Chemotherapy-Free Bone Marrow Transplants Move Closer to Reality

Bone marrow transplants, also called stem cell transplants, have revolutionized the treatment of many cancers and hematological conditions like sickle cell disease. These involve infusing healthy blood-forming hematopoietic stem cells into a person’s body to replace dysfunctional blood cells.

Before receiving new stem cells, patients must undergo treatments to get rid of existing cells and suppress the immune system to avoid transplant rejection. “These approaches can be highly effective but are associated with substantial short- and long-term complications, limiting the access to frail patients,” said Gabriele Casirati, a postdoctoral fellow in hematology researcher Pietro Genovese’s lab at the Dana-Farber Cancer Institute, in an email to The Scientist. “We wanted to develop a strategy in which donor stem cells could be genetically protected from a targeted antibody-based conditioning agent, allowing selective depletion of unedited host cells while sparing the edited graft,” he added.

Now, Genovese, Casirati, and their team has developed an approach to selectively deplete existing stem cells using therapeutic antibodies, while engineering donor stem cells to ensure that the graft is spared.¹ Their strategy, published in Nature, combines non-genotoxic immunotherapy for bone marrow depletion and receptor engineering to improve the safety of stem cell transplants.

Researchers had previously investigated the utility of monoclonal antibodies (mAbs) that recognize the hematopoietic stem cell marker KIT to deplete stem cells.² However, these mAbs cannot differentiate between existing and donor cells, posing safety challenges in transplants.

To overcome this problem, Genovese and Casirati turned to genome-editing tools to alter a recognition site, or epitope, on the donor stem cell surface. Previously, their team had used a similar epitope editing strategy to selectively shield healthy stem cells from cancer immunotherapies.³

In the present study, the researchers used base editing to mutate a domain in the gene encoding KIT in cultured blood cell lines. They altered the gene’s expression such that a mAb would not bind to these donor cells, while preserving the normal function of the KIT protein. This rendered the cells resistant to attack by mAbs, while leaving unedited cells vulnerable.

For a proof-of-principle, Genovese, Casirati, and their team injected the gene-edited stem cells into mice and treated the animals with the KIT-targeting mAb. Tracking transplanted stem cells revealed that they survived mAb treatment, integrated into the animals’ bone marrow, and increased in numbers gradually, indicating that the new, edited cells eventually replaced existing cells.

According to Casirati, their approach also creates a framework for in vivo selection of gene-edited cells, such that modified donor cells could be enriched directly in the body. This could likely reduce the need for intensive regimens to prepare the recipient’s body for stem cell transplants, improving the efficiency of cell and gene therapies.

“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 Genovese in a statement. “By combining targeted biological conditioning with molecularly protected therapeutic stem cells, this strategy offers a new framework for safer and more accessible treatments for a wide range of blood diseases.”