Rescuing frataxin expression by alternative splicing reprogramming with base editing

In the last few years, scientists have started using a powerful tool called CRISPR to modify the DNA of patients in a new form of gene therapy; the first example of a CRISPR medicine was approved at the end of 2023. Friedreich’s Ataxia is potentially treatable with CRISPR by introducing DNA modifications that reduce or remove altogether the GAA expansion that causes the disease. This is a very powerful technology but comes with the potential to introduce unwanted genome alteration. With this proposal, Dr Quattrone and his team suggest a radically different approach: instead of directly modifying the gene mutation, they aim to modify how the gene’s instructions are used by the cell, compensating for the effects of the mutation at a different level. Dr Quattrone’s research has uncovered a new version of the gene’s instructions, called FXN2, which seems to be abundant but non-functional in FA-affected organs. Using a state-of-the-art form of CRISPR they were able to modify how the cell processes the genetic information necessary to make frataxin and boost the production of the protein threefold in lab tests. The group plans to expand this research by testing this method in cells from FA patients and in FA mouse models to see if it improves symptoms. This could lead to a new way of treating FA by indirectly correcting the genetic error.