Université de Montréal edits stem cells

Université de Montréal researchers said this week they are working on a gene-editing approach meant to let doctors attack acute myeloid leukemia without wiping out healthy blood-forming cells. The strategy uses CRISPR-Cas9 to remove CD33 from hematopoietic stem cells — the cells that regenerate the blood system — so those edited cells become resistant to anti-CD33 treatment, according to Université de Montréal and prior published research. The idea is to preserve the donor graft while still allowing CD33-directed therapy to hit residual leukemia cells. Université de Montréal described the work on May 15 as the first time in Canada that blood stem cells were genetically modified with CRISPR-Cas9 in a North American clinical study for aggressive blood cancers. ### Why does CD33 matter in leukemia treatment? CD33 is a myeloid-cell surface protein that is also found on many acute myeloid leukemia cells, making it an attractive drug target. The problem, researchers have said for years, is that CD33 is also present on normal myeloid cells and their precursors, so anti-CD33 therapies can damage healthy blood production as well as leukemia. A 2018 Cell paper showed that deleting CD33 from human hematopoietic stem and progenitor cells could create a blood system resistant to anti-CD33 immunotherapy while preserving myeloid development and function. (umontreal.ca) ### What exactly are the Montréal researchers changing? The Université de Montréal description says blood stem cells were modified with CRISPR-Cas9 in patients treated through the UdeM-affiliated Hôpital Maisonneuve-Rosemont. In this approach, CD33 is removed from donor-derived stem cells before transplant, so the reconstituted blood system lacks the marker that anti-CD33 drugs would otherwise attack. That is the same core logic used in the CD33-deleted allogeneic transplant strategy reported in Nature Medicine last week. (cell.com) Nature Medicine reported that the first-in-human trial combined transplantation of CD33-negative CRISPR-edited hematopoietic cells with the CD33-targeted antibody-drug conjugate gemtuzumab ozogamicin. The study said the edited graft was intended to shield normal hematopoietic cells from post-transplant CD33-directed therapy. ### What does “invisible to anti-CD33 treatment” mean in practice? (umontreal.ca) Anti-CD33 therapy works by recognizing the CD33 protein on cell surfaces. If CRISPR editing deletes CD33 from healthy donor stem cells, the blood cells that grow from those stem cells should no longer display the target, meaning the therapy is less likely to hit them. Researchers have framed that as a way to widen the therapeutic window for AML treatment by separating leukemia killing from damage to normal marrow. (nature.com) Clinical trial records for CD33-ablated stem-cell approaches say the goal is to allow escalating doses or tighter dosing intervals of gemtuzumab ozogamicin by making healthy hematopoietic stem and progenitor cells resistant to the drug’s CD33-directed effect. ### Where do genotoxicity and retrons fit into this story? Genotoxicity remains a central safety issue for any therapeutic genome editing platform because DNA cutting and repair can create off-target edits, chromosomal rearrangements or other unintended changes. (cell.com) A recent Cell Stem Cell study reported “distinct platform- and cell type-specific patterns” in comparative genotoxicity profiling, underscoring that safety findings can vary depending on both the editing method and the cell being edited. (clinicaltrials.gov) Bacterial retrons are a separate but related tool for precise editing. Prior studies have shown that retrons can generate donor DNA inside cells and, when coupled with CRISPR systems, improve homology-directed repair efficiency in human cells. That makes them relevant to efforts to raise targeted editing efficiency, though the retron work surfaced in the source material is broader genome-engineering research rather than a clinical leukemia result on its own. (sciencedirect.com) ### What happens next? Université de Montréal said the clinical work involved patients at Hôpital Maisonneuve-Rosemont, and the university’s May 15 report tied the program to an international trial in acute leukemia. Nature Medicine has now published related first-in-human CD33-deleted transplant data, while ongoing trial records continue to track CD33-ablated stem-cell transplantation followed by gemtuzumab ozogamicin in patients with CD33-positive AML. (umontreal.ca) (pmc.ncbi.nlm.nih.gov)