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Study: "Bubble boy" disease has been cured

Photo of 2-year-old boy, Gael, who is playing with his Mom after receiving therapy for SCID
Gael Jesus Pino Alva, a 2-year-old treated with gene therapy, with his mother, Giannina Alva. Photo: Peter Barta/St. Jude

Scientists announced that they have "cured," at least for the near-term, the rare genetic disorder that causes a male baby to be born with little or no immune system, or what's commonly known as the "bubble boy disease."

Why it matters: It's estimated that only 40–100 babies are born yearly with this disorder, but almost all of them died within 2 years unless they were diagnosed and placed into sterile environments, like those dramatized in movies and real documentaries. The study, published on Wednesday in the New England Journal of Medicine, says the therapy already has helped a couple of the toddlers enough to play like healthy children and even enter day care.

Background: X-SCID (X-linked severe combined immunodeficiency) is a life-threatening genetic disorder male babies can get if there's a mutation in a gene on the X chromosome called IL2RG.

  • Babies born with SCID have no defense against germs — even the common cold can be deadly.
  • Currently, the most effective treatment is to find a bone marrow match, preferably from a sibling, and transplant stem cells. This works particularly well if done in the first 3 months of a child's life, but it is very difficult to find a match.
  • Because gene therapy is relatively new, scientists consider diseases with mutations in single genes, like SCID, to be prime candidates. However, it's still experimental, so this trial was only done on children without a bone marrow match.
  • Prior therapies had mixed results (they only produced one type of immune cell) or were halted after causing leukemia, likely resulting from the different vector that transports the new gene to the cell.
  • But before this study, the National Institutes of Health tested a treatment using a new lentivirus vector on 5 older SCID patients with promising early results.

What they did: St. Jude Children's Research Hospital, which led the study and co- developed the new lentivirus vector with NIH, used a novel approach to the therapy combining the new vector and a low dose of chemotherapy.

  • The new lentivirus vector was engineered from a de-activated HIV virus and includes insulators to block activation of genes adjacent to the insertion to prevent leukemia.
  • They selected 8 children, ages 2 months to 14 months without donor matches, and collected their bone marrow, inserted the gene in the lab, and froze it while they did quality testing.
  • Before having it reinfused, the infants received 2 days of low-dose busulfan chemo to make space for the new bone marrow cells to grow.

What they found: James Downing, president and CEO of St. Jude, said in a press conference that the trial had "outstanding results" with children "responding to vaccines and able to live normal lives."

  • Most patients were discharged from the hospital within 1 month, and within 3 months, immune cells were present in the blood of all but 1 patient, who required a second dose of gene therapy.
  • Study co-author Ewelina Mamcarz said in a press conference that they were thrilled to see the development of all 3 main types of immune cells: T-cells, B-cells and natural killer cells.
  • 4 infants were able to discontinue intravenous immunoglobulin treatment that give additional antibodies to boost immunity. And 3 of the 4 developed normal antibody responses to normal vaccinations — an indication of robust B-cell function, she said.
  • While acknowledging that it is rare in the scientific community to claim a "cure," Mamcarz says, "They are cured because for the first time we were able to restore all three cells that constitute the immune system."
  • There was no early indication of leukemia up to 2.5 years after the first treatment, she adds. However, the authors said, the children will be closely monitored to see how durable the cure will be.

What they're saying: Rebecca Hatcher Buckley, immunology professor at Duke University School of Medicine who was not part of this study, says the vector in particular is "very promising," particularly as the treatment so far has not produced leukemia.

  • However, she says right now it's not clear they will all have robust B-cell functions and the children will need to be watched for side effects from the chemo, such as possible infertility.
  • "Compared with previously tested gene-therapy strategies for X-SCID, which used other vectors and chemotherapy regimens, the current approach appears safer and more effective," NIH said in a press release.

What's next: The trial is ongoing and St. Jude has signed an exclusive license with Mustang Bio to determine the best strategy to commercialize the immunotherapy for other genetic disorders, possibly including sickle cell disease.