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A clinical trial of a gene therapy for a rare neurological disease is on hold after a participant in the study developed a bone marrow disorder that can lead to leukemia, the trial’s sponsor, bluebird bio, announced Monday. The company said the cancer was likely caused by the virus that ferries a therapeutic gene into patients’ stem cells.

Bluebird researchers and others say the issue may not arise for other gene therapies that rely on the same type of virus, known as a lentivirus, because of a unique feature of the version used for the halted trial. Another type of gene-delivering virus, or vector, has been implicated in cancers in clinical trials, but never a lentivirus.

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

The phase 3 trial targets a disease called cerebral adrenoleukodystrophy, which is caused by a mutation in the gene for the enzyme adrenoleukodystrophy protein (ALDP). The enzyme helps break down certain fats, and for people without a functioning copy of its gene, the fats build up in the brain. This damages the insulating sheaths that allow nerves to convey electrical signals quickly and efficiently. Because the gene lies on the X chromosome, the condition, which usually emerges in childhood, primarily affects boys; if a copy gets mutated, they don’t have a backup gene on a second X.

Without treatment, adrenoleukodystrophy damages hearing, vision, cognition, and coordination, and leads to death within 10 years of the beginning of symptoms. Done at an early age, a bone marrow transplant to replace blood stem cells that give rise to ALDP-producing cells in the brain can halt neurological damage. But finding a matching cell donor can be difficult, and a transplant can lead to graft-versus-host disease, a potentially deadly condition in which donor cells attack a patient’s cells. (A controversial, experimental treatment known as Lorenzo’s oil, developed in the 1980s by parents of a boy with the condition, inspired a 1992 film.)

For the gene therapy, researchers collect a patient’s own bone marrow stem cells and treat them in a dish with the lentivirus carrying a healthy version of the gene for ALDP. They infuse these modified cells back into the body after chemotherapy that depletes existing bone marrow cells. Bluebird bio’s treatment won market approval in Europe last month based on safety and efficacy data from a previous trial of 32 patients ages 17 and younger; a second trial in 35 more patients is set to conclude in 2024.

But one participant in the ongoing trial developed a condition called myelodysplastic syndrome (MDS), a blood-cell disorder that is a precursor to leukemia, about 1 year after treatment, the company revealed Monday. And two more patients who received the gene therapy have abnormalities in their bone marrow cells that could develop into MDS, said Philip Gregory, bluebird bio’s chief scientific officer, in the company’s quarterly earnings call. The U.S. Food and Drug Administration (FDA) put the trial on hold “out of an abundance of caution,” bluebird’s president of rare genetic diseases Andrew Obenshain said in the call.

Researchers have long known viruses that insert genetic material into a person’s genome may risk activating a nearby cancer gene. In the early 2000s, FDA halted dozens of gene therapy trials involving a different type of virus, a mouse-derived retrovirus, when patients developed leukemia after being treated for an inherited immune disorder. Those side effects led scientists to switch to lentiviruses, a subset of retroviruses that includes HIV. These vectors can be engineered to be much safer, says Punam Malik, a hematologist at Cincinnati Children’s Hospital whose team is developing a gene therapy for the blood disorder sickle cell disease.

Lentiviruses have had a strong track record in gene therapy, despite a recent scare: In February, bluebird bio halted two sickle cell gene therapy trials, which also use lentiviruses, after a participant developed MDS. But it relaunched the studies after concluding that the virus was unlikely to have caused the cancer.

This new case is different, Gregory explained in the conference call: In the patient’s blood cells, researchers found lentiviral DNA inserted at a site in the genome linked to MDS in some previous gene therapy trials that used mouse-derived retroviruses. That finding suggests the viral DNA may have prompted blood stem cells to proliferate abnormally.

The culprit, Gregory suggested, is a design feature of the vector in this trial, a genetic sequence packaged in the virus, known as a promoter, that helps turn on the therapeutic gene. The promoter used for this study has especially broad activity, driving expression of nearby genes in all blood cell types where it’s inserted, including stem cells. (Other promoters, including the ones bluebird used in its blood disorder therapies, activate nearby genes in only certain types of mature blood cells.)

Using such a strong promoter helped ensure that brain cells could make high enough levels of ALDP to treat the disease, but risked turning on nearby cancer genes, says Donald Kohn, a pediatric bone marrow transplant physician and gene therapy researcher at the University of California, Los Angeles, who has previously consulted for bluebird bio and helped design this viral vector. Researchers have since identified other promoters that might prompt cells to make sufficient ALDP with less cancer risk, Kohn says. He knows of no other lentivirus-based gene therapies using this type of promoter.

Bluebird bio still plans to complete its data submission to FDA this year “pending resolution of the [FDA] hold,” Obenshain said Monday. Gregory added that given the debilitating effects of cerebral adrenoleukodystrophy and the risks involved in the only other treatment, bone marrow transplant, “We believe the benefit-risk profile of [the gene therapy] remains favorable.”

Malik stresses that the safety concern revealed this week doesn’t diminish the benefits of the many lentivirus-based gene therapies approved or under investigation, which she notes have now been used to treat more than 300 patients with more than a dozen medical conditions. “This is a severe adverse event,” she says, but “we should never lose sight of the fact that so many patients … have been helped.” And the company’s finding could “help scientists and researchers design safer and better vectors for the future.”


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