cystic fibrosis mutations are placed into different classes, depending on HOW the CFTR protein is dysfunctional in the cell. Researchers are looking at two major concepts when classifying:
Think of it as a piece of origami. Every single fold must be made correctly, and in the right order, or it will get crumpled up and thrown in the trash. DF508’s first problem is that it gets misfolded in nucleotide binding domain 1 (NBD1). Technically, a base pair is missing from the genetic sequence, which is why it is sometimes called a “deletion” mutation. Anyway, correctors like VX-809 work to chemically fill that deletion and restore the folding mechanism. I am hopeful because the amount of protein that they could restore through combination treatment was dose dependent (more VX-770, more CFTR), and also, that they never reached a ceiling or peak on clinical improvement in the short amount of time that patients were on the combo (only 1 week), so they are truly unsure what pumped up dosages might achieve. VX-809 degrades the action of VX-770, so when the two drugs are combined, they found that they needed to increase the normal dosage of VX-770 to get the best effects. I am curious and hopeful that a higher dosage combination might be able to reach that critical threshold of benefit and proceed to phase 3 clinical trials. In vitro (lab), they were able to achieve a 35% restoration with the combo, so it has a real chance. The ongoing clinical trial will determine if this same restoration can be reached when actually administered to live people. If this combo were to succeed and reach the market, it is estimated for 2016.
This interface problem can also be improved with a different type of corrector compound, designed to stabilize this site. They found that when two different corrector compounds with different actions(one to fix misfolding, one to stabilize interface) were combined, they worked synergistically-- in other words--the combined result is greater than the sum of the two individually. This means you might get 20% restored with one corrector alone, and 20% out of the other corrector alone, but when combined…20% + 20% = 70% or more CFTR restoration!
VX-770 will absolutely be a part of this combination, because even when DF508 proteins fold and assemble properly—they also exhibit a gating defect if they manage to make it to the cell membrane. This is where VX-770 comes in. VX-770 works to open ANY CFTR that makes it to the cell membrane, thereby overcoming the gating defect. DF508 is also suspected to suffer increased cell turnover/premature cell death (defect similar to class 6 mutations) at the cell surface, further reducing the ability to transport Chloride. So let’s review all the different issues that must be overcome to restore function of the DF508 mutation:
One final note for Class 1 or stop mutations. I sense the frustration with the lack of data on the final Ataluren trial. 10% of CFers have a mutation in this class and are curious to see whether this is a viable option or not. I don’t have any inside data on the effectiveness of Ataluren alone, but one presenter at the NACFC talked at length about the lab data that VX-770 might be combined with a drug to promote translational read-through of the protein (what Ataluren is supposed to do) to increase Chloride transport activity. I guess I wanted to include this data because even if Ataluren alone doesn’t prove to be the magic bullet for nonsense mutations, that doesn’t necessarily mean back to the drawing board. VX-770 may be able to be combined with a drug like Ataluren to increase the CFTR rescue for this mutation class. Because VX-770 is already FDA approved, it would shave years off the clinical trial process, so that is great news.
You can check out a lot of this information for yourself in the first Plenary session at the NACFC last fall: http://www.cff.org/research/NACFC/2011NACFC/
Additional information was taken from my notes from:
Speaker Steven Rowe from University of Alabama at Birmingham and John Boyle from John's Hopkins
|Dr. Thomas began working on the molecular pathology of cystic fibrosis as a postdocatoral fellow at Johns Hopkins University. In 1993, he moved to UT Southwestern where he is now a professor of Physiology. His group is focused on elucidating the molecular basis of CFTR function and dysfunction with the goal of developing improved, targeted therapies. Current efforts include studies of the folding of CFTR and its interaction with other proteins in the membrane.|