EVALUATION OF THERAPEUTIC STRATEGIES TO CORRECT THE BASIC DEFECT IN PRIMARY CILIARY DYSKINESIA

The cells lining the airways in the respiratory system are provided with microscopic cilia whose beating allows the transport of mucus. Primary ciliary dyskinesia (PCD) is an inherited disease in which the function of cilia is altered. Consequently, PCD patients are unable to expel the mucus, which remains trapped in the airways creating a favorable environment for bacterial colonization.  The ensuing infections progressively damage the lungs.  Presently, there are no effective therapies to restore cilia beating in PCD.  Our project aims at evaluating the efficacy of two different approaches to correct the basic defect.  For the first approach, we will consider so called “nonsense” mutations, which are present in most genetic diseases and result in the production of truncated proteins. In the specific case of PCD, nonsense mutations impair the synthesis of one of the proteins that are essential for cilia function.  Our proposal is to use nasal epithelial cells from PCD patients to test drugs that have been already shown to be effective on nonsense mutations in other genetic diseases.  For the second approach, we will test the possibility to correct the PCD basic defect by treating cells in vitro with a “therapeutic” messenger RNA (mRNA) carrying the genetic information to replace the mutant protein with the correct one.  The results obtained in our experiments, focused on a selected panel of mutations and genes, will provide the basis for new advanced projects to evaluate therapeutic approaches for all PCD patients.