Since 2019, a triple therapy has been available in the United States to treat cystic fibrosis. Its results are spectacular, but its precise mechanism of action remained unknown until then. Work by Inserm has just lifted the veil on this operation.
An article to be found in the Inserm magazine n°55
« Some treatments work well, but it’s unclear exactly how. This observation, stated by Stefano Marullo, research director Inserm at the Cochin Institute in Paris, perfectly illustrates the case of tritherapy against cystic fibrosis (Kaftrio®). Deployed since 2019 in the United States, and now accessible from the age of 6 in France, this drug is very effective. ” The work we have done explains why two of the three compounds in this pharmaceutical cocktail are beneficial for patients “, rejoices the researcher.
Cystic fibrosis is due, in the vast majority of cases, to a mutation that affects the CFTR gene. Because of this anomaly, the protein produced from this gene cannot reach its normal final destination: the cell surface. She gets stuck inside, in a compartment called endoplasmic reticulum. The protein cannot therefore play its physiological role and this results in dysfunctions responsible for the symptoms of the disease (breathing difficulties, increased risk of infection and damage to digestive functions).
Dose-dependent surface transfer
« Our laboratory seeks to understand how the proteins present on the surface of our cells are regulated. This is how we came to work on CFTR “, reports Stefano Marullo. At the level of the endoplasmic reticulum, another protein, PRAF2, plays an important role in the retention of the CFTR protein: the first binds to the second just before their transfer to the cell surface. ” Nevertheless, we have shown that PRAF2 interacts identically with the CFTR protein, whether it is mutated or not. “, specifies the researcher. It is therefore that the problem of transfer lies upstream. ” This transfer is dose-dependent “, he continues. It takes a sufficient amount of CFTR accumulated at the exit sites of the reticulum to trigger it. ” We have shown that the mutated version of CFTR accumulates there in smaller quantities, because it is previously recognized as abnormal by the body, which tries to get rid of it. »
On the strength of these discoveries, the researchers wanted to know if they had a link with the functioning of triple therapy, which has been revolutionizing the prognosis of children with cystic fibrosis for several years. ” These treatments are developed by screening molecules: we test thousands of them and select those that have a beneficial functional effect, without necessarily knowing the exact mechanism involved. We therefore had the idea of checking whether the compounds of this drug interacted with PRAF2. » Bingo! There is a link: one of the compounds of the triple therapy (tezacaftor) stabilizes the mutated version of CFTR. It is thus less likely to be eliminated by the body and is present in greater quantity at the exit sites, where it binds to PRAF2. A second compound (elexacaftor) inhibits the binding between CFTR and PRAF2, which decreases the retention of CFTR in the reticulum and increases the dose transferred to the cell surface.
These results could also be used to improve the understanding of other pathologies also due to a problem of protein transfer to the cell surface, such as diabetes insipidus or familial hypocalciuric hypercalcemia. ” We will be able to study the role of PRAF2 in these pathologies », message Stefano Marullo.
Stefano Marullo is leader of the Receptor Signaling and Molecular Scaffolding team at the Cochin Institute (unit 1016 Inserm/CNRS/University of Paris), in Paris.
Source : K. Saha et coll. Pharmacological chaperone-rescued cystic fibrosis CFTR-F508del mutant overcomes PRAF2-gated access to endoplasmic reticulum exit sites. Cell Mol Life Sci., September 27, 2022, doi: 10.1007/s00018-022–04554‑1