**Abstract**

Individuals with cystic fibrosis (CF) have seen a substantial change in their life expectancy since the introduction of coordinated multi-disciplinary care. This is expected to continue with the recent availability of treatment options that focus on targeting the underlying genetic defect. Two different approaches to altering the consequence of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene include "genetic medicines", in particular gene therapy, and CFTR modulator agents. Gene therapy requires further development prior to it being a treatment option because to date the best clinical outcomes are that of a reduction in the rate of lung function decline. Modulator therapies on the other hand have provided exciting results in both clinical trials and real-world settings. Potentiator agents alter dysfunctional ion channel gating and are suitable for gating mutations. Corrector agents target abnormal protein trafficking. The combination of potentiator and corrector therapy provides options for homozygotes with the commonest mutation Phe508del and for those with Phe508del and some residual function mutations. Newer modulator therapies are in continued development with progressively impressive outcomes. It is likely that future CF care will comprise of personalized strategies with the focus centered upon an individual's specific mutations.

**Keywords:** cystic fibrosis, CF pathophysiology, CFTR modulator therapy, gene therapy

### **1. Introduction**

Cystic fibrosis (CF) is an autosomal recessive condition that results from mutations in the cystic fibrosis transmembrane conductor regulator (CFTR) gene located on the long arm of chromosome 7. The gene was identified 30 years ago and since then over 2000 CFTR mutations have been discovered with more than 300 known to be disease causing [1, 2]. The commonest mutation is Phe508del (F508del; c.1521\_1523delCTT), where a phenylalanine is substituted at position 508 on chromosome 7. Worldwide approximately 80–90% of individuals with CF have at least one copy of the Phe508del-CFTR mutation, although mutation rates varying depending upon the population cohort [3–5].

CF is a multi-system disease with the highest disease prevalence being in Europe, North America and Australia. There are approximately 80,000 people with CF worldwide. The disease is characterized by chronic airway infection, pancreatic insufficiency and malnutrition, diabetes, liver disease, absent vas deferens and premature death.

Due to the multi-system nature of the disease, treatment has classically focused on therapies and systems of care that aim to improve salt and fluid balance and nutritional status, alongside reducing airway inflammation and lung parenchymal destruction. These multi-disciplinary management approaches have been instrumental in the improvements seen in life expectancy. The median predicated survival of an individual born today with CF is 47 years, compared with 20 years at the time when CFTR was discovered in 1989 [2]. However, to have a true impact upon the management of these patients and to alter the disease trajectory, treatment options needed to also include approaches targeting the underlying genetic mutation.

This chapter will include a review of the structure of the CFTR protein, its biosynthesis and the pathophysiology of CF so as to provide a basis from which to discuss the various therapeutic strategies that have more recently been developed for modulating CFTR protein function. Also, a discussion regarding gene therapy will be included so as to enable contrasts and comparisons to be made between the different therapies being evolved to address the underlying genetic defect in CF patients.
