Cystic fibrosis: current therapeutic targets and future approaches

Abstract

Objectives: Study of currently approved drugs and exploration of future clinical development pipeline therapeutics for cystic fibrosis, and possible limitations in their use.

Methods: Extensive literature search using individual and a combination of key words related to cystic fibrosis therapeutics.

Key findings: Cystic fibrosis is an autosomal recessive disorder due to mutations in CFTR gene leading to abnormality of chloride channels in mucus and sweat producing cells. Respiratory system and GIT are primarily involved but eventually multiple organs are affected leading to life threatening complications. Management requires drug therapy, extensive physiotherapy and nutritional support. Previously, the focus was on symptomatic improvement and complication prevention but recently the protein rectifiers are being studied which are claimed to correct underlying structural and functional abnormalities. Some improvement is observed by the corrector drugs. Other promising approaches are gene therapy, targeting of cellular interactomes, and newer drugs for symptomatic improvement.

Conclusions: The treatment has a long way to go as most of the existing therapeutics is for older children. Other limiting factors include mutation class, genetic profile, drug interactions, adverse effects, and cost. Novel approaches like gene transfer/gene editing, disease modeling and search for alternative targets are warranted.

Keywords: CFTR; Chloride; Hereditary; Respiratory; Sweat.

Fig. 1

The main pathophysiological dysfunctions and treatment modalities for CF patients. Inner trapezoid boxes depict the pathophysiological abnormalities and outer rectangular boxes depict the main treatments. The texts connecting the outer boxes show non-pharmacological management

Fig. 2

Depicting the action of Orkambi (lumacaftor + ivacaftor) and other agents in cystic fibrosis. Orkambi is a combination of two drugs which acts by a two-step method. Lumacaftor assists in moving the defective protein to its correct location and ivacaftor rectifies the gate opening time and enhances its activity eventually increasing the conductance of chloride ions followed by water. Read through agents for example Ataluren increase read through of Premature Termination codon enhancing production of immature protein. Possible “Corrector” drugs act on post translational modifications to increasing stability and reducing degradation by binding to various domains of CFTR. p-TM post translational modifications, GB golgi bodies, ER endoplasmic reticulum