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A cancer gene therapy approach for treatment of EB-associated skin cancer

New scientific publication from the Piñón /Gruber working group

The goal of each cancer treatment is to kill the malignant (= tumor) cells, but to spare the healthy cells as much as possible. Unfortunately, conventional methods such as chemotherapy often lack tumor specificity, resulting in a wide range of negative side effects. A promising approach to overcome this obstacle is a trans-splicing mediated gene therapy. This method was developed by EB House scientists and has been successfully tested on colon cancer cells. Now the researchers have adapted the strategy to treat squamous cell carcinoma (SCC) from individuals with recessive dystrophic EB (RDEB), in whom this tumor displays high mortality rates. In the trans-splicing cancer therapy, a cell toxin is inserted into the genome of SCC cells through delivery of a trans-splicing molecule (RTM) to which the toxin is coupled. The RTM is designed to specifically bind to the gene transcript (RNA) of a particular tumor marker that is found only in SCC cells and not in healthy cells. If it comes to a successful trans-splicing reaction, the cell toxin fuses with the tumor marker, so that the latter is reprogrammed. By then adding a specific drug, the cell toxin gets activated, and cell death is triggered as a result. The researchers have shown in laboratory studies that this method efficiently and specifically kills the RDEB-SCC cells. No negative effect on non-SCC cells was demonstrated, indicating that the RTM fuses exclusively with the tumor marker. However, this must be investigated in detail in further studies, as any unwanted fusion with other gene transcripts could induce cell death in healthy cells.
Studies have shown that the more of the tumor marker's RNA is present in the cancer cells, the more efficient trans-splicing cancer gene therapy is. Accordingly, the amount of the marker should be determined for each tumor, in order to select those patients most likely to benefit from this treatment strategy.

For a possible clinical application, it also needs to be clarified how the RTM will be effectively and safely delivered into the tumor cells. Currently, investigated means of transport use microneedles for injection, or creams that utilize nanoparticles to deliver the RTM into the nucleus of the cancer cells. Other possibilities include sonoporation, in which ultrasound is applied to the cells to facilitate RTM delivery, or biolistic methods, in which the RTM is shot into the cells with a gene gun using localized high pressure pulses.


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