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ERC grant for Sebastian Pomplun to precisely influence gene expression

In order to stop a whole range of diseases or disorders at their source, you would have to be able to switch certain genes on or off. Sebastian Pomplun wants to develop substances that can do this very precisely. For example, he wants to disrupt cancer processes and make cells produce an important missing protein in sickle cell disease. Pomplun is receiving an ERC grant of 1.85 million euros over five years to do this.

Traditional drugs target only a small fraction of the human proteome. But what if you could stop a disease by ensuring that a cell does not make the wrong proteins at all? Or that it does make an important missing protein? This is possible if you switch certain genes off or on. In a cell, transcription factors determine whether genes are on or off or more or less active. These are proteins that bind to a kind of beginning of a gene.

Engineering synthetic transcription factors and target unique genes

Pomplun's goal with his project SynTra is engineering synthetic transcription factors (STFs) that can enter cells and activate or deactivate specific genes. First, the drug discovery chemist will engineer transcription factors that can enter cells and bind to any given DNA base pair triplet. Such a triplet is like a letter in the alphabet, which stands for one of the twenty different amino acids that make up proteins. 

Pomplun: 'After that I will prepare combinations of STFs that can target unique genes within the entire human genome with high specificity. With a hexameric transcription factor that recognizes eighteen DNA base pairs, I will target a specific gene promoter and trigger γ-globin production as a promising strategy for sickle cell disease treatment.'

Disrupt cancer-related DNA-processes

In the last part of his project, Pomplun will use STFs to displace the oncogenic transcription factor MYC from its DNA binding site. 'MYC is overexpressed in over 50% of all human cancers. If we displace it from it DNA binding site we can disrupt the oncogenic activity of this protein. A functional MYC inhibitor has game changing potential.’

This is not the first attempt, lessons have been learned

'It is a little early to say if and when these substances become therapeutics', Pomplun says. 'There have been several efforts over the last few decades to create modalities that can control genes and a lot lessons have been learned. In our design we try to address several of the issues related to previous attempts. For example by providing scaffolds with a better cell penetration.'

If everything works out well, SynTra will deliver powerful and practical synthetic tools for studying and targeting disease mechanisms. Researchers at the interface of biology and chemistry will then use the STFs developed in SynTra, for basic research and drug development. Pomplun: 'I hope that we can at least create a platform that makes talking about the development of therapeutics realistic.'

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