Immunoresponse to Gene-Modified Hematopoietic Stem Cells

Gene transfer to and correction of hematopoietic stem cells (HSCs) are ideal strategies to cure a number of congenital and acquired disorders. However, transgene products may trigger immunological rejection of modified cells, limiting their therapeutic benefits. Preclinical and clinical data indicate that myeloablative total body irradiation (TBI) allows for efficient engraftment and tolerance to gene-modified HSCs. In contrast, myeloablative chemotherapy using busulfan or similar agents is only sufficient to induce tolerance to gene-modified HSCs producing no or non-immunogenic protein. If cells are modified to produce a protein that is xenogenic or congenitally absent in the patient, additional immunosuppression may be required to prevent an immunological reaction to the transduced cells. New gene editing and in vivo gene therapy techniques could pose additional immune concerns compared to ex vivo gene therapy methods. This review is intended to guide the design of conditioning and immunosuppression therapy in HSC-targeted gene therapy, as well as gene editing.