Indagini genetiche di nuova generazione e terapia personalizzata: L'esempio vincente della Fibrosi Cistica

Cystic Fibrosis (CF) is a complex genetic disease. The causative gene is the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Although monogenic, this disease has a complex genotype - phenotype relationship. Several factors originate this complexity. The most important are the high number of CFTR mutations, the difficulty of a full mutational analysis, the incomplete knowledge of the functional effect of mutations and their variable outcome, as well as the existence of modifier genes (different from CFTR) that modulate the clinical severity. This complexity impairs the diagnostic, prognostic and therapeutic ability. Next generation sequencing approaches represent a revolution in genetic studies, because of their rapidity, low-cost and high-throughput. They allow a near complete mutational characterization of CFTR mutated genotypes, with the potentiality of studying several other genes involved in CF clinical modulation. These methods are a perfect precondition for personalized therapeutic approaches of CF. In fact, a full genetic characterization appears to be crucial to applying mutation-specific therapies. Drugs specific for some CFTR mutations are already in clinical practice or in phase 3 trials. The enlargement of the CF personalized therapy to an increasing number of mutated genotypes needs a growing knowledge of structural and functional defects of CFTR. The synergy between next generation genetic approaches, the enhancement of the comprehension of molecular mechanisms of CFTR mutations and the spreading of personalized therapies, are revolutionizing the cure of CF.