Design and synthesis of SynGR library to probe into the role of NSD-2,3 proteins in FXN expression in FRDA

Pioneering work from the Ansari lab at St. Jude Children’s Research Hospital has resulted in the discovery of compounds called SynGRs or Synthetic Gene Regulators which consist of DNA-binding ligands conjugated to small molecules that modulate the expression of genes. One of these SynGRs is SynTEF1, a molecule that binds the GAA repeats and increases the expression of frataxin (FXN). A derivative of SynTEF1 is now in clinical development as a treatment for FA (DT-216P2). With this fellowship, Dr Achari plans to build on this knowledge and design the next generation of SynGRs to work on the FXN gene. Her idea is that the same GAA binding molecule can be fused to small molecules that, through a mechanism different from that of SynTEF1, will relive FXN silencing and increase its expression. Dr Achari will design a library of such compounds and test which ones are best at increasing frataxin levels in cells. Together with identifying potential new therapeutics for FA, her work will provide mechanistic insights into the regulation of FXN and its reactivation.