A team including Pietro Genovese and lead author Gabriele Casirati has published epitope editing of donor stem cells in Nature. The approach would allow donor stem cells to survive antibody treatment that clears existing bone marrow stem cells, without requiring chemotherapy or radiation. In allogeneic transplantation, patients must overcome both physical space constraints in bone marrow and immunological barriers. According to the researchers, the work remains preclinical.
Before stem cell transplantation, patients typically receive intensive and often toxic chemotherapy or radiation to make room for new cells in the bone marrow. This nonspecific damage can harm the lungs, liver, kidneys and nervous system, and trigger aplasia with infection, anemia and bleeding. Survivors face lifelong risks of secondary cancers, hormonal disorders and infertility. Monoclonal antibodies against the stem cell marker KIT, also called CD117, have been investigated as a gentler alternative, but normally cannot distinguish between original and newly transplanted stem cells.
Cell protection in the experiment
Using adenine base editing or prime editing, the team introduced KIT mutations into stem and progenitor cells, combined with BCL11A enhancer disruption to promote fetal hemoglobin. In cell culture, the antibody Fab-79D markedly inhibited growth of cells lacking KIT editing after 7 days, while KIT-H378R cells proliferated similarly to untreated cells, including with BCL11A changes. In mice, animals received six doses of Fab-79D antibody at 0.5 milligrams each starting in week six, given on different schedules, while control mice received saline. After 18 weeks, examination of bone marrow and spleen showed edited human cells marked with mtBFP comprised 21.38 percent in sham treatment and 71.48 percent with the ten-day dosing interval. A separate feasibility experiment included five control and seven treated mice. Extended antibody treatment enabled stronger enrichment without preferring individual cell clones, verified by genetic marking.
Epitope editing in leukemia
The same team previously used epitope editing to protect healthy blood stem cells from cancer immunotherapies such as CAR-T cells or therapeutic antibodies, while these approached leukemia cells. A review article describes how epitope editing of FLT3, CD123 and KIT in human stem cells and humanized mice enabled targeted immunotherapy against acute myeloid leukemia, with CAR-T cells eliminating patient-derived leukemia and sparing edited healthy progenitor cells. The team notes that these targeted conditioning approaches particularly suit autologous gene therapies where immune suppression or full hematopoietic replacement may not be necessary. The authors also flag limitations: base editors can inadvertently alter neighboring bases, and prime editing generally works less efficiently than gene knockout or base editing. Boston Children's Hospital and Dana-Farber Cancer Institute jointly hold rights to the technology used, according to GEN.