Therapy with Kaftrio (or ETI) brings clinical benefits to people with cystic fibrosis (CF), however, at the molecular level it only restores 50% of the function of the mutated F508del-CFTR channel: impaired mucus secretion, infection and inflammation therefore persist in people with CF. 
The PI3Kγ mimetic peptide (PI3Kγ MP) may enhance the efficacy of ETI by acting as a stimulator of cyclic AMP (cAMP), a metabolite that acts as a messenger and is crucial for CFTR regulation. Indeed, increasing cAMP levels could in turn optimise the efficacy of ETI, further improving CFTR function and clinical outcomes for people with CF.

CFTR activity assessments were performed on primary bronchial epithelial cells derived from patients with F508del/G542X mutations; cells were treated with ETI and PI3Kγ MP, and CFTR-dependent chloride secretion through the CFTR channel was measured.
To analyse the peptide’s mechanism of action, biochemical techniques were used: experiments were performed to quantify the CFTR channel in the plasma membrane and to assess its stability over time by monitoring protein degradation rates. In the cells analysed, it was observed that treatment with ETI and PI3Kγ MP increased total CFTR activity by 25% compared to ETI alone. This combination doubles CFTR stability, leaving 67% of the channel undegraded after 6 hours of protein synthesis blockade (compared to 30% with ETI alone). 
Finally, protein changes in response to PI3Kγ MP treatment were studied, identifying a protein, called PKD1, which acts as a key mediator of the stabilising effect of PI3Kγ MP.

PI3Kγ MP thus acts as an effective stabiliser of CFTR, increasing the channel’s total activity, density and membrane stability. 

Further research will be needed to validate the compound’s effect and mechanism of action on other CF genotypes, i.e. other combinations of CFTR gene mutations.