Rational design of new CNS neuronal models for selective vulnerability in FRDA

The earliest impacted system in FRDA are the peripheral sensory neurons that control limb movement. Cell type models that match these early affected neurons have proven valuable for FRDA therapeutic discovery. However, other brain neuron types may also be affected and eventually have negative effects for the patient, particularly if peripheral symptoms are ameliorated. This project proposes a novel strategy to derive many different neuronal subtypes, by directly reprogramming cells collected from FA patients. The method involves the use of many combinations of transcription factors (proteins that determine cell fate) applied to FA skin cells to first determine which combination will produce each neuronal subtype of interest, and second test whether they are susceptible to low levels of frataxin seen in patients. This new platform provides a scalable and modular method for systematically discovering and modeling FRDA-affected neuronal types. It enables both hypothesis-driven and unbiased identification of vulnerable subtypes, offering insights into new disease mechanisms and new means to screen for effective therapeutics.