Leukocyte adhesion deficiency (LAD) is one of many diseases with the potential to be cured by hematopoietic stem cell (HSC) gene therapy. In LAD, mutations in the CD18 gene prevent expression in blood cells that then fail to migrate into tissues, resulting in life-threatening bacterial infections. LAD has been treated with allogeneic bone marrow transplantation, but there can be significant regimen-related toxicity and graft-versus-host disease, and many patients lack an HLA-matched donor. While there have been notable successes in treating some genetic diseases with stem cell gene therapy, proto-oncogene activation by the viral vectors used can cause malignancies. Thus there is a need for less genotoxic vectors that efficiently transduce HSCs. Foamy Virus (FV) vectors are an alternative retroviral vector system that is less genotoxic than other types of retroviral or lentiviral vectors. Prior research showed that the canine model of LAD (CLAD) could be cured by FV vectors expressing CD18. The experiments proposed here will develop and test FV vectors to treat human LAD. These vectors will be analyzed for efficacy and safety in human cells, including hematopoietic cells from LAD patients. The possibility that specific genetic elements such as insulators are responsible for the reduced genotoxicity of FV vectors will be explored. A GMP grade stock of the vector intended for clinical use will be prepared. The CLAD dogs previously treated with FV vectors will also be followed for 5 additional years to provide long-term data in a large animal model. The proposed experiments will generate essential preclinical data for an LAD gene therapy trial and they are crucial for the future development of the promising FV vector system.
Here we will develop a cure for leukocyte adhesion deficiency (LAD) based on stem cell gene therapy with foamy virus (FV) vectors, with direct relevance for the treatment of human LAD. This would be the first clinical trial of FV vectors, and if safe and successful, it would support their use in treating many hematopoietic diseases.
|Nasimuzzaman, Md; Lynn, Danielle; Ernst, Rebecca et al. (2016) Production and purification of high-titer foamy virus vector for the treatment of leukocyte adhesion deficiency. Mol Ther Methods Clin Dev 3:16004|
|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|
|Deyle, D R; Khan, I F; Ren, G et al. (2013) Lack of genotoxicity due to foamy virus vector integration in human iPSCs. Gene Ther 20:868-73|
|Bauer Jr, T R; Olson, E M; Huo, Y et al. (2011) Treatment of canine leukocyte adhesion deficiency by foamy virus vectors expressing CD18 from a PGK promoter. Gene Ther 18:553-9|
|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|
|Josephson, Neil C; Russell, David W (2010) Production of foamy virus vector and transduction of hematopoietic cells. Cold Spring Harb Protoc 2010:pdb.prot5481|
|Andrianaki, A; Siapati, E K; Hirata, R K et al. (2010) Dual transgene expression by foamy virus vectors carrying an endogenous bidirectional promoter. Gene Ther 17:380-8|
|Trobridge, Grant D; Allen, James; Peterson, Laura et al. (2009) Foamy and lentiviral vectors transduce canine long-term repopulating cells at similar efficiency. Hum Gene Ther 20:519-23|
|Taylor, Jason A; Vojtech, Lucia; Bahner, Ingrid et al. (2008) Foamy virus vectors expressing anti-HIV transgenes efficiently block HIV-1 replication. Mol Ther 16:46-51|