Genetic mutant p53 – wild-type switch: towards dual nanoparticle-based oligonucleotide therapy for glioblastoma (NANO-REPLACE)
Glioblastoma (GBM) is the most devastating primary malignancy of the central nervous system in adults. The lack of the 'guardian of the genome' function of the tumor suppressor protein p53 in GBM is considered as key for tumor aggressiveness and resistance to therapy. Prior efforts for repairing function of p53 in GBM by genetic approaches, however, revealed disappointing outcomes in patients so far.
This collaborative project explores a new gene therapy concept and improved techniques for restoring p53 function in GBM cells, in order to overcome recently identified hurdles in p53 gene therapy. More specifically, this relies on the simultaneous delivery of a codon-optimized p53 (gain-of-function) and siRNA for knockdown of endogenous p53 (loss-of-function). In the case of any p53 mutation in GBM, this leads to a 'genetic p53 mutant – wild-type switch'. For therapeutic application, innovative and versatile polymer-based nucleic acid nanocarrier systems are developed for co-formulation and simultaneous delivery of the respective oligonucleotides. This also allows for the implementation of defined, additional therapeutic siRNA molecules, affecting cell division, resistance to apoptosis and autophagy in GBM cells, in order to further boosting the anti-tumor function of the delivered p53.
