Gene Therapy

Gene therapy for ‘bubble boy disease’ sets stage for cure

Infants with a rare, life-threatening genetic disorder that renders their immune system obsolete may have a new lease on life, after eight patients with “bubble boy disease” saw their body’s defense system restored by a gene therapy developed by scientists at the National Institutes of Health and St. Jude Children’s Research Hospital in Memphis, Tennessee.

The condition — called X-linked severe combined immunodeficiency (SCID) — almost exclusively occurs in boys and is caused by mutations in the IL2RG gene, which is in charge of making sure a protein that is vital for the growth and maturation of developing immune cells called lymphocytes is produced. Without functioning lymphocytes, which defend the body against pathogens, make antibodies, and help regulate the immune system, the smallest infections such as the common cold can be fatal.

A bone marrow transplant — though medically risky — from a genetically-matched sibling can be curative, but patients don’t always have an optimal donor. The condition, which occurs in roughly 1 per 200,000 births, makes patients so susceptible to infections that they typically do not live past infancy, without treatment.

On Wednesday, researchers published a report in the The New England Journal of Medicine detailing the safe, curative potential of their therapy in a clinical trial with patients under the age of two. It involves extracting stem cells from the patient, using a modified version of the HIV virus to insert the missing IL2RG gene and infusing the calls back into the subject to refurbish the immune system. Before the cells were infused, the patients were given a low dose of chemotherapy to prime the bone marrow for the production of fresh blood cells from the genetically corrected stem cells.

Harry Malech

A similar approach a few decades ago triggered leukemia in some patients — which scientists suspect was because the vector unintentionally activated genes that control cell growth. Therefore, the vector used in the study reported on Wednesday was engineered to dodge that outcome, researchers said. While other older gene therapy approaches restored T cell function, they did not fully revive the function of other key immune cells, including B cells and natural killer (NK) cells, they added.

Normal levels of immune cells — including T cells, B cells and  NK cells — emerged within three to four months after therapy in seven of the eight infants in the trial. The eighth patient initially had low T cell numbers, but the numbers climbed following a second infusion of the genetically modified stem cells.

Viral and bacterial infections that participants had prior to treatment resolved afterwards, and four infants were also able to discontinue treatment with intravenous immunoglobulins — antibody infusions used to enhance immunity.

“The broad scope of immune function that our gene therapy approach has restored to infants with X-SCID — as well as to older children and young adults in our study at NIH — is unprecedented,” said Harry Malech, chief of the genetic immunotherapy section in National Institute of Allergy and Infectious Diseases (NIAID’s) laboratory of clinical immunology and microbiology.

Malech co-led the development of the lentiviral gene therapy approach with St. Jude’s Brian Sorrentino, who died in late 2018. In the trial, a total of 10 infants have received the therapy, although the published data reflects results from eight infants who were followed for a median of 16.4 months.

New York-based biotech Mustang Bio acquired the gene therapy for a song last summer, paying St. Jude $1 million upfront for rights to the program and offering up to $13.5 million in milestone payments. Its market cap today just swelled more than $100 million, and its shares $MBIO skyrocketed nearly 146% to $6.55 in Thursday morning trading. The data presented on Wednesday follow positive results from the trial posted by Mustang last August.

A gene therapy developed by GSK $GSK for a different form of SCID (adenosine deaminase (ADA) deficiency SCID) was approved in Europe in 2016, but the British drugmaker struggled to find customers (roughly 15 cases are diagnosed in Europe each year) for the pricey treatment, despite offering a money-back guarantee. Limited access was the big hurdle, as patients could only be treated in a single center in Milan. Eventually, GSK palmed off the gene therapy to UK’s Orchard Therapeutics.

The name “bubble boy disease” comes from a famous case in the 1970s, in which a boy in Texas literally lived in a protective plastic bubble to create a germ-free sterile environment. The case also entered the cultural zeitgeist with an episode of the popular sitcom Seinfeld, in which protagonist George Costanza is taunted by a boy called Donald who is afflicted with the condition (and is enveloped by a bubble) during a game of Trivial Pursuit. Things get heated, and when Donald endeavors to strangle a visibly hot and bothered George, George’s girlfriend inadvertently punctures the bubble, resulting in a decidedly macabre end to the scene.


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VP Oncology Biology
Skyhawk Therapeutics Waltham, MA
Associate Director CMC
Elektroki Boston, MA
Director Process Development
Elektroki Boston, MA
Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT

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