Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine

Abstract

An improved understanding of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein structure and the consequences of CFTR gene mutations have allowed the development of novel therapies targeting specific defects underlying CF. Some strategies are mutation specific and have already reached clinical development; some strategies include a read-through of the specific premature termination codons (read-through therapies, nonsense mediated decay pathway inhibitors for Class I mutations); correction of CFTR folding and trafficking to the apical plasma membrane (correctors for Class II mutations); and an increase in the function of CFTR channel (potentiators therapy for Class III mutations and any mutant with a residual function located at the membrane). Other therapies that are in preclinical development are not mutation specific and include gene therapy to edit the genome and stem cell therapy to repair the airway tissue. These strategies that are directed at the basic CF defects are now revolutionizing the treatment for patients and should positively impact their survival rates.

Keywords: CFTR; CFTR modulator; cystic fibrosis; gene therapy; ivacaftor.

Figure 1

Variable CFTR protein defects causing CF disease and the corresponding therapeutic strategies.

Figure 2

In vivo and ex vivo strategies of mutation independent approaches. Modified nucleic acids (upper panel – nucleic acids) are delivered to cells by various methods (second upper panel – vehicles). In ex vivo cell therapy, stem or progenitor cells are derived from the subject, and after the required modification, the cells are transferred back into the patient (lower left part of the panel). In in vivo DNA/RNA editing therapy, a direct transfer of genes to the patient is performed by viral or non-viral methods (lower right part of the panel).

Figure 3

The CRISPR/Cas9 system. Cas9 endonuclease binds to the target site using a guide RNA to precisely cut DNA allowing genome editing. CRISPR/Cas9 may drive to gene correction or DNA insertion through HDR or modify the sequence through NHEJ, which results in insertions/deletions.