RETROVIRAL MARKING OF CANINE BONE-MARROW - LONG-TERM, HIGH-LEVEL EXPRESSION OF HUMAN INTERLEUKIN-2 RECEPTOR COMMON GAMMA-CHAIN IN CANINE LYMPHOCYTES

Optimization of retroviral gene transfer into hematopoietic cells of t he dog will facilitate gene therapy of canine X-linked severe combined immunodeficiency (XSCID) and in turn advance similar efforts to treat human XSCID. Both canine and human XSCID are caused by defects in the common gamma chain, gamma c, of receptors for interleukin-a and other cytokines. In this study, normal dogs were given retrovirally transdu ced bone marrow cells with and without preharvest mobilization by the canine growth factors granulocyte colony-stimulating factor (G-CSF) an d stem cell factor (SCF). Harvey sarcoma virus and Moloney murine leuk emia virus constructs were used, both containing cDNA encoding human g amma c. The Harvey-based vector transduced into cytokine-primed marrow yielded persistent detectable provirus in bone marrow and blood and e xpression of human gamma c on peripheral lymphocytes. In three dogs, h uman gamma c expression disappeared after 19 to 34 weeks but reappeare d and was sustained, iri one dog beyond 16 months posttransplantation, upon immunosuppression with cyclosporin A and prednisone, with up to 25% of lymphocytes expressing human gamma c. The long-term expression of human gamma c in a high proportion of normal canine lymphocytes pre dicts that retrovirus-mediated gene correction of hematopoietic cells may prove to be of clinical benefit ih humans affected with this XSCID . This is a US government work. There are no restrictions on its use.