Gene therapy for fatal child brain disease may cause blood cancers

A gene therapy that halts a childhood-onset fatal brain disease has been associated with an increased risk of developing blood cancer.

Long-term follow up of 67 children who received the gene therapy Skysona for the treatment of the rare disease cerebral adrenoleukodystrophy (ALD), has shown that although the therapy is effective in treating the disease, around ten percent of treated children (seven out of 67) developed blood cancer, most likely as a side effect of the therapy itself.

'This disease can go very quickly and you have to stop the progression. I honestly don't know what I would do if it was my own child' Professor Ami Shah, a pediatric haematologist at Stanford Medicine, part of the team that tested the treatment, told Science magazine.

Untreated, ALD is a severe neurological condition causing progressive neurodegeration and a wide range of symptoms including seizures, blindness, and loss of motor function, as well as severely shortened life expectancy. It is caused by a faulty ABCD1 gene, located on the X chromosome. Alternative treatment options are limited, mainly relying on stem cell transplantation from a matched donor, which can be very hard to find.

Skysona treatment involves the collection of stem cells from the blood of patients, to which a functional copy of the ABCD1 gene is inserted using a lentiviral vector (an inactive version of the HIV virus). The stem cells are then injected back into the bloodstream of the patient. Early results in 2017 showed the treatment to be safe and effective (see BioNews 921), and Skysona was approved by the FDA in 2022.

In the long-term follow-up study focused on outcomes, published in the New England Journal of Medicine, the treatment showed clear benefits, with 30 out of 32 patients evaluated showing stable neurological function scores, and 26 no functional disabilities.

A second long-term follow up study that focused on the risk of blood cancer, also published in the New England Journal of Medicine, discussed how six children developed myelodysplastic syndrome (MDS), 14-92 months after receiving treatment, and one developed the more severe acute myeloid leukaemia (AML) after four years and nine months.

Six of the children received cancer treatment in the form of a stem cell transplant and four of the children diagnosed with MDS are now cancer free. One of the children with MDS died as a result of graft vs host disease (an adverse reaction to the stem cell transplant). The child with AML was alive and responding well to the transplant, and the final child with MDS was still awaiting transplant, at the time of study publication.

Functional analyses of the blood cancer cells from affected children showed insertions of the lentiviral vector cargo next to cancer-related genes in the patient's cells. However, how the therapy is causing the cancers remains unclear. 'There's some biology that we need to understand better,' Dr David Williams, from Boston Children's Hospital, who led the studies, told Science magazine.

The risk of haematological malignancies (blood cancers) is now included as important safety information on the label for Skysona, as well as on the website for the treatment. Families considering treatment will need to carefully weigh the benefits versus the risks.

'There is still a role for Skysona,' said Dr Christine Duncan, a senior physician at Boston Children's Hospital and first author on the risk of blood cancer paper, writing in a New England Journal of Medicine editorial. 'But it needs to be one that is very thoughtful and the family needs to be given all the information.'