Aclinical trial testing a novel gene therapy for a rare neurological disease has been put on hold after one of the participants in a Phase 3 trial developed a bone marrow disorder that can lead to cancer. The pause, announced Monday by the trial’s sponsor, bluebird bio, and mandated by the US Food and Drug Administration (FDA), was taken “out of an abundance of caution,” the company’s president of rare genetic diseases, Andrew Obenshain, said in a recent quarterly call

The therapy targets cerebral adrenoleukodystrophy, which is caused by a mutation in the gene for an enzyme called adrenoleukodystrophy protein (ALDP) that breaks down fats. The mutation causes fat to build up in the brain, where it breaks down the insulating myelin that allows neurons to communicate with one another. Because the gene is on the X chromosome, women typically have a least one good copy, so the disease primarily strikes men. Left untreated, it causes damage to hearing, vision, cognition, and coordination. It is often fatal. 

Bluebird’s gene therapy uses an engineered lentivirus to correct the mutation associated with the disease. Lentiviruses belong to the same family as HIV—retroviruses—and have been widely used in gene therapies and other medical applications for many years. While other virus-based platforms using retroviruses had previously been linked to cancer among patients, it is only recently that a lentivirus has been implicated in such an outcome: in February of this year, bluebird bio paused another trial, one for a blood disorder, after two patients developed leukemia-like cancer, Science reports, although it was later determined that the virus was likely not the cause, and the trial resumed.

“Most in the field were hoping that we would not see such an event with lentiviral vectors,” Harry Malech, a gene therapy researcher at the National Institutes of Health, tells Science, adding, “I don’t think anybody’s been . . . saying this couldn’t happen.”

The cerebral adrenoleukodystrophy therapy involves taking samples of a patient’s bone marrow and treating the stem cells therein with the modified virus that contains a corrected copy of the gene that encodes ALDP. After a round of chemotherapy to reduce the person’s bone marrow cells, the treated cells are infused back into the patient. Thereafter, the patient’s stem cells produce healthy blood cells with a functional copy of the gene for ALDP. The therapy entered the market in Europe last month following a previous safety and efficacy trial that included 32 patients. A second trial, the one that has now been paused, was set to finish in 2024.

Speaking on the call, bluebird bio’s Chief Scientific Officer Philip Gregory said that one patient in the second trial developed myelodysplastic syndrome (MDS), a blood disorder that sometimes leads to leukemia, and another two had abnormal bone marrow cells that could progress to MDS. When scientists examined their cells, they found lentiviral DNA inserted at a site in the genome that has previously been linked to MDS in retrovirus-based therapies, suggesting that the virus may have caused the changes.

Specifically, Gregory said the issue is likely caused by the virus’ promoter, the DNA sequence that “turns on” the therapeutic copy of the gene. To ensure the gene produces enough ALDP in the brain to be an effective treatment, the researchers needed a strong promoter, but as a consequence, the promoter had off-target effects, turning on other genes in the area around the mutation, including cancer genes, Gregory speculated. 

Donald Kohn, a gene therapy researcher at the University of California, Los Angeles, who helped design the viral vector, tells Science that in the time since bluebird bio first began developing the therapy, researchers have identified other promoters that might be able to do the job with a lower risk of causing cancer. He adds that this particular incident shouldn’t preclude scientists from pursuing other lentivirus treatments, as the issue seems to come down to design, and Kohn doesn’t know of any other lentivirus therapies that use the same type of promoter.

Panam Malik, a hematologist at Cincinnati Children’s Hospital who was not involved in the work, similarly tells Science that virus-based platforms should be highlighted for the good they have done. “This is a severe adverse event,” she says, but adds, “we should never lose sight of the fact that so many patients . . . have been helped.” Despite this rare incident, the findings could “help scientists and researchers design safer and better vectors for the future.”