Phenotyping Rare CFTR Mutations Reveal Functional Expression Defects Restored by TRIKAFTA^TM

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations H609R and I1023_V1024del are linked to severe lung disease.
• Existing CFTR therapies lack approval for these specific mutations due to unknown molecular defects.

Purpose of the Study:

• To investigate the impact of H609R and I1023_V1024del CFTR mutations on protein processing and channel function.
• To evaluate the efficacy of current and novel CFTR modulators for these rare mutations.

Main Methods:

• HEK293 cell transfection with H609R and I1023_V1024del CFTR variants.
• Assessment of CFTR protein processing and channel function.
• In vitro testing of lumacaftor, ivacaftor, and the triple combination (tezacaftor, elexacaftor, ivacaftor).

Main Results:

• H609R and I1023_V1024del mutations, similar to F508del, impaired CFTR protein processing and function.
• Lumacaftor and ivacaftor showed limited efficacy in correcting these mutants.
• The triple modulator combination TRIKAFTA™ significantly rescued trafficking and function of both H609R and I1023_V1024del CFTR variants.
• The presence of the I148T mutation did not further diminish the function of I1023_V1024del-CFTR.

Conclusions:

• H609R and I1023_V1024del CFTR mutations result in processing and functional defects.
• TRIKAFTA™ demonstrates potential as a therapeutic option for patients with H609R or I1023_V1024del mutations, including those with the I148T variant.