Coffee with Bob and day 2 of NACFC

Today started off with the second Plenary Session, entitled CFTR2.  The CFTR2 project has a goal to identify and classify as many CFTR mutations as possible (they have close to 1900 different mutations identified now), and put that information into a database that can be easily accessed by both patients/families as well as researchers.  Beyond simply identifying mutations, CFTR2 will attempt to offer more clinical information on what is known about each of those mutations.  For example, some are associated with pancreatic sufficiency, or less severe lung disease.  It will be a place to go to find out all about each particular mutation.  This might not seem like much, but the CFF has worked hard over the years to gather extensive amounts of patient information through their patient registry program to be able to provide this type of clinical data correlated to mutation.  As we are learning--mutation matters, so this will be a wonderful resource that should be up and running sometime next year. 

Next, everyone went their respective ways to attend morning sessions.  I decided to attend a talk about  Gene Modifiers of CF Lung Disease.  Studies have shown variability in lung function between siblings and twins, indicating that other forces may be at work in determining the clinical outcomes.  Specifically, two sites on the chromosome were discovered to have significance in determining severity of lung disease.  It was a very technical talk, but I will try to boil it down.  One of the sites they found to be significant regulates cell death and the other site helps regulate the body's inflammation response.  They hope to be able to learn how to manipulate functions at these crucial sites, so that therapies might be developed to correct for alleles associated with more severe lung disease.  Understanding these types of modifying genes could help explain why two children from the same family can have drastically different "cases" of CF.  As we know, inflammation plays a huge role in CF.  Getting control over those inflammation genes would sure be nice...

I also attended a talk entitled: Antimicrobials in the CF Airways--How disease alters innate immunity.  This was an interesting session that showed how loss of CFTR function impacts the normal defense mechanisms in the respiratory tract.  Healthy individuals possess an "antimicrobial shield" that keeps the lungs from becoming infected.  That shield is missing or impaired in individuals with CF.  CFTR plays an important role in regulating airway surface liquid (necessary for mucociliary clearance).  Impaired bicarbonate secretion alters the pH of that airway surface liquid.  Lower pH reduces the "killing power" of the antimicrobials so that the body is unable to defend against something such as pseudomonas, which is an infection fairly exclusive to the CF pop.  They are using pig and ferret animal models to study the primary effects of loss of CFTR and will continue that line of research.

Genetic Suseptibility for CF-related Diabetes Identified by Genome-wide Association.  While there are similarities, CFRD is unlike type 1 or type 2 diabetes.  Diabetes develops frequently in people with CF, occuring in 25-50% of adolescents and adults with CF.  CF related diabetes develops over time as the capacity of pancreatic beta cells to secrete insulin declines over time.  They used a continuum to explain how CFers can exhibit transient and significant drops in insulin sensitivity when ill or having a pulmonary exacerbation.  In other words, it isn't a clear case of diabetic or not...it is more like diabetic while taking steroids or during a flare-up, and then a swing back toward more normal function when well.  These swings between good function and bad function go on over time until the patient is chronically on the bad side, when interventions typically begin.  The mechanisms of the development of CFRD are not well known, but several genetic markers have been located as risk factors in the development of type 2 diabetes(totally unrelated to CFTR or what genotype of CF you have).  CF patients who also had these markers, were more likely to develop CFRD.  With that information in mind, individuals with CF who have a family history of type 2 diabetes were found to be 3X more likely to develop CFRD than those who don't.

After lunch I attended my coffee meeting with Dr. Beall and the VP of Commications for the CFF, Marybeth McMahon.  This time, I had my act together.  They were both very interested in how issues are perceived within the community and what they can do to better address or educate about those issues.  They wanted news from the inside.  I spoke frankly about the impatience and worry over the success of the combination Vertex trials and the bittersweet nature of a breakthrough like VX-770 for people who won't benefit from this right away.  They are acutely aware that time is of the essence and were genuinely interested in what they could do (besides hurry up with that damn cure!) to address the concerns of those still waiting.  For me, this topic has caused me many sleepless nights.  There is a certain amount of guilt that I just can't shake about having the child that will benefit first.  But at the same time, I know that VX-770 will likely be a part of the treatment regimen for many mutations of CF (as they will require both corrector and potentiator compounds), so it is absolutely a good thing for everyone that it is approved.  I think there is also a misconception that the F508 mutation has been put in the backseat while G551D has taken all the focus.  As I will explain, the dysfunctions of the F508 mutation are numerous and complex.  The G551D mutation is functionally, one of the easiest to correct for and VX-770 was discovered while screening millions of compounds with robots and supercomputers.  It was not, by any means, an intentional snubbing of fixing the most common mutation...rather, a place to start.  The "potentiating" action of VX-770 is a single piece of a larger puzzle for F508.  I think it is an appropriate time to revisit the new information I learned yesterday about fixing F508.  They now know that there are 2 distinct and separate problems that occur in F508 that cause misfolding of the protein.  Misfolded proteins do not mature and travel to the cell membrane.  If they only correct for one misfolding problem, they seem to top out at about 15% retrieval of CFTR function for F508 patients, which isn't enough to have clinical benefits.  The good news is that they've shown that when both of these misfolding problems are corrected for in the lab, the two correctors work synergistically (the action of the 2 correctors together is greater than the sum of the two individually), producing the clinically significant outcomes we all want.  Blah blah blah...So what does that mean for VX-809 and VX-661?  I'm afraid they still aren't sure.  From what I've learned since I've been here, I have a gut feeling that the VX-809/VX-770 combo alone won't be enough.  A third compound (or different corrector) will need to be factored in to correct for the second misfolding site.  This is just my opinion.  

Highlights and tidbits:  During our coffee today, Bob said "When VX-770 is approved in April...."  He sounded pretty damn sure that next April is when it is all going to happen.  I asked about the pediatric trial and he says it will not be placebo controlled, and of fairly short duration (3 months).  This trial is about safety and appropriate dose for kids, not proof that it works.  I asked him when it will begin enrollment and he promised to find out something more concrete than "sometime in 2012" and report back to me within the next 2 days.  Then he invited me the dinner reception this evening for Conference Speakers and Fellows as his personal guest.  That's right...it's a date.  Naturally I accepted.  He also went on and on about the book and how much he loved it.  He even brought it to registration this morning to show his friends.  He is very proud of it :)   After coffee, I went to film "my dream for CF."  I was so nervous.  I hope I did alright.  Of course, it rained here today so my hair was all funky. I'm sure that I'm leaving things out, but I will write more either tonight or tomorrow.  Right now, I've got to get ready to meet my new boyfriend Bob for our date!   Once again, sorry for the screw-ups, I'm trying to get this updates done FAST!