Gene therapy vector DNA found integrated into patient's brain tumour

Adeno-associated virus (AAV) gene therapy vector DNA has been found integrated within tumour tissue in a patient with Hurler syndrome who had been treated years earlier.

A patient with Hurler syndrome underwent gene therapy as part of a Regenxbio clinical trial four years ago, at 13 months old. An AAV vector was used to deliver a therapeutic gene to the patient's cells. The patient later developed a brain tumour, and researchers at the Children's Hospital of Philadelphia have now reported that the viral vector DNA had integrated into the DNA of the patient's brain cells at sites associated with tumour development. The tumour was successfully removed, and the patient recovered well.

'There are several possible factors that may have contributed to this observation, and those factors differ across AAV treatments and patients,' said Dr Lindsey George, director of clinical in vivo gene therapy at the Children's Hospital of Philadelphia, and co-senior author of the study published in the New England Journal of Medicine. 'Because this report describes just one case – and AAV therapies overall have thus far demonstrated excellent long-term safety in more than 6000 people – it would be premature to generalise this single finding to all other AAV gene therapies.'

Hurler syndrome, a severe form of mucopolysaccharidosis type I, is a rare genetic lysosomal disorder caused by mutations in the IDUA gene. The gene therapy, known as RGX 111, delivered a functional copy of the IDUA gene using an AAV vector.

AAV gene therapies are generally designed to remain outside the genome as episomal DNA rather than integrating into chromosomes. However, analysis of the tumour tissue showed that vector DNA had integrated near the PLAG1 gene, a proto-oncogene associated with tumour formation when abnormally activated. PLAG1 is usually active only during early development, but researchers found evidence that the integration event may have reactivated the gene, suggesting a possible role in the tumour's development.

Integration of AAV vectors into the genome is considered uncommon, and this is believed to be the first reported case linking integration of an AAV gene therapy vector with tumour development in a human patient. Following the case, the US Food and Drug Administration (FDA) placed clinical holds on two experimental gene therapy programmes from Regenxbio – RGX-111 for Hurler syndrome and RGX-121 for Hunter syndrome. The FDA extended the hold to RGX-121 because of similarities in the vector design, even though no comparable tumours have been reported among participants receiving that therapy.

While these findings underscore the importance of long-term monitoring and continued safety research for gene therapies, this treatment also significantly improved management of the patient's condition. According to the report, the patient has not experienced the cognitive decline typically associated with Hurler syndrome.

'Knowing what we know now, we would choose gene therapy again,' said the patient's mother. 'It gave our son a chance to live, to learn, and to truly thrive. Even facing the hardest moments, watching him laugh, discover, and grow has made the risk worth taking.'