Engineering PTEN-L for Cell-Mediated Delivery
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| Authors: | Lavictoire, SJ; Gont, A; Julian, LM; Stanford, WL; Vlasschaert, C; Gray, DA; Jomaa, D; Lorimer, IAJ |
| Year: | 2018 |
| Journal: | Mol.Ther.-Methods Clin. Dev. 9: 12-22 Article Link (DOI) PubMed |
| Title: | Engineering PTEN-L for Cell-Mediated Delivery |
| Abstract: | The tumor suppressor PTEN is frequently inactivated in glioblastoma. PTEN-L is a long form of PTEN produced by translation from an alternate upstream start codon. Unlike PTEN, PTEN-L has a signal sequence and a tract of six arginine residues that allow PTEN-L to be secreted from cells and be taken up by neighboring cells. This suggests that PTEN-L could be used as a therapeutic to restore PTEN activity. However, effective delivery of therapeutic proteins to treat CNS cancers such as glioblastoma is challenging. One method under evaluation is cell-mediated therapy, where cells with tumor-homing abilities such as neural stem cells are genetically modified to express a therapeutic protein. Here, we have developed a version of PTEN-L that is engineered for enhanced cell-mediated delivery. This was accomplished by replacement of the native leader sequence of PTEN-L with a leader sequence from human light-chain immunoglobulin G (IgG). This version of PTEN-L showed increased secretion and an increased ability to transfer to neighboring cells. Neural stem cells derived from human fibroblasts could be modified to express this version of PTEN-L and were able to deliver catalytically active light-chain leader PTEN-L (lclPTEN-L) to neighboring glioblastoma cells. |
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