However if we aimed to functionally characterize most CFTR

However, if we aimed to functionally characterize most CFTR mutants, then it is also important to determine how to measure CFTR activity with a rare mutation when testing corrector candidates and how to take into consideration the genotype of the epithelial CF model cells. In other words, if we want to personalize future treatments for CF patients, would it be necessary to systematically study most CF-related mutations or group of mutations during pre-clinical phase, and if the answer is yes, then how? In this issue of , a research group led by Margarida Amaral () described a method to functionally characterize the activity of CFTR in human primary lung akt inhibitor by measuring the forskolin plus genistein-inducible equivalent short-circuit current in perfused open-circuit Ussing chamber (forskolin and genistein being pharmacological stimulators of CFTR). This study provides important information. The authors evaluated and compared the efficacy of correctors lumacaftor (VX-809) and its analogue C18 on epithelial cell preparations obtained from donors with different CF genotypes — homozygous for F508del, A561E or heterozygous N1303K/G542X, F508del/G542X, F508del/Y1092X. This strategy allowed them to compare, using a robust functional assay, different CFTR mutations in their native cell environment. Although they observed great variability in VX-809 responses among patients, they were able to discriminate CFTR mutants positively responding to the correctors such as A561E and Y1092X and those that failed to respond, such as N1303K. They also compared the efficacy of the correctors and again found differences for a given mutation. In principle, the protocol used by . is simple and can be implemented in many research laboratories worldwide, but it is not a common practice to use human bronchial epithelial cells with different genotypes because such material is rare. It is usually a long process to obtain enough patient samples and enough epithelial cell quantities within the tissue sample to complete a study and collaboration between transplantation and research centers are generally complicated to set up. These results are thus telling us that not only might it be important to use human primary epithelial cells with various genotypes but it might equally be important to test several correctors for each CFTR mutant due to different mechanisms of action. Therefore, whereas the study of confirms the feasibility of exploring how CFTR might work with different mutations and with the best front-runner CF correctors, if the future for the disease is to tailor an appropriate pharmaceutical product, then it will require a great amount of effort to correlate drug effect with specific CF mutations. Conflicts of interest
Sickle cell disease (SCD) comprises a group of genetic disorders in which the red blood cells (RBCs) produce abnormal sickle haemoglobin (HbS) that can polymerise when oxygen concentrations are low. The clinical manifestations of SCD are numerous, and vary from patient to patient, but recurrent vaso-occlusive processes can cause significant organ damage, resulting in increased morbidity and mortality in these individuals (). Polymerised HbS confers a characteristic sickle shape to the RBC, in association with other cellular alterations; furthermore, these RBCs are more likely to rupture, releasing damaging cell-free haemoglobin (Hb) into the circulation (haemolysis), with significant consequences that include vascular nitric oxide (NO) consumption and oxidative stress (). Newborn and very young infants with sickle cell anaemia (SCA) still produce significant amounts of foetal haemoglobin (HbF), the Hb that is made during intrauterine life, although this HbF production will begin to decline after the first few months due to the Hb-switching process (). As high concentrations of HbF inhibit the polymerisation of HbS, young infants are asymptomatic and are generally thought to display little in the way of pathophysiological alterations.