The European Research Council awarded 327 Consolidator Grants, worth in total €655 million. Among the researchers obtaining the prestigious grant – selected through a rigorous competitive process that lasted almost a year – there is Raffaella Di Micco, group leader of the San Raffaele Telethon Institute for Gene Therapy in Milan. Raffaella Di Micco is one of 47 Italian researchers funded by ERC in this turn (the most represented nationality), despite being only one of 17 to receive the funding while working in an Italian research institute.

Thanks to this grant, which comes just a few months after the New York Stem Cell Foundation Award, worth $1.5 million, Di Micco will be able to study how blood stem cells react to manipulation techniques used in gene therapy, focusing in particular on the activation of a premature aging phenotype that could contribute to decrease the functionality of the engineered cells after treatment. The ultimate goal is to improve the long-term efficacy and safety of gene therapy, making it available for more and more diseases.

 

Stem cell aging

The cells that build most of our tissues age, die, and are replaced several times during our lifetime. In the case of blood cells, their life cycle is on average of just 4 months. But where do new cells that substitute the old ones come from? From stem cells.

"The problem is that even stem cells can age and activate a program of cellular senescence," explains Di Micco. "Because of this process, our tissues - such as the blood, of which the immune system is also a part - are no longer able to regenerate efficiently and progressively lose function. This reduced regenerative capacity of cells also increases the likelihood that secondary mutations can accumulate, eventually leading to cancer development."

Di Micco dedicated her career to study how this aging process occurs and what regulates it in stem cells: what are the phenomena that accelerate the biological clock and how we can slow them down.

 

The consequences of gene therapy on treated cells

Since Raffaella Di Micco returned to Italy, after five years at the New York University, her research shifted to the study of cellular aging processes in a very particular field: stem cell-based gene therapies.

"Since 2016, my collaborators and I have been asking a fundamental question: what happens to blood stem cells when they are engineered during a gene therapy treatment? The hypothesis is that this process, in addition to correcting the genetic defect for which it was designed, inadvertently triggers other cellular mechanisms."

Cells subjected to gene therapy protocols are in fact exposed to a series of abnormal and stressful conditions: they are grown for extended time in vitro, treated with high doses of viral vectors - viruses made harmless and transformed into "therapeutic gene carriers" - and, in the case of genomic editing, cut and modified in their most delicate and protected part: the DNA.

According to the first results obtained by the researchers of Micco's group, the manipulation of the DNA, even if done with great precision and without causing any damage, can alert the cell activating the DNA damage response that in turn accelerates the aging process.

 

Improving efficacy and safety of therapies

This premature aging phenotype, in addition to reducing the effectiveness of gene therapy products – because the corrected stem cells struggle to repopulate the bone marrow - could give rise to problems in the long-term.

"If we want to minimize the possible long-term side effects of gene therapy and at the same time make the approach available for more and more diseases, it is essential to study cellular aging programs and to develop strategies to prevent their activation," Di Micco concludes. "This is exactly what we will do thanks to the ERC Consolidator Grant."