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Published on: December 3, 2013
Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors
Thomas R Bauer1, James M Allen, Mehreen Hai
1Experimental Transplantation and Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC1203, Building 10-CRC, Room 3-3330, Bethesda, Maryland 20892, USA.
Abstract:
Recent successes in treating genetic immunodeficiencies have demonstrated the therapeutic potential of stem cell gene therapy. However, the use of gammaretroviral vectors in these trials led to insertional activation of nearby oncogenes and leukemias in some study subjects, prompting studies of modified or alternative vector systems. Here we describe the use of foamy virus vectors to treat canine leukocyte adhesion deficiency (CLAD). Four of five dogs with CLAD that received nonmyeloablative conditioning and infusion of autologous, CD34+ hematopoietic stem cells transduced by a foamy virus vector expressing canine CD18 had complete reversal of the CLAD phenotype, which was sustained more than 2 years after infusion. In vitro assays showed correction of the lymphocyte proliferation and neutrophil adhesion defects that characterize CLAD. There were no genotoxic complications, and integration site analysis showed polyclonality of transduced cells and a decreased risk of integration near oncogenes as compared to gammaretroviral vectors. These results represent the first successful use of a foamy virus vector to treat a genetic disease, to our knowledge, and suggest that foamy virus vectors will be effective in treating human hematopoietic diseases.
Insights
Foamy virus vectors successfully treated canine leukocyte adhesion deficiency (CLAD) in dogs, offering a safer gene therapy alternative. This stem cell gene therapy approach showed sustained reversal of CLAD symptoms without genotoxic complications.
Area of Science:
- Gene therapy
- Hematopoietic stem cell transplantation
- Vectorology
Background:
- Stem cell gene therapy shows promise for genetic immunodeficiencies.
- Gammaretroviral vectors caused leukemia due to oncogene activation.
- Safer vector systems are needed for gene therapy.
Purpose of the Study:
- To evaluate foamy virus vectors for treating canine leukocyte adhesion deficiency (CLAD).
- To assess the safety and efficacy of foamy virus-mediated gene transfer in hematopoietic stem cells.
Main Methods:
- Autologous CD34+ hematopoietic stem cells were transduced with a foamy virus vector expressing canine CD18.
- Dogs with CLAD received nonmyeloablative conditioning and cell infusion.
- In vitro assays and integration site analysis were performed.
Main Results:
- Four of five dogs showed complete and sustained reversal of the CLAD phenotype for over 2 years.
- In vitro assays confirmed correction of lymphocyte proliferation and neutrophil adhesion defects.
- No genotoxic complications were observed; integration analysis indicated reduced oncogene proximity risk.
Conclusions:
- Foamy virus vectors represent a safe and effective option for treating CLAD.
- This study demonstrates the first successful use of foamy virus vectors for a genetic disease.
- Foamy virus vectors hold potential for treating human hematopoietic diseases.
