Project Summary Ataxia telangiectasia (A-T) is a genetic disorder resulting from mutations in the ATM protein, essential for DNA repair and maintaining genomic integrity. Patients with A-T experience neurodegeneration, immune deficiencies, an elevated risk of lymphoma, and pathological inflammation due to DNA damage. The increased likelihood of lymphomas, immune deficiency, and neurological decline contribute significantly to the high rates of mortality and morbidity in A-T. While allogeneic HSCT has been explored using reduced-intensity genotoxic conditioning, outcomes have varied. In this proposal, we aim to investigate the role of allogeneic HSCT with non-genotoxic conditioning using immunotoxin in A-T murine models, focusing on correcting underlying immune deficiency, reducing lymphoma risk, and attenuating the chronic inflammatory phenotype. We hypothesize that this strategy will correct immune deficiencies, diminish lymphoma risk, and lessen DNA damage-induced inflammation. The specific aims of the proposal are: 1) To examine the effect of HSCT with non-genotoxic conditioning on the likelihood of lymphoma in an A-T murine model. 2) To assess the impact of HSCT with non-genotoxic conditioning on infection risk and inflammatory response in the A-T murine model. We will employ recombinant saporin-based immunotoxins, including CD117 and CD45- antibody saporin conjugates, combined with non- genotoxic immune ablation strategies. Completing this research could open avenues for innovative treatments for A-T and similar genetic disorders by addressing the elevated risk of infection, inflammatory stress, and associated lymphoma risk through a non-genotoxic HSCT approach.