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Drug research and development » Pre-clinical development » CFTR-modulating therapies (mutation-specific therapies)

CFTR-modulating therapies (mutation-specific therapies)

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This section summarises the development of therapeutic approaches to target different classes of CFTR mutations.

Class I mutations targeting agents (read-through agents)

Class I mutations result in defective protein production and no or little functional CFTR protein being produced. These mostly include nonsense mutations, which lead to a premature stop or termination codon. This produces either a truncated non-functional CFTR, or prevents full translation of mRNA so that no CFTR protein is expressed.1,2

Other class I mutations included canonical splice mutations and chromosomal deletions, also resulting in no function protein production. Agents targeting this type of mutation act to restore production of the functional protein.

One strategy is to target the premature stop codons. An example of this approach are agents that act to ‘read-through’ the stop codon, to facilitate/restore full translation and synthesis of the full protein.1,2

Ataluren (PTC124)

Class II mutations targeting agents (correctors)

Class II mutations result in defective protein processing, where the misfolded CFTR protein is recognized by the cellular machinery and degraded. Agents targeting this mutation are primarily chemical and molecular chaperones that promote protein folding and so facilitate the CFTR to avoid cellular machinery and reach cell surface.1 Mutant CFTR protein may have defective regulation when rescued to the cell membrane. When this is the case, potentiators (see Class III mutations targeting agents (potentiators)) in combination with correctors are indicated.

Lumacaftor (VX-809)

Class III mutations targeting agents (potentiators)

Class III mutations result in defective protein regulation, leading to impaired CFTR protein channel gating. Agents targeting this mutation class work by increasing the opening of the CFTR channel.1


Ivacaftor (VX-770)

Class IV mutations targeting agents

Class IV mutations result in reduced chloride ion flow through the ion channel. As potentiators may increase wt CFTR gating, this strategy could also be used to increase function in class IV mutations. The trial results in patients with the R117H mutations that has characteristics of a class III as well as a class IV mutation, partly validate this approach.3

Class V mutations targeting agents

Class V mutations affect protein production, resulting in reduced amounts if both aberrant and normal CFTR protein produced. Potentiators could be of use in patients with these mutations. Another option would be to target these mutations with the use of anti-sense oligonucleotides (AONs).1 Antisense oligonucleotides correct splicing defects through exon skipping.4

Class VI mutations targeting agents

Class VI mutations result in decreased retention and/or anchoring of the protein at the cell membrane, resulting in reduced surface stability of the CFTR protein at cell surface. Agents targeting these mutations should enhance retention and anchoring of the CFTR protein at the cell surface. This may include targeting cell signalling processes, such as activating Rac-1 signalling to encourage anchoring to the actin cytoskeleteon.1


Compounds with dual corrector and potentiator activity5

A drug with dual function may be able to increase the trafficking of the CFTR protein to the membrane as well as increase the activity of the ion channel at the cell surface.5

  1. Bell SC, De Boeck K, Amaral MD. New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol Ther 2015;145:19-34.
  2. Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med 2013;1:158-63.
  3. ClinicalTrials.Gov USNIoH: Study of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Have the R117H-CF Transmembrane Conductance Regulator (CFTR) Mutation (KONDUCT). 2015. (Accessed 31 March, 2015, at
  4. Siva K, Covello G, Denti MA. Exon-skipping antisense oligonucleotides to correct missplicing in neurogenetic diseases. Nucleic Acid Ther 2014;24:69-86.
  5. Rowe SM, Verkman AS. Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harb Perspect Med 2013;3.