Regular Article GENE THERAPY Intravenous injection of a foamy virus vector to correct canine SCID-X1

a foamy virus carrying a corrective gene facilitates immune cell development in a canine model of SCID-X1. • Integration site analysis revealed polyclonal reconstitution in all dogs with evidence for clonal dominance in at least 1 time point. Current approaches to hematopoietic stemcell (HSC) gene therapy involve the collection andexvivomanipulationofHSCs, aprocess associatedwith loss of stemcellmultipotency and engraftment potential. An alternative approach for correcting blood-related diseases is the direct intravenous administration of viral vectors, so-called in vivo gene therapy. In this study,weevaluated thesafetyandefficacyof in vivogene therapyusinga foamyvirus vector for the correction of canine X-linked severe combined immunodeficiency (SCID-X1). In newborn SCID-X1 dogs, injection of a foamy virus vector expressing the human IL2RG gene resulted in an expansion of lymphocytes expressing the common g chain and the development of CD31 T lymphocytes. CD31 cells expressed CD4 and CD8 coreceptors, underwent antigen receptor gene rearrangement, and demonstrated functional maturity in response to T-cell mitogens. Retroviral integration site analysis in 4 animals revealed a polyclonal pattern of integration in all dogs with evidence for dominant clones. These results demonstrate that a foamy virus vector can be administered with therapeutic benefit in the SCID-X1 dog, a clinically relevant preclinicalmodel for in vivo gene therapy. (Blood. 2014;123(23):3578-3584