A gene therapy given to a 13-month-old boy has, years later, led to a tumour in his brain after the virus carrying the gene inserted part of it directly into his DNA, researchers reported last week. The mass was safely removed, but his case appears to be the first time a gene therapy delivered directly into the body has been linked to cancer, reports the journal Science.
Researchers involved with the case and others stress that the rare case does not mean the adeno-associated virus (AAV) the boy received, which has been given to thousands of people as part of gene therapies, should not be used.
“We have to be really cautious in extrapolating this to other AAV trials,” said Lindsey George, who co-led the trial and presented the work at the annual meeting of the American Society of Gene & Cell Therapy in Boston last week.
The boy was born with Hurler syndrome, also known as MPS I, a condition in which certain sugars build up in the brain and damage it. It stems from a mutation in the gene encoding an enzyme called IDUA, which cells need to break down the sugars.
After a bone marrow transplant aimed at getting IDUA-making cells into his brain failed to help the boy, he joined a clinical trial sponsored by the company Regenxbio.
Researchers at the Children’s Hospital of Philadelphia inserted a needle into the back of his skull and infused into his brain trillions of copies of an AAV carrying the IDUA gene.
The therapy seemed to work – his cognitive development stayed on track – but at the age of five, a routine scan found a walnut-size brain tumour, Regenexbio reported to US regulators of the trial in January.
They asked the company to pause the study and another clinical trial using the same approach for a similar disease while researchers studied the boy’s cancer.
Eight months after the boy had the brain tumour removed, he is cognitively advanced for his age, although he’s small for his age and has some skeletal and joint problems.
“Clinically, he’s doing fantastically well,” George said. “This little guy is in kindergarten reading books.”
Lab tests have now shown the AAV triggered cancer when it integrated some of its cargo into the genome of the boy’s brain cells, the team reported n The New England Journal of Medicine. Parts of the viral DNA landed within and switched on a gene called PLAG1, which can cause cancer when mutated.
Since the early 2000s, cancers have developed in several people with inherited immune diseases who received ex vivo gene therapies, in which their bone marrow cells were removed, given a therapeutic gene in lab dishes, then returned to the body.
Those treatments used viruses intended to integrate their DNA cargo into the genome, raising cancer risks. But AAV, the vector of choice for in vivo therapies, normally adds its DNA to a cell as a loop that sits inside the cell’s nucleus. Because the viral DNA does not usually integrate into the genome, the cancer risk is far lower.
Still, studies in mostly newborn mice have found that AAVs infused into the blood can sometimes integrate into liver cells and cause cancer; AAVs have also inserted their cargo into the genome of dogs given intravenous gene therapy. George thinks a “confluence of points” may have contributed to the Hurler patient’s tumour.
First, the type of AAV used has an affinity for the cells lining the brain’s ventricles, and this is where the tumour developed. Second, the boy was young enough that these cells could still have been dividing. Third, the DNA for the IDUA gene included a strong promotor, a snippet of DNA that helps drive the gene’s expression.
Finally, his immune system was still recovering from the earlier bone marrow transplant and might have been too weak to wipe out nascent tumour cells.
George noted that cancer risks are part of the trial consent forms reviewed by the parents and that without the gene therapy, the boy would probably have brain damage by now.
“It underscores the importance of really careful risk-benefit analysis,” she said.
“I wouldn’t stop anything now based on this one report. It’s not a huge safety signal,” agreed gene therapy researcher Charles Venditti of the National Human Genome Research Institute, who led some of the mouse studies on AAV and liver cancer.
He and George said researchers should consider testing less powerful promotors for in vivo gene therapies. And Venditti said the case underscores the importance of monitoring gene therapy recipients for many years – not only those in trials, but the thousands who are now receiving approved AAV gene therapies for diseases like spinal muscular atrophy and Duchenne muscular dystrophy.
“I do think we have to continue to be vigilant,” he said.
Study details
Neuroepithelial Tumour with AAV Integration after Intracisternal Magna Vector Delivery
Rebecca Ahrens-Nicklas, Chelsea Kotch, Aoife Roche et al.
Published in The New England Journal of Medicine on 13 May 2026
Summary
Recombinant adeno-associated virus (AAV) vectors are predominantly non-integrating, but rare genomic integration events have been associated with oncogenesis in neonatal murine models. Here we report a case of a neuroepithelial tumour that developed in a 5-year-old boy with severe mucopolysaccharidosis type I (MPSI, Hurler subtype) four years after intracisternal magna administration of AAV serotype 9 gene therapy. The patient underwent successful resection of the primary tumour. Postoperatively, he has continued to have advanced cognitive function for his age, a finding that indicates mitigation of MPSI. Molecular analysis of the tumour showed clonal integration of rearranged AAV vector elements into the gene PLAG1 and expression of a chimeric AAV-PLAG1 transcript.
Science article – Boy’s brain tumour tied to gene therapy (Open access)
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