Engineering PTEN-L for Cell-Mediated Delivery

Engineering PTEN-L for Cell-Mediated Delivery

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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 iphone 14 price arizona neural stem cells are here 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.

Keywords: PTEN, PTEN-L, glioblastoma, cell-mediated therapy, signal sequence, neural stem cell.