Rescuing PNPase defects in bacterial and human cell models (RESPNP)

The main goal of the RESPNP project is to find small molecules that can help fix mutated forms of a crucial enzyme called polyribonucleotide phosphorylase (hPNPase). This enzyme is important for various functions in our cells' mitochondria. When the gene responsible for hPNPase, called PNPT1, has mutations, it can lead to serious neurological disorders. These disorders are very rare, and because of their rarity, pharmaceutical companies are unlikely to invest in developing treatments for them. Therefore, we need affordable ways to tackle this issue. To address this, I suggest using a drug repurposing strategy. This means we will look for so-far ignored activities of existing drugs that might help restore the function of the mutated hPNPase. We will screen about 3500 compounds that are either already approved for the human use or have passed early phases of clinical experimentation. The promising candidates will undergo further testing to see how well they work and if they are specific to the mutated enzyme. The assays I plan to apply in the different cell models and in vitro have been already set up in my laboratory thanks to previous support to my research by the Telethon Foundation. I believe that by speeding up the drug development process, this project can lead to significant progress in finding a cure for these rare mitochondrial disorders.