A trial of gene therapy discontinued this week aims to treat cerebral adrenoleukodystrophy, a disease that destroys nerve-isolating myelin (colored blue in a photomicrograph of a healthy brain, above).
JJ HAUW/Science source
A clinical trial of a gene therapy for a rare neurological disease has been suspended after a study participant 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 puts a therapeutic gene into patients’ stem cells.
Bluebird researchers and others say the problem 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 discontinued trial. Another type of gene-delivery virus, or vector, has been implicated in cancers in clinical trials, but never a lentivirus.
“Most in the field hoped we wouldn’t see such an event with lentiviral vectors,” said Harry Malech, a gene therapy researcher at the National Institutes of Health. But, he adds, “I don’t think anyone said this can’t happen.”
The phase 3 study focuses on 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 the gene, the fats accumulate in the brain. This damages the insulating sheaths that allow nerves to transmit electrical signals quickly and efficiently. Because the gene is located on the X chromosome, the condition, which usually develops in childhood, mainly affects boys; if a copy is mutated, they have no backup genes on a second X.
Without treatment, adrenoleukodystrophy damages hearing, vision, cognition, and coordination and leads to death within 10 years of the onset of symptoms. A bone marrow transplant performed at an early age to replace blood stem cells that cause ALDP-producing cells in the brain can stop neurological damage. But finding a suitable cell donor can be difficult, and a transplant can lead to graft-versus-host disease, a potentially fatal 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 that carries a healthy version of the gene for ALDP. They put 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 involving 32 patients aged 17 and under; a second study in 35 more patients will be completed in 2024.
But a 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 can develop into MDS, Philip Gregory, Bluebird Bio’s chief scientific officer, said in the company’s quarterly earnings call. The U.S. Food and Drug Administration (FDA) has suspended the trial “out of an abundance of caution,” Andrew Obenshain, bluebird’s chairman for rare genetic diseases, said in the call.
Researchers have long known that viruses that insert genetic material into a person’s genome may run the risk of activating a nearby cancer gene. In the early 2000s, the FDA halted dozens of gene therapy trials of another 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 could be designed 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 a strong track record in gene therapy, despite a recent fear: In February, bluebird bio halted two studies of sickle cell gene therapy, which also use lentiviruses, after a participant developed MDS. But it restarted the investigations after it concluded that the virus was unlikely to have caused the cancer.
This new case is different, Gregory explained on the conference call: In the patient’s blood cells, researchers found lentiviral DNA inserted into a site in the genome linked to MDS in some previous gene therapy studies using mouse retroviruses. . That finding suggests that the viral DNA prompted the 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 a particularly broad activity, stimulating the expression of nearby genes in all blood cell types into which it has been introduced, including stem cells. (Other promoters, including the bluebird used in its therapies for blood disorders, activate nearby genes in only certain types of mature blood cells.)
Using such a strong promoter helped ensure that brain cells could make enough ALDP levels to treat the disease, but ran the risk of turning on nearby cancer genes, says Donald Kohn, a pediatric bone marrow transplant doctor and gene therapy researcher. the University of California, Los Angeles, who previously consulted for bluebird bio and helped design this viral vector. Researchers have since identified other promoters that could prompt cells to make enough ALDP with less cancer risk, Kohn says. He knows of no other lentivirus-based gene therapies that use this type of promoter.
Bluebird bio still plans to complete data submission to FDA this year “pending resolution of the” [FDA] keep,” Obenshain said Monday. Gregory added that given the debilitating effects of cerebral adrenoleukodystrophy and the risks associated with the only other treatment, bone marrow transplantation, “We believe the benefit-risk profile of [the gene therapy] remains favourable.”
Malik emphasizes that the safety risk revealed this week does not negate the benefits of the many lentivirus-based gene therapies that have been approved or are under investigation, which she says have now been used to treat more than 300 patients with more than a dozen medical conditions. to treat ailments. “This is a serious side effect,” 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.”