01 December 2023

Gene therapy for sickle cell disease can lead to DNA mutations in stem cells, British researchers have warned.

Gene therapy has recently gained approval in the UK as a treatment for sickle cell disease. However, previous studies have raised concerns that the gene therapy process may trigger the development of myeloid malignancies.

These conditions include myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukaemia.

The research team was jointly led by Professor David Kent of the University of York, Dr Peter Campbell of Wellcome Sanger Institute, and Dr David Williams from Boston Children’s Hospital and Harvard Medical School.

The team used highly sensitive whole-genome sequencing to track haematopoietic stem cells and identify mutations present. Samples came from six patients with sickle cell disease, taken before and after gene therapy.

Following the therapy, there was an increase in clones carrying driver mutations linked with myeloid malignancies.

This “suggests positive selection of mutant clones during gene therapy,” state the authors in Nature Medicine.

“This work sheds light on hematopoietic stem cell clonal dynamics and the mutational landscape after gene therapy in sickle cell disease,” they add.

Professor Kent said: “Our research indicates that gene therapy imposes a selection on different blood stem cells, the ‘seed’ cells of our blood and immune system. After gene therapy, the treatment might favour growth of stem cells with certain mutations.

“In other settings, such expansions have been associated with development of blood cancers, particularly in older individuals, but the relationship of this study’s findings to the risk of blood cancers is not yet fully understood.”

Joint lead author Dr Alyssa Cull, added: “We now require more in-depth studies to uncover the precise connections behind specific mutations and the gene therapy procedure.”

“There are pressing questions regarding how we can refine gene therapy to avoid stem cells that might contain mutations that affect blood cell growth.”


Spencer Chapman M, Cull AH, Ciuculescu MF, Esrick EB, Mitchell E, Jung H, O'Neill L, Roberts K, Fabre MA, Williams N, Nangalia J, Quinton J, Fox JM, Pellin D, Makani J, Armant M, Williams DA, Campbell PJ, Kent DG. (2023) “Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease.” Nature Medicine, doi: 10.1038/s41591-023-02636-6

Link: https://www.nature.com/articles/s41591-023-02636-6

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