Defining the therapeutic window and threshold for neuronal gene therapy in Friedreich Ataxia

Gene replacement therapy is an experimental technique that uses genetic material to treat or prevent a disease. One promising gene replacement therapeutic approach for Friedreich ataxia (FA) is to deliver the frataxin gene to affected cells using viral vectors. Several groups have recently shown that this type of approach could prevent and treat the disease in relevant mouse models. However, there are a number of questions that need to be addressed to optimize the development of a safe therapeutic protocol. In particular, it is now accepted in the field that too much frataxin expression can be detrimental to the normal function of the cell. It is, therefore, essential to develop a therapeutic vector that will mimic the normal endogenous expression of frataxin. Furthermore, it is important to estimate the number of neurons that need to be corrected to produce a clinical benefit. Recent studies have shown that the sensory ataxia in FA might be partly related to problems during development, and it is, therefore, important to determine if gene replacement can correct this very early damage to the tissue. Dr. Puccio and her team will address these questions with a particular focus on the neurological aspects, using two relevant mouse models of the disease and a novel viral vector that expresses frataxin at near physiological levels.