A team led by Pietro Genovese and first author Gabriele Casirati has published work in Nature describing epitope editing of donor stem cells. This could allow donor stem cells to survive antibody treatment that removes existing stem cells from bone marrow without requiring chemotherapy or radiation. In allogeneic transplants, overcoming both the need to create space in bone marrow and an immunological barrier is necessary, according to the Nature study. The researchers note their work remains preclinical.
Before stem cell transplantation, patients currently typically receive intensive, often toxic chemotherapy or radiation to create space in bone marrow for new cells. This non-specific damage can harm the lungs, liver, kidneys, and nervous system, triggering bone marrow failure with infections, anemia, and bleeding. Survivors face lifetime risks of secondary cancers, hormone disorders, and infertility. Monoclonal antibodies against the stem cell marker KIT, also called CD117, have therefore been studied as a gentler alternative, but normally cannot distinguish between original and newly transplanted stem cells.
How Cell Protection Worked in the Experiment
Using adenine base editing or prime editing, the team introduced KIT mutations into stem and progenitor cells, combined with disruption of the BCL11A enhancer to promote fetal hemoglobin. In cell culture, the antibody Fab-79D after 7 days substantially inhibited growth of unedited cells while KIT-H378R cells multiplied similarly to untreated cells, including in combination with the BCL11A change. In animal studies with NBSGW mice, animals received six doses of Fab-79D antibody at 0.5 milligrams each starting in week six, distributed over different dosing intervals, while control animals received saline. After 18 weeks, examination of bone marrow and spleen showed the proportion of mtBFP-marked, KIT- and BCL11A-edited cells in human grafts was 21.38 percent with sham treatment and 71.48 percent in the ten-day dosing interval schedule. A separate feasibility trial involved five control and seven treated mice. According to the authors, extended antibody treatment enabled stronger enrichment without favoring individual cell clones, which they verified using genetic marking.
Comparison: Epitope Editing in Leukemia
The same team had previously used epitope editing to protect healthy blood stem cells from cancer immunotherapies like CAR-T cells or therapeutic antibodies while those treatments attacked leukemia cells. A review describes how epitope editing of FLT3, CD123, and KIT in human stem cells and humanized mice enabled targeted immunotherapy against acute myeloid leukemia, allowing CAR-T cells from patient sources to eliminate leukemia xenografts while sparing edited healthy progenitor cells. The targeted immunotherapies for conditioning described by the team are particularly suitable for autologous gene therapies where immunosuppression or complete blood replacement is not necessarily required. The review authors also point out limitations: base editors can unintentionally alter adjacent 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.