-to-treat form of "bubble boy" disease are living normal lives after receiving a new gene therapy approach, researchers say.
Experts said the findings are a major advance for children with the disease -- a subtype of severe combined immunodeficiency (SCID).
SCID refers to a group of rare genetic diseases that cause babies to be born without a functioning immune system. It became widely known as "bubble boy" disease in the 1970s and '80s, due to the case of David Vetter, a boy with SCID who lived in a plastic, germ-free bubble for 12 years.
There are different forms of SCID, based on which gene mutations are involved, but all render the body unable to produce normal B cells and T cells -- critical infection-fighting components of the immune system.
That means ordinary childhood ills can prove fatal. Without treatment, children with SCID typically die within two years.
Right now, the standard treatment is a bone marrow transplant from a donor, which provides infants with the cells necessary to build a healthy immune system. Ideally, the donor is a sibling who is an identical "match" -- meaning their body tissues are compatible from the immune system's point of view.
The transplant is less risky, and most likely to be successful, in that scenario.
But bone marrow transplants, even from a matched sibling, often do not work well for children with a type of SCID known as Artemis-deficient SCID, said Dr. Morton Cowan, the lead researcher on the new study.
Even after a transplant, Cowan said, children with ART-SCID rarely have a reconstitution of their B cells -- which produce the immune system's antibodies.
ART-SCID is a rare subtype of a rare disease: SCID affects roughly 1 in 65,000 newborns in the United States. The Artemis form is mainly diagnosed in babies of Apache or Navajo descent, and accounts for only 2% to 3% of all SCID cases, according to Cowan, from University of California, San Francisco Benioff Children's Hospital.
Bone marrow transplant is not, however, the only option for SCID. In recent years, gene therapy has been successfully used to treat some babies with X-linked SCID, the most common form of the disease, as well as another type called ADA-SCID.
And now Cowan and his colleagues are reporting initial success in using gene therapy to treat 10 children with ART-SCID.
The approach involves removing bone marrow stem cells from babies newly diagnosed with ART-SCID, inserting a functional copy of the Artemis gene into the cells, then infusing them back into the body.
A "critical" point, Cowan said, is the reliance on babies' own cells, which skirts the risks of using donor cells. That includes a potentially fatal complication called graft-versus-host disease, where the new immune system sees the body's tissues as foreign and attacks.
And based on the first babies treated, the gene therapy tactic also works: The children, all still under the age of 5, are living normal lives -- going to day care or preschool and playing outside, Cowan said.
Watch the video below to learn more about the years-long effort to find a gene therapy to treat this devastating disease:
The findings were published Dec. 21 in the New England Journal of Medicine.
Laverna Shorty's grandson, "HT," was the first child enrolled in the study, in 2018.
"He's not sick anymore," Shorty said in a journal news release. "He discarded all of his medication. He's happy and he's growing to be a young man."
Dr. Sung-Yun Pai, of the U.S. National Cancer Institute, wrote an editorial accompanying the study.
“This study is groundbreaking for patients with this rare and devastating genetic disorder," she said.
"The innovative approach of using the patient's own cells instead of a donor has the promise to improve safety, efficacy, and potentially accessibility," Pai added.
Dr. Stephen Gottschalk chairs the department of bone marrow transplantation and cellular therapy at St. Jude Children's Research Hospital in Memphis, Tenn.
He and his colleagues are studying gene therapy for X-linked SCID, and have so far treated 24 children who've been tracked for up to five years.
"Their outcomes remain excellent," Gottschalk said.
The children have responded normally to routine vaccinations, and recovered from colds like other kids do. "Most importantly, they live normal lives," Gottschalk said.
The new findings, he said, show that the promise of gene therapy is not limited to X-linked SCID.
However, both doctors cautioned that the long-term outlook remains to be seen. One big question is whether gene therapy has permanent effects.
"How durable will this be?" Gottschalk said. "'Cure' is a strong word. That remains to be seen."
The children in the ART-SCID trial have been followed for varying lengths of time. All are able to produce T cells and B cells. Of six who've been followed for at least two years, five have full T cell immunity.
Meanwhile, four have had enough of a B cell restoration to stop receiving antibody infusions to protect them from infections. It's a far better result, so far, than is seen with bone marrow transplants, according to Cowan.
He said that time will tell whether the gene therapy helps avert the longer-term problems seen in kids with ART-SCID, like poor growth, chronic lung disease and abnormal teeth.
The initial gene therapy approaches to X-linked SCID did reveal a potential risk: Inserting the corrected gene into cells can inadvertently "switch on" cancer-promoting genes, which led to leukemia in some patients.
Techniques have been refined since then, and Gottschalk said there has been no evidence of that problem so far in children treated with the current approach.
At this point, gene therapy for SCID is experimental, and only considered when a child has no matched sibling donor -- though, Cowan noted, that is the case far more often than not.
Eventually, both doctors said, gene therapy might prove to be better than bone marrow transplants, even from a sibling. But that remains to be seen.
The Immune Deficiency Foundation has more on SCID.
SOURCES: Morton Cowan, MD, professor, pediatrics, and medical director, pediatric cell therapy laboratory, University of California, San Francisco Benioff Children's Hospital; Stephen Gottschalk, MD, chair, department of bone marrow transplantation and cellular therapy, St. Jude Children's Research Hospital, Memphis, Tenn.; Sung-Yun Pai, MD, chief, immune deficiency cellular therapy program, U.S. National Cancer Institute; New England Journal of Medicine, Dec. 22, 2022