Friedreich’s ataxia (FA) is the most common inherited ataxia. In FA, there is an expansion of a fragment of the DNA genetic code in the frataxin (FXN) gene. This results in the depletion of the FXN protein, leading to the disease. Increasing FXN protein levels is therefore key to treating the condition.

Although there has been progress towards understanding the molecular mechanisms underlying FA, there are no drugs approved to treat the condition. According to researchers at the University of Oxford: “There is a clear need to find new molecular targets that can pave the way to the developing drugs to increase FXN levels.”

These researchers have developed a new approach to perform genome-wide screening to discover new molecular pathways that could be involved in increasing FXN levels using a new and exciting gene editing technique called CRISPR Cas-9. This method works by simultaneously switching off the genes within a group of cells, whereby one gene is switched off in each cell at a time. The cells are then analysed to see which ones contain more FXN protein, and those with increased levels of FXN protein have their genes sequenced. This gives the researchers information about which genes contributed to the increase in protein levels and reveals new biological pathways that may be useful to target with drugs to regulate FXN protein expression.

This project is a part of the collaborative drug discovery consortium between Ataxia UK, Oxford University, University College London, Imperial College London and the pharmaceutical company, Pfizer. The aim of that Consortium, funded by Pfizer with a contribution from Ataxia UK, was to work towards identifying a compound that could increase FXN levels in patients with FA (Ataxia Magazine 190 and 201). The project later evolved, with additional funding from Friedreich’s Ataxia Research Alliance (FARA) to investigate the genes that increase FXN levels (Ataxia Magazine 201).

The researchers managed to generate a list of genes that control FXN expression and identify a total of 23 new biological pathways and molecules that could be targeted to restore FXN protein levels in patients. They have prioritised and confirmed two of these targets.

Head researcher Richard Wade-Martins said: Moving forward, priority will be given to targets for which drugs already exist. One approach could maybe even be to use a drug which is already in use for another disease as that represents a quicker way to translate our findings into the clinic.

Posted on 17/12/2019