Non-genotoxic HSCT for ATM

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.

Grant Number: 5R03HL174883-02
NIH Institute/Center: NIH
Principal Investigator: Shanmuganathan Chandrakasan