In vivo competitive studies between normal and common gamma chain-defective bone marrow cells: Implications for gene therapy

Corrective gene transfer into hematopoietic stem cells (HSCs) is being inve stigated as therapy for X-linked severe combined immunodeficiency (XSCID) a nd it is hoped that selective advantage of gene-corrected HSCs will help in achieving full immune reconstitution after treatment. Lines of evidence fr om the results of allogeneic bone marrow transplantation in patients with X SCID support this hypothesis that, however, has not been rigorously tested in an experimental system. We studied the competition kinetics between norm al and XSCID bone marrow (BM) cells using a murine bone marrow transplantat ion (BMT) model. For easy chimerism determination, we used genetic marking with retrovirus-mediated expression of the enhanced green fluorescent prote in (EGFP), We found that XSCID BR I cells were able to compete with normal BR I cells for engraftment of myeloid lineages in a dose-dependent manner, whereas we observed selective repopulation of T, B, and NK cells deriving f rom normal BM cells. This was true despite the evidence of competitive engr aftment of XSCID lineage marker-negative/c-Kit-positive (Lin(-)/c-Kit(+)) c ells in the bone marrow of treated animals. From these results we extrapola te that genetic correction of XSCID HSCs will result in selective advantage of gene-corrected lymphoid lineages with consequent restoration of lymphoc yte populations and high probability of clinical benefit.