These studies aim to identify new methods of gene transfer into hematopoietic stem cells using the genetic disease canine leukocyte adhesion deficiency (CLAD) as a model. We are using the canine model to identify new vectors for gene transfer and conditioning regimens to enable sufficient numbers of gene modified hematopoietic stem cells to engraft and reverse the disease phenotype. The canine form of this disease is an optimal model for these studies since: 1) the defect involves a membrane receptor on the surface of leukocytes, flow cytometry allows fascile detection and analysis of the number of gene corrected cells;2) low levels of gene-corrected cells result in reversal of the disease phenotype;and 3) studies in the canine model have been predictive of success in humans in the field of hematopoietic stem cell biology. The presence of a human counterpart to the canine disease allows the results from the animal model to be directly extrapolated to humans. The long-term objective of these studies is to develop strategies that will allow levels of expression of CD18 in hematopoietic cells of children with leukocyte adhesion deficiency (LAD) that are sufficient to reverse the clinical phenotype. We have utilized this model to test retroviral and foamy viral gene transfer into the bone marrrow cells of dogs. The foamy viral vector demonstrated greater efficacy and a more favorable integration profile than the conventional retroviral vectors. The foamy viral vector-treated dogs are being followed for the durability of the correction, and for any possible genotoxicity from the vector. To date, there has been no genotoxicity. These results represent the first successful use of a foamy virus (FV) vector to treat a genetic disease, and they suggest that foamy virus vectors will be effective in treating human hematopoietic diseases. We are currently testing third-generation foamy viral vectors and lentiviral vectors with cellular promoters and lentiviral vectors with cellular rather than viral promoters in our canine model.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Clinical Sciences
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Goodman, Michael Aaron; Arumugam, Paritha; Pillis, Devin Marie et al. (2018) Foamy Virus Vector Carries a Strong Insulator in Its Long Terminal Repeat Which Reduces Its Genotoxic Potential. J Virol 92:
Bauer Jr, Thomas R; Pratt, Suzanne M; Palena, Christina M et al. (2017) Feline leukocyte adhesion (CD18) deficiency caused by a deletion in the integrin ?2 (ITGB2) gene. Vet Clin Pathol 46:391-400
Gopinath, Chitra; Nathar, Trupti Job; Ghosh, Arkasubhra et al. (2015) Contemporary Animal Models For Human Gene Therapy Applications. Curr Gene Ther 15:531-40
Bauer Jr, Thomas R; Tuschong, Laura M; Calvo, Katherine R et al. (2013) Long-term follow-up of foamy viral vector-mediated gene therapy for canine leukocyte adhesion deficiency. Mol Ther 21:964-72
Hunter, Michael J; Tuschong, Laura M; Fowler, Cedar J et al. (2011) Gene therapy of canine leukocyte adhesion deficiency using lentiviral vectors with human CD11b and CD18 promoters driving canine CD18 expression. Mol Ther 19:113-21
Hunter, Michael J; Zhao, Huifen; Tuschong, Laura M et al. (2011) Gene therapy for canine leukocyte adhesion deficiency with lentiviral vectors using the murine stem cell virus and human phosphoglycerate kinase promoters. Hum Gene Ther 22:689-96
Ohmine, Ken; Li, Yi; Bauer Jr, Thomas R et al. (2011) Tracking of specific integrant clones in dogs treated with foamy virus vectors. Hum Gene Ther 22:217-24
Nelson, E J R; Tuschong, L M; Hunter, M J et al. (2010) Lentiviral vectors incorporating a human elongation factor 1alpha promoter for the treatment of canine leukocyte adhesion deficiency. Gene Ther 17:672-7
Peranteau, William H; Heaton, Todd E; Gu, Yu-Chen et al. (2009) Haploidentical in utero hematopoietic cell transplantation improves phenotype and can induce tolerance for postnatal same-donor transplants in the canine leukocyte adhesion deficiency model. Biol Blood Marrow Transplant 15:293-305
Bauer Jr, Thomas R; Adler, Rima L; Hickstein, Dennis D (2009) Potential large animal models for gene therapy of human genetic diseases of immune and blood cell systems. ILAR J 50:168-86

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