Genome editing may enable a less toxic approach to stem cell transplantation

Donor stem cells that underwent a precise type of genome editing could pave the way for safer, chemotherapy-free transplants, new results in mice show.

Donor hematopoietic (blood-forming) stem cell transplants are used to treat serious blood disorders and cancers. However, patients must first undergo a preconditioning treatment – often chemotherapy and radiotherapy – to clear out existing stem cells, make room for new ones, and suppress the immune system. This can cause significant side effects, including organ damage and infertility. Now, researchers in Massachusetts have developed a new approach, based on editing the genomes of donated cells, that would allow chemotherapy to be replaced by a less toxic, more targeted type of preconditioning treatment.

'Although this work is still preclinical, it points toward a future in which patients may receive curative stem cell therapies with less toxicity, less reliance on chemotherapy, and greater precision,' said Dr Pietro Genovese, senior author of the study published in Nature, who led the research at the Boston Children's Hospital and Dana-Farber Cancer Institute in Massachusetts.

Monoclonal antibodies treatments are a promising alternative to preconditioning chemotherapies, as they rely on directing the immune system to eliminate specific target cells – in this case, blood-forming stem cells. However, antibody-based drugs linger in the body for extended periods, meaning that they can also target donor cells following transplants.

To solve this issue, the team used genome editing tools to equip donor cells with 'molecular camouflage' by altering parts of genes coding for epitopes. Epitopes are segments of the protein-based antigens on the cell surface that monoclonal antibodies use to identify which cells the immune system should eliminate. By editing donor cells before transplanting them into the patient, researchers have managed to make these cells 'invisible' to monoclonal antibodies while the patients' own stem cells remain vulnerable.

With this approach, it also becomes possible to continue administering monoclonal antibody drugs after transplantation, giving donor stem cells more room to proliferate by regularly clearing the old disease-causing ones. This would enable more donor cells to take root in the patient's bone marrow, helping to address another major stem cell transplant limitation, where too few donor cells survive to have a clinical effect.

The same research group has previously shown that epitope editing can make cancer immunotherapies, known as CAR-T therapies, significantly safer in mice. With their work, the authors hope to overcome safety and efficacy limitations in a variety of new therapies.

'By avoiding chemotherapy, we can open up stem cell transplants for diseases that are less severe or for fragile patients normally too sick or too high risk for transplantation, said first author Dr Gabriele Casirati.

The approach has so far only been applied in mice, and further research is required before it can be tested in patients.