Repurposing CFTR correctors in Allan Herndon Dudley syndrome

Allan Herndon Dudley syndrome (AHDS), cystic fibrosis (CF), sarcoglycanopathy and Brody disease (BD) have nothing in common by the genetic and clinical point of view. Nevertheless, many AHDS subjects share with sarcoglycanopathy, BD and CF patients the molecular mechanism responsible for the loss of function of the mutated protein causing the disease. There is strong evidence that CFTR correctors, developed to treat CF are effective also in sarcoglycanopathy, BD and other pathologies. On this base, we propose to evaluate the efficacy of a panel of CFTR correctors in rescuing mutants of MCT-8 conserving a residual functionality. After a screening in cellular models, the most promising correctors will be validate in human pathologic cells deriving from inducible pluripotent stem cells (iPSCs) reprogrammed from fibroblasts, donated by AHDS subjects. Even though not all the MCT-8 mutations have been yet tested for functional activity, we estimate that about one quarter of AHDS patients may benefit from this pharmacological strategy.