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Hematopoietic stem/progenitor cell (HSPC) transplantation (HSCT) remains the only curative option for many hematologic and immunologic disorders, but its broader application is severely limited by the toxicity of current conditioning regimens. Chemotherapy- and radiation-based conditioning can cause organ damage, infertility, and life-threatening complications, especially in vulnerable patients. Monoclonal antibody (Ab)- and chimeric antigen receptor (CAR)-based immunotherapies targeting the stem cell marker KIT (CD117) have been proposed as a less toxic alternative for conditioning in preparation for HSCT. However, these biological conditioning agents do not discriminate between endogenous and transplanted HSPCs, so the transplant must be delayed until the drug is inactivated or eliminated, thereby reducing overall engraftment and therapeutic efficacy. We pioneered the concept of epitope editing as a strategy to shield therapeutic cells from immunotherapy (Casirati et al., Nature, 2023) and are now demonstrating proof-of-concept of improved engraftment after antibody-mediated conditioning of human HSPCs engineered with base and prime editing (manuscript under invited revision at Nature). While highly effective, those methods involve permanent genomic edits. Here, we propose a transformative alternative: a transient, RNA-based approach that retains the benefits of immune shielding without altering the HSPC genome. Our central hypothesis is that transient expression of a “stealth” (antibody-resistant) KIT receptor via self-replicating RNA will enable donor HSPCs to evade antibody-mediated depletion, restore KIT signaling, and successfully engraft without requiring permanent genome modification. Using self-amplifying RNA (saRNA), we will encode an epitope-engineered KIT variant that evades Briquilimab binding. This temporary expression will preserve KIT function during early engraftment, enabling transplantation at the antibody's peak activity while endogenous cells are being counter-selected. If successful, this project will establish a first-in-class strategy for transient reconstitution of an essential cell-surface receptor to overcome antibody-based conditioning barriers. This approach has the potential to redefine HSCT by removing the need for genotoxic conditioning and permanent gene editing, while maximizing graft efficiency. This concept is inherently high-risk, but if proven, it will launch a new paradigm of transient immune shielding for transplantation and cell therapy, fully aligned with ISAC’s mission to accelerate disruptive innovation in hematology.
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