Research highlight

Gene therapy: Concerns for the long-term safety of AAV gene therapy

Nature Biotechnology

November 17, 2020

A decade-long study of adeno-associated virus (AAV) gene therapy in haemophilic dogs found genomic changes that may increase the risk of liver cancer. These findings, published in Nature Biotechnology, suggest that further research is necessary to determine whether AAV—a vector that is used in two FDA-approved gene therapies—might promote cancer in rare instances.

AAV is a natural virus that has been engineered into a delivery vector to carry therapeutic genes into the cells of patients with genetic diseases, such as haemophilia. AAV vectors are considered safe and usually do not insert their own genomes into the human genome. However, several studies in mice have shown that the genomic integration of AAV gene therapy vectors can cause liver cancer.

Denise Sabatino and colleagues studied AAV gene therapy in nine dogs for up to ten years. The therapeutic gene delivered via the AAV vector synthesized a protein called coagulation factor VIII. The authors found that the treatment corrected the dogs’ haemophilia symptoms throughout the length of the study. They also examined whether the AAV vector inserted its own genome into the dogs’ genomes and detected integrations into genes associated with cell growth and cancer. Some of these events appeared to cause a proliferation of the cells, which could potentially lead to malignancy.

In two dogs, the amount of coagulation factor VIII in their blood remained steady for four years but then unexpectedly began to rise, reaching triple the early levels by the end of the study. The final levels were still much lower than those of healthy dogs, and therefore not considered dangerous. Nevertheless, the authors could not pinpoint the reason for this increase. Such increases have not been observed in ongoing clinical trials of AAV gene therapy.

The authors found no signs of liver cancer in the dogs. However, the genomic changes may represent safety concerns that require further research and long-term monitoring of patients treated with AAV vectors.

doi: 10.1038/s41587-020-0741-7

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