Characteristics of a Foamy Virus-Derived Vector that allow for safe Autologous Gene Therapy to correct Leukocyte Adhesion Deficiency Type 1

by McNichol, Ryan Matthew

The hematopoeitic stem cell is a prime target for gene therapy in the attempt to correct a number of single gene inherited genetic defects that affect the immune system. In persons affected by leukocyte adhesion deficiency type 1 (LAD-1) the gene for the Beta-2 subunit of the integrin molecule is mutated. This autosomal recessive gene defect yields a phenotype with little or no beta-2 integrin expression on leukocytes. Beta-2 integrin expression is essential for leukocytes to travel from the blood to the tissues to fight infection. Persons with this disease have lowered leukocyte counts in the tissues and as a result are beset with recurrent infections which often cause death within the first year of life. As an alternative to using sibling bone marrow transplants, a treatment using retroviral vectors in autologous gene therapy is being studied to correct the disease. Problems surrounding retroviral vectors include 1) a dependence on cell division for integration, 2) short term transgene expression, 3) insertional mutagenesis and 4) the potential of becoming replication competent. The latest alternative in the treatment of LAD-1 is the use of vectors derived from human foamy viruses. These viruses show no human pathogenicity. The foamy viruses have displayed promising integration patterns in cells and are able to survive in quiescent cells that will later divide. Furthermore, these viruses can be modified to become replication incompetent. Using the promoter sequence for the integrin subunit CD18 to direct transgene expression will further increase the safety of this vector in treating LAD-1.