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A safer gene-therapy protocol for blood diseases

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An aseptic virus laboratory, where vectors for gene therapy are prepared. Credit: Boonchai Wedmakawand/ Moment/ Getty Images.

Researchers in Milan have developed a method that could spare patients who are about to receive gene-corrected stem cells from toxic chemotherapy. The protocol, outlined in Cell1, was successfully tested on genetically modified mice.

Gene therapy is increasingly used to treat diseases caused by DNA defects in blood cells, such as immunodeficiencies, thalassemia, and cancer. In particular, it targets hematopoietic cells, the progenitors of blood cells that are found mainly in the bone marrow.

These cells have membrane molecules that make them adhere to the bone marrow niche. Gene therapies typically starts by administering compounds that counteract these molecules, and force the cells out of the bone marrow towards peripheral blood, where they are collected. Their DNA is then corrected in vitro, inserting a therapeutic gene by a viral vector or by gene-editing techniques. Finally, the corrected hematopoietic cells are infused back to the patient’s blood and they home back to the bone marrow.

Before receiving corrected stem cells, patients need to undergo a chemotherapy treatment to clear the defective hematopoietic cells from the bone marrow and make space for the modified ones. But that has serious toxic effects, in the short and long term.

“After the mobilization of defective stem cells there is a short time window when the bone marrow stays temporarily depleted,” says Luigi Naldini, director of the Istituto San Raffaele-Telethon per la terapia genica (SR-Tiget) and lead author of the paper.

“Our idea was to use that window to partially repopulate the bone marrow with a new type of engineered stem cells, giving them a competitive advantage on non-modified cells from the blood stream”. The team applied recent advancements in mRNA technology to induce the DNA-corrected cells to over-express membrane molecules that link them to bone marrow. The modification makes the cells more suitable to replete the niche in the bone marrow than the remaining uncorrected ones, without the need for chemotherapy. The result is a niche partly populated by engineered cells and partly by the original defective cells, a status that is stable enough to provide therapeutic benefit in several diseases.

Timing was essential in the protocol tested by the researchers. They had to harvest defective stem cells, gene-correct them while also treating them with mRNA, and infuse them back within the mobilization time window.

“Future improvements of the protocol may include making the corrected cells resistant to a monoclonal antibody coupled with a toxin, then infuse them back to the patient along with the antibody,” says Naldini. “The toxin would clean the remaining original hematopoietic cells from bone marrow without affecting the corrected cells, allowing them to fully repopulate the niche.” That would have fewer side effects than chemotherapy, and could also be applied to grafts from donors that require a complete substitution of recipient’s own stem cells to prevent rejection.



  1. A. O. Javed, G. Pedrazzani, L. Albano et al, Cell 22, 00537-2 (2022).

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