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Eliminating preexisting hematopoietic stem cells (HSC) is a necessary step before HSC transplant. Traditionally this "adjuvant" treatment is performed by means of high dose chemotherapy and radiotherapy, which cause serious toxicity and increases secondary cancer risk. This risk is even higher in gene therapy as it may be misinterpreted as insertional mutagenesis of retroviral vectors. For example, bluebird bio’s gene therapy trial was once put on hold for several months after two recipients developed MDS and AML, until they proved that the cancers were not due to retroviral vectors.

In recent years we have made great progresses in monoclonal antibodies and small molecule kinase inhibitors. Unlike conventional chemotherapy causing DNA damages directly, these drugs specifically attack the surface markers (e.g., HER2) of cancer cells or interfere with the growth signals (e.g., MAPK/ERK). So can we apply similar strategies on HSC by targeting their surface markers or inhibiting the signaling pathways that maintain their “stemness”?

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Possibly, but "can we" is only really answerable once it's been done; there are lots of things that are within some plausible range of possibility (including those that seem within grasp and those closer to science fiction). It's often difficult to predict which of these goals will be achieved easily and which will turn out to be harder than expected.

Here's one recent paper:

Persaud, S. P., Ritchey, J. K., Kim, S., Lim, S., Ruminski, P. G., Cooper, M. L., ... & DiPersio, J. F. (2021). Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation. The Journal of clinical investigation, 131(24).

They're testing in mice an alternative "conditioning" (the term for the pre-transplant elimination of HSCs) step using an antibody conjugated to highly toxic saporin. The antibody is targeted to cell-surface markers expressed on the target cells. This is exactly the same family of methods used to target chemotherapy to cancer cells more generally as you describe.

This isn't my field, and there may be many more papers out there, I have not attempted anything like a comprehensive literature review, this was just the first hit I got looking for recent papers with the search terms "Hematopoietic stem cell transplantation conditioning". One paper that cites the one I mentioned is a review of antibody-based conditioning:

Griffin, J. M., Healy, F. M., Dahal, L. N., Floisand, Y., & Woolley, J. F. (2022). Worked to the bone: antibody-based conditioning as the future of transplant biology. Journal of Hematology & Oncology, 15(1), 1-21.

so that's probably a good place to start. It looks like two are in phase 3 clinical trials and another 15 or so in earlier clinical trials. You may also wish to read about reduced-intensity conditioning approaches, for example:

Giralt, S., Ballen, K., Rizzo, D., Bacigalupo, A., Horowitz, M., Pasquini, M., & Sandmaier, B. (2009). Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biology of Blood and Marrow Transplantation, 15(3), 367-369.

Typically, the existing conditioning paradigms used are meant to be sparing of other tissues, and while they certainly aren't perfect, these antibody-based methods aren't going to be perfect either: there's no guarantee of no effects on other cells, and no guarantee that all target cells are killed. Importantly, these transplants are typically done for treatment of cancers, and this approach will only work if the cancerous cells express the target surface marker. Traditional chemotherapeutic approaches have the benefit that their effectiveness is biased against proliferative cells, giving them a more generalized efficacy against cancer cells.

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