It is possible to silence a desired gene by hiding it from the molecular machinery that has the task of reading it and expressing its function. This is the result of a research carried out at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) published this week in Cell. This technique allows, for instance, to abolish the effects of a mutated gene which results in a disease. To date the alternative has been to inactivate the gene or target its reading and expression mechanisms. These techniques however have several limitations both in terms of efficacy and safety. For this reason, the work carried out by the SR-Tiget researchers at the San Raffaele Hospital, one of 18 centers of excellence in the San Donato Hospital Group, is important; it allows gene silencing in a safer and more effective way, with applications spanning from the treatment of diseases caused by mutated genes to the modification of immune cells for cancer immunotherapy.
The group of SR-Tiget researchers led by Angelo Lombardo and Luigi Naldini synthesized artificial proteins capable of recognizing a chosen target gene, on which they add chemical changes onto it (so-called epigenetic modifications) rendering it inaccessible to reading mechanisms.
Epigenetic modifications are normally used by cells to determine which genes to use for their own activity, allowing the cells of an organism, which all have the same genetic information, to specialize in very different functions, such as in muscle, brain or even skin cells. The epigenetic modifications are transmitted to daughter cells during cell replication, a process that does not alter the original genetic information. Turning off a gene with genetic or epigenetic modifications can be compared to tearing or covering up a page from an instruction manual. «Cells also use epigenetics to regulate their gene expression network according to the developmental stage of the organism and in response to environmental stimuli. For example, during embryonic development, epigenetics turns off those genes that are no longer needed in adult life,» explains Angelo Lombardo, «In our study we have copied the epigenetic processes which are active during embryonic development and directed them to our genes of interested, thus obtaining targeted and permanent silencing.»