Correction of the F508del-CFTR Protein Processing Defect In Vitro by the Investigational Drug VX-809

Incurable diseases were the main problem in every decade. The twenty-first century is not an exception. The current article examines one of the irremediable sicknesses called cystic fibrosis. It is an inherited fatal disorder of the secretory function of the cells (Van Goor et al., 2011; Mayo Clinic Staff, 2012; National Institutes of Health, 2013). The disease damages the cells’ production of mucus, sweat, and digestive juices. The disorder harms cystic fibrosis’s transmembrane regulator’s (TR) gene. This gene impairs the function of afflicted TR, the special channel required for proper function of some organs (Van Goor et al., 2011). The illness makes fluids thick and sticky; that is why they do not function in a proper way (National Institutes of Health, 2013). Prognoses are not optimistic. Only with the recent improvements in treatments and screening of the disease, people can live longer now. Statistics says that almost all patients live until their 20s-30s, but only some of them their 40s-50s (Mayo Clinic Staff, 2012; National Institutes of Health, 2013). The treatment depends on what kind of problem or complication one has. The alternative way is to correct the function of the stricken transmembrane regulator with peculiar molecules (Van Goor et al., 2011). Van Goor et al. (2011) worked on the improvement of the ad hoc molecules’ strategy to cure people. For such purposes, doctors used drugs that work like correctors. One of the latest invented correctors was VX-770. However, it could only improve processes in the living organisms: measures of lung function and chloride transport in patients with the rare G551D defect. Statistically speaking, only 5% of humans with cystic fibrosis had that mutation. Thus, the authors tried to find the corrector that targeted the deformity in TR compelled by the F508del deviation. 90% of patients represent F508del transmembrane regulator’s mutation. The mutation worsens damaged TR processing in the endoplasmic reticulum. As a result, endoplasmic reticulum retains and degrades proteins, reducing the delivery to the cells’ surfaces. The primary target of scientists’ research work was to find peculiar corrector that could help people. Overall, the expected corrector had to target only patients with cystic fibrosis with the F508-del deviation (Van Goor et al., 2011). To reach that goal the scientists tried to synthesize better analogs of VRT-768. Then they checked the influences of the acid and the amine moieties independently. Consequently, they identified interesting facts. Such identification led to the discovery of VX-809. It was thought to correct proteins with F508del deviation. To check what VX-809 could do, the scientists had measured the fractional conversion of the core-glycosylated to the complex-glycosylated, and the maturation of TR form. After 24 hours of treatment with VX-809, serious improvements took place in the corrected cells compared to the thick cells. They proved that the effect occurred because VX-809 worked. Later, they found that the maximum effect of VX-809 could be reached after a 24-hour treatment (Van Goor et al., 2011). Nevertheless, at the same time, the authors found some pitfalls. VX-809 could not correct hERG or P-glycoprotein. The whole work led to the hypothesis that VX-809 was able to be combined with other correctors to improve results.

This memoir is a proof of the tremendous amount of research that the authors have done. However, there is no literature review in it. Notwithstanding, the research article has the reference list and in-text citations. 45 references speak for themselves. No doubt, those authors knew those books by heart. In general, articles in science journals follow a strict format, so there is usually not much attention to the literature review.

As it has been already mentioned, cystic fibrosis, for today, is an incurable disease. That is why one can say with certainty that this research is original and relevant to health issues existing today. Furthermore, its results can help to cure people and save lives. It should be mentioned that it is a huge step forward in pharmacology. It gives hope to patients with cystic fibrosis that one day it will be curable once and for all.

The authors utilized experimental type of the research. Van Goor et al. (2011) discovered VX-809 experimentally. Data analyzes required alternative way to show results. That is why figures and graphs presented the experimental data. Only at the end of the work, when results were ready, the authors discussed some theoretical hypothesis.

It is a high-level research work. However, it is not worth rating this work too high. The reason is that they have not processed with their pop-up theory before writing this article. The researchers considered the hypothesis that it was possible to combine VX-809 with other correctors and did not look at the problem from this angle. Although, one should not forget that the authors discovered a new corrector and gathered data needed to evaluate its importance. It is undeniable that the research was appropriate and significant.

Talking about practical use of the new corrector, it should be mentioned that VX-809 speaks for itself. The authors talked about how important this discovery was for patients and how they needed something like VX-809. This article describes the in vitro pharmacology of the invented corrector that has been advanced into clinical development for the treatment of cystic fibrosis (Van Goor et al., 2011). As a matter of fact, it is known that it can be a treatment for approximately 90% of the patients with this kind of gene mutation. 90% can now live more with new corrector’s medication. On the other hand, this article discusses such a fact as selectivity of the new medicine. The experiments explained that VX-809 could not correct normal or mutant forms of hERG or P-glycoprotein. Instead, VRT-325 and Corr-4a were able to improve the processing of any forms of hERG or P-glycoprotein. Nevertheless, they were worse than VX-809 for any transmembrane regulator’s mutations. Also, VX-809 could not correct other disease-causing proteins, including α1-antitrypsin Z mutant and N370S-β-glucosidase, but VRT-325 and Corr-4a could. The different selectivity of VX-809, VRT-325, and Corr-4a suggested that they might complement each other to correct transmembrane regulator’s illnesses (Van Goor et al., 2011). The research did not stop on reached results. It all led to the hypothesis that correctors could be additive and get better improvements in vitro or even in vivo. They explained why it was possible to combine correctors using VX-770 as an example of how it could help VX-809 improve proteins’ folding. Considering the problem from this angle, it makes perfect sense that further research may lead to a discovery of new treatment that can cure patients with cystic fibrosis.

Considering everything mentioned and highlighted in the article, it is possible to say that this article could be better. The authors added VX-770 to VX-809 to improve the open probability (P0) of the transmembrane regulator’s channel. VX-770 stimulated chloride transport in mutated human bronchial epithelial pretreated with medicines for 48 hours. As a result, chloride transport achieved meterage coincidence to 25% of levels in healthy human bronchial epithelial (Van Goor et al., 2011). These results came together with increase in Po in studied cells (Van Goor et al., 2011). Unfortunately, the authors did not examine how VX-770 or VX-809 could improve VRT-325 and Corr-4a correction. Those data could have made this article more informative and deeper.

Taking into consideration all pros and cons, another good aspect about this article is that writing is clear and straightforward. The researchers summarized, compared, and discussed a lot of experimental data and presented it mostly in figures and graphs. Such way of presentation is easy to understand and read. Huge reference list, summaries of methods and materials used, supporting information and even extra figures are included in this research work to enable readers to understand this topic as much as they want to. It is possible to allocate this presentation method as another good thing about this article.

Doubtless, the authors will continue the research. It is understandable that the research needs some improvements. More data required to discover new treatments or maybe even the possibility to cure people with cystic fibrosis. The scientists mentioned some hypothesis and theories and it will not be surprising if they go further and try something even newer. For example, after further optimization of VX-809 they will discover the different corrector that will cure all types of mutations discovered; or, maybe, VX-809 requires long-term treatments in vivo to work properly. Only further examinations will show the way to cure patients.

To end the discussion, VX-809 is different from other correctors by the significance of its improvements in cultures of F-508del human bronchial epithelial. It is extraordinary that VX-809 is selective in processing of cystic fibrosis’s transmembrane conductance regulators compared with other proteins. The scientists showed evidences that VX-809 worked by stimulating the proper folding of the mutated proteins. VX-809 allows F-508del proteins to go out from the endoplasmic reticulum, reach the surface of the cell, and act like healthy. What is more, fraction of afflicted transmembrane conductance regulators reached a better protein design and reticulum’s pathways did not recognize it as defective. Unfortunately, VX-809 cannot cure mutated genes and make them healthy. It is probably the reflection of the limit of corrector’s action. Although, it can be a sign that the chain needs further optimization to improve results. The possibility of complementation of invented medicines with each other is a good sigh. The scientists showed that VX-770, compared with VX-809, significantly improved data that VX-809 could provide only by itself. The results support the hypothesis of combining the corrector’s compounds to achieve better correction of F508del cystic fibrosis’s TR deviations. Besides, the authors included only few proteins in their research. Some of them used similar pathways as damaged TR (hERG-called mutations). Others were chemically related to TR (some kinds of P-glycoproteins). Also, of course, they studied few more proteins that used different pathways. The mechanism of the action of new medicines is not clear yet. This topic requires additional studies. The discovery of a new and selective cystic fibrosis’s TR corrector is convenient for the development of potential new therapies to treat gene defects in patients with the F508del cystic fibrosis transmembrane regulator mutation.