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Innovative Therapeutic Strategies for Cystic Fibrosis: Moving Forward to CRISPR Technique


Innovative Therapeutic Strategies for Cystic Fibrosis: Moving Forward to CRISPR Technique

Michele Marangi et al. Front Pharmacol.


One of the most revolutionary technologies in recent years in the field of molecular biology is CRISPR-Cas9. CRISPR technology is a promising tool for gene editing that provides researchers the opportunity to easily alter DNA sequences and modify gene function. Its many potential applications include correcting genetic defects, treating and preventing the spread of diseases. Cystic fibrosis (CF) is one of the most common lethal genetic diseases caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although CF is an old acquaintance, there is still no effective/resolutive cure. Life expectancy has improved thanks to the combination of various treatments, but it is generally below average. Recently, a significant number of additional key medications have become licensed in Europe for the CF treatment including CFTR modulators. But innovative genomically-guided therapies have begun for CF and it is predictable that this will lead to rapid improvements in CF clinical disease and survival in the next decades. In this way, CRISPR-Cas9 approach may represent a valid tool to repair the CFTR mutation and hopeful results were obtained in tissue and animal models of CF disease.

Keywords: CRISPR gene editing; CTFR mutation; cystic fibrosis; gene therapy; ivacaftor; lumacaftor.


Comparative representation of CRISPR-Cas9 and CRISPR-Cpf1-mediated genome editing. The gRNA directs endonuclease Cas9 (A) to the target DNA sequence (blue) where it induces a double-strand break, leading to a sequence deletion. Cas9 uses a structural region of gRNA as a handle (red) and a variable targeting region (green) which identifies the target sequence to match and cleave. Cas9 can be specifically directed to the any target site of genome simply by modifying the sequence of the gRNA. Cpf1 endonuclease (B) contains a shorter and single identified nuclease domain (CRISPR-RNA), in contrast to the two nuclease domains present in Cas9. Cpf1-crRNA efficiently cleaves target DNA without the requirement for any additional RNA species. Cpf1 generates a staggered cut, in contrast to the blunt ends generated by Cas9. In both cases, the DSBs are subsequently repaired by two major cellular mechanisms, non-homologous end joining (NHEJ) and homology-directed repair (HDR).

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