Truncated Cell Surface Markers Fused with Mutant Human Tmpk: Versatile Cell Fate Control Safety Cassettes for Lentiviral Vector Mediated Correction of Fabry Disease
Lentivirus-mediated gene therapy has curative potential for a variety of disorders, however, insertional oncogenesis still remains a concern. One approach to increase safety of such treatment modalities is to include a ‘cell fate control safety cassette’ in lentiviral vectors (LVs), enabling pharma...
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| Language: | en_ca |
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2010
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| Online Access: | http://hdl.handle.net/1807/25794 |
| Summary: | Lentivirus-mediated gene therapy has curative potential for a variety of disorders, however, insertional oncogenesis still remains a concern. One approach to increase safety of such treatment
modalities is to include a ‘cell fate control safety cassette’ in lentiviral vectors (LVs), enabling pharmacological control over the survival of gene-modified cells (GMCs).
Two novel LVs with engineered expression of truncated cell surface molecules (CD19 or
LNGFR) fused to a ‘cell fate control’ gene (TmpkF105YR200A) were constructed. Results demonstrated these safety cassettes could be used to control the survival of GMCs in a murine xenogeneic leukemia models. For treatment of Fabry disease, a bicistronic LV containing the fusion safety element and
therapeutic α-galactosidase A was constructed. Transduction with this vector restored enzyme activity in Fabry patient’s fibroblasts.
These collective results demonstrate that this approach is sufficient to eradicate GMCs, and when combined with a corrective cDNA can provide therapeutic benefit for Fabry disease. |
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