title: Gene therapy for canine leukocyte adhesion deficiency with lentiviral vectors using the murine stem cell virus and human phosphoglycerate kinase promoters.
abstract: Children with leukocyte adhesion deficiency type 1 (LAD-1) and dogs with canine LAD (CLAD) develop life-threatening bacterial infections due to mutations in the leukocyte integrin CD18. Here, we compared the human phosphoglycerate kinase (hPGK) promoter to the murine stem cell virus (MSCV) promoter/enhancer in a self-inactivating HIV-1-derived lentiviral vector to treat animals with CLAD. Four CLAD dogs were infused with CD34(+) cells transduced with the hPGK vector, and two CLAD dogs received MSCV vector-transduced CD34(+) cells. Infusions were preceded by a nonmyeloablative dose of 200 cGy total body irradiation. Comparable numbers of transduced cells were infused in each group of animals. Only one of four CLAD animals treated with the hPGK-cCD18 vector had reversal of CLAD, whereas both MSCV-cCD18 vector-treated dogs had reversal of the phenotype. Correction of CLAD depends both upon the percentage of CD18(+) myeloid cells and the level of expression of CD18 on individual myeloid cells. In this regard, the hPGK promoter directed low levels of expression of CD18 on neutrophils compared to the MSCV promoter, likely contributing to the suboptimal clinical outcome with the hPGK vector.
authors.affiliation: Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1203, USA. huntermj@mail.nih.gov
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hunter
authors.forename: Huifen
authors.initials: H
authors.lastname: Zhao
authors.forename: Laura M
authors.initials: LM
authors.lastname: Tuschong
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bauer
authors.forename: Tanya H
authors.initials: TH
authors.lastname: Burkholder
authors.forename: Derek A
authors.initials: DA
authors.lastname: Persons
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Hickstein
mesh_terms: D000818:Animals; D018821:CD18 Antigens / Q000235:genetics*; D004283:Dog Diseases / Q000628:therapy*; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000628:therapy* / Q000662:veterinary*; D051379:Mice; D010735:Phosphoglycerate Kinase / Q000235:genetics; D011401:Promoter Regions, Genetic; D013234:Stem Cells; D014161:Transduction, Genetic / Q000379:methods; D014916:Whole-Body Irradiation
chemical_list: D018821:CD18 Antigens; D010735:Phosphoglycerate Kinase