Triple potentiator combinations increase the functional correction of several CFTR gating mutants

Area of Science:

• Biochemistry
• Pharmacology
• Genetics

Background:

• Cystic fibrosis (CF) is caused by mutations in the CFTR gene.
• Trikafta (tezacaftor/ivacaftor/elexacaftor) is FDA-approved for ~300 CFTR mutations but has limited efficacy in some variants.
• A therapeutic gap exists for CFTR mutations with partial response to current therapies.

Purpose of the Study:

• To investigate if elexacaftor (VX-445) potentiator activity can complement ivacaftor (VX-770) and co-potentiators in partially responsive CFTR mutants.
• To develop novel co-potentiator compounds for enhanced CFTR functional restoration.
• To explore triple potentiation strategies for poorly responsive CFTR gating mutants.

Main Methods:

• Functional clustering of potentiator profiles.
• Testing potentiator additivity in gene-edited bronchial and nasal epithelia expressing specific CFTR mutants (G551D, N1303K, W1282X).
• Single-channel electrophysiology.
• Development of novel co-potentiator compounds.

Main Results:

• VX-445 represents a distinct potentiator class, showing additivity with VX-770 and co-potentiators across five CFTR mutants.
• This triple potentiation strategy was validated in gene-edited human epithelia and at the single-channel level.
• Novel co-potentiator compounds with low micromolar potency were developed.

Conclusions:

• Triple potentiation significantly enhances functional restoration of poorly responsive CFTR gating mutants.
• This approach offers novel therapeutic avenues for cystic fibrosis patients with limited response to existing treatments.
• Further development of co-potentiator compounds holds promise for addressing the therapeutic gap in CF.