Lentiviral vectors incorporating a human elongation factor 1α promoter for the treatment of canine leukocyte adhesion deficiency

• Published in: Gene therapy Vol. 17; no. 5; pp. 672 - 677
• Main Authors: NELSON, Ejr, TUSCHONG, L. M, HUNTER, M. J, BAUER, T. R, BURKHOLDER, T. H, HICKSTEIN, D. D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.05.2010
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Applied cell therapy and gene therapy; Autografts; Biological and medical sciences; Biotechnology; Bone marrow; Care and treatment; CD18 antigen; CD34 antigen; Elongation; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic aspects; Genetic vectors; Health aspects; Health. Pharmaceutical industry; Immunological deficiency syndromes; Industrial applications and implications. Economical aspects; Juveniles; Leukocytes (neutrophilic); Medical sciences; Neutrophils; Phenotypes; Physiological aspects; Radiation; Transcription factors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; United States; Leukocyte; Elongation factor; Hemopathy; EF1α promoter; Leukocyte adhesion deficiency; leukocyte adhesion; lentiviral vector; CLAD; Ex vivo; immunodeficiency; ex vivo gene therapy; Dog; Vector; Human; Fissipedia; Immunopathology; Carnivora; Retroviridae; Adhesion; Immune deficiency; Lentivirus; Genetic disease; Virus; Vertebrata; Mammalia; Treatment; Gene therapy; Leukocyte disease
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2010.7

Canine leukocyte adhesion deficiency (CLAD) provides a unique large animal model for testing new therapeutic approaches for the treatment of children with leukocyte adhesion deficiency (LAD). In our CLAD model, we examined two different fragments of the human elongation factor 1a (EF1α) promoter (EF1αL, 1189 bp and EF1αS, 233 bp) driving the expression of canine CD18 in a self-inactivating (SIN) lentiviral vector. The EF1αS vector resulted in the highest levels of canine CD18 expression in CLAD [CD34.sup.+] cells in vitro. Subsequently, autologous [CD34.sup.+] bone marrow cells from four CLAD pups were transduced with the EF1αS vector and infused following a non-myeloablative dose of 200 cGy total-body irradiation. None of the CLAD pups achieved levels of circulating [CD18.sup.+] neutrophils sufficient to reverse the CLAD phenotype, and all four animals were euthanized because of infections within 9 weeks of treatment. These results indicate that the EF1αS promoter-driven CD18 expression in the context of a RRLSIN lentiviral vector does not lead to sufficient numbers of [CD18.sup.+] neutrophils in vivo to reverse the CLAD phenotype when used in a nonmyeloablative transplant regimen in dogs. Gene Therapy (2010) 17, 672-677; doi: 10.1038/gt.2010.7; published online 18 February 2010 Keywords: EF1α promoter; lentiviral vector; ex vivo gene therapy; CLAD; leukocyte adhesion; immunodeficiency