Foamy Virus Vectors Come of Age
Authors: David A Williams
Journal: Molecular Therapy (2008)

A recent report by Dennis Hickstein's group at the National Institutes of Health heralds the maturation of many years of work on foamy virus vectors.1Bauer Jr, TR Allen JM Hai M Tuschong LM Khan IF Olson EM et al.Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors.Nat Med. 2008; 14: 93-97Crossref PubMed Scopus (135) Google Scholar The data presented in the report show correction of canine leukocyte adhesion deficiency (CLAD) using recombinant foamy virus vectors and suggest that foamy virus vectors have a relatively safe integration profile. CLAD is a genetic disease in dogs that closely resembles certain genetic types of leukocyte adhesion deficiency (LAD) in humans. It arises from a deficiency of the integrin CD18 and resulting absence of the CD11/CD18 heterodimeric adhesion receptor on bone marrow–derived leukocytes. The deficiency leads to a complex phenotype of abnormally high peripheral white blood cell counts with reduced or absent migration of affected leukocytes into areas of infection. Individuals suffer life-threatening infections with shortened life expectancy. At the cellular level, CD18-deficient leukocytes demonstrate reduced adhesion, migration, and spreading in vitro, and a characteristic defect in the integrin-mediated firm adhesion and transendothelial migration out of the circulation in vivo following the dynamic rolling of these cells along the endothelium. The report by Bauer et al.1Bauer Jr, TR Allen JM Hai M Tuschong LM Khan IF Olson EM et al.Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors.Nat Med. 2008; 14: 93-97Crossref PubMed Scopus (135) Google Scholar cites the phenotypic correction and long-term survival of four of five dogs with CLAD infused with autologous bone marrow cells transduced with a foamy virus vector expressing canine CD18. The vector makes use of a self-inactivating configuration with the CD18 complementary DNA (cDNA) expressed from an internal murine stem cell virus long terminal repeat (LTR) and a deletion of the foamy virus LTR enhancer. Several aspects of the report are noteworthy. The transduction was carried out with a short (overnight) vector exposure that yielded sufficiently high engraftment of corrected cells after nonmyeloablative radiation treatment to effectively reverse the cellular and disease phenotypes of the surviving animals. In addition, analysis of integration sites up to 2 years after infusion was consistent with polyclonal reconstitution of the bone marrow, with no indication of integration-site skewing with time. Finally, careful analysis of some integration sites by gene identification showed significantly fewer integrations in or near expressed genes and no evidence of expansion of cells with integrations of the vector near genes involved in proliferation. The authors conclude that the data suggest that foamy virus vectors may be safer than gammaretrovirus vectors. One should remain open-minded about this latter claim, given that only a limited number of animals was followed for a relatively short time. Gammaretroviruses using the same U3 LTR enhancer deletion and expressing transgenes via weaker cellular promoters have been shown, at least in vitro, to have improved safety profiles.2Zychlinski Schambach AD Modlich U Meyer J Knoess S Grassman E et al.Self-inactivating retroviral vectors harboring cellular promoters reduce the risk of insertional transactivation and transformation.Mol Ther. 2007; 15: S1-404Abstract Full Text Full Text PDF Google Scholar Indeed, in the report by Bauer et al. there were documented insertions near the MDS-EVI1 locus, which has proven problematic in previous mouse, primate, and human studies.1 Foamy virus vectors have been reported to have potentially important advantages over gammaretrovirus vectors. These putative advantages include a larger capacity for transgenes, the lack of pathogenicity in both human and primate infections, and a stable cDNA genome leading to more stable provirus structures in cells in G0/G1. Although Bauer and colleagues' report does not directly address any of these issues from an experimental standpoint, the results are impressive with respect to the application of this vector technology to a large animal model of a serious human disease. The work represents a culmination of many years of preclinical studies led largely by David Russell. With this report, one can anticipate a human trial in the near future.