Myeloablative conditioning and late complications in ARTEMIS-deficient SCID

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PROJECT ABSTRACT The vastly diverse antigen receptor genes are assembled from numerous V, D and J coding segments via the lymphoid specific DNA rearrangement, V(D)J recombination. Defective V(D)J recombination impairs lymphocyte development and thus, results in immunodeficiency. The non-homologous end joining (NHEJ) pathway is required during V(D)J recombination by virtue of its role as one of the major DNA double strand break (DSB) repair pathways. Mutations in nearly all of the NHEJ genes have been found in association with human primary immunodeficiency syndromes. ARTEMIS is the most frequently mutated NHEJ gene and was initially discovered in the radiation sensitive severe combined immunodeficiency syndrome, RS-SCID. NHEJ- deficient patients can undergo hematopoietic cell transplantation to reconstitute T and B cell functions. However, because NHEJ is critical for DSB repair in all cell types, conditioning regimens involving radiation cause excessive tissue damage and can lead to mortality. ARTEMIS-deficient patients have been successfully engrafted with T and B cells with myeloablative conditioning using alkylating agents. However, these patients exhibit late complications including growth failure, endocrine deficiencies and dental abnormalities. The goals of this proposal are to elucidate the mechanisms underlying the toxicities associated with myeloablative conditioning with alkylating agents using our previously developed and characterized mouse models of NHEJ- deficient SCID and to determine the efficacy of alternative conditioning regimens. The potential for late onset tumorigenesis associated will also be examined. Together, these studies will provide mechanistic insight into the causes of late toxicities in NHEJ-deficient primary immunodeficiencies and potentially lead to the development of more effective therapies.