Intravenous injection of a foamy virus vector to correct canine SCID-X1

• Published in: Blood Vol. 123; no. 23; pp. 3578 - 3584
• Main Authors: Burtner, Christopher R., Beard, Brian C., Kennedy, Douglas R., Wohlfahrt, Martin E., Adair, Jennifer E., Trobridge, Grant D., Scharenberg, Andrew M., Torgerson, Troy R., Rawlings, David J., Felsburg, Peter J., Kiem, Hans-Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-06-2014; American Society of Hematology
• Subjects: Animals; Blood Cells - metabolism; Cell Lineage - genetics; Disease Models, Animal; Dogs; Foamy virus; Gene Therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; HEK293 Cells; Humans; Injections, Intravenous; Spumavirus; Virus Integration - genetics; X-Linked Combined Immunodeficiency Diseases - therapy
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-11-538926

Current approaches to hematopoietic stem cell (HSC) gene therapy involve the collection and ex vivo manipulation of HSCs, a process associated with loss of stem cell multipotency 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, we evaluated the safety and efficacy of in vivo gene therapy using a foamy virus 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 γ chain and the development of CD3+ T lymphocytes. CD3+ 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 preclinical model for in vivo gene therapy.
•Intravenous injection of 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.