Sunday, November 6, 2011

More hope than you can shake a stick at

Ok.  I've been reading a lot of questions about hope for other mutations, like F508 to see a great control drug similar to VX-770.  I know people are scared that the VX-809/VX-770 combo might not work and that it will send us back to the drawing board, tacking years and years onto the waiting time for a real change for that population.  I completely understand that concern and I feel like I need to try harder to make it clear how much hope you should have that this WILL HAPPEN.
Drug Discovery: High through-put screening
VX-770 was discovered through a process called high throughput screening, which is a technology powered with robots and supercomputers to scan a huge number of compounds very quickly.  They look for molecules that perform specific actions (like opening the gate for chloride ions in the example of VX-770) Before high throughput screening, researchers might be able to screen, let's say 100 compounds a year with old school techniques.  I'll go back to the burned out light bulb analogy I used before.  If you had to check every light bulb on the planet to discover a single burned out bulb, you would never find it in your lifetime...or in a million lifetimes.   High throughput screening changed the face of medical research.  It enables millions of compounds to be screened, in a relatively short amount of time.  Now, instead of going one light bulb at a time, they can check entire cities or even States at once.  It improves your chances exponentially.  Researchers will typically get their hands on a collection of compounds that someone sort of "owns."  Nearly all of the compounds being screened have never been used for any type of therapeutic purpose.  Remember, we are talking about millions or billions of potential compounds.  If a molecule is found that makes a little blip on their graph, they isolate it and take it to the lab.  This is where they tweak it chemically to see if they can turn that little blip into a big blip(bigger positive effect).  Then they can start testing it in the lab on epithelial cells to see how it affects the function of things like the cilia (those little hair like projections that sweep particles like bacteria off the surface of the cell.)  After lots of tweaking, the clinical trials process begins.  This is exactly what they did with VX-770.  

Other mutations:
One thing that blew me away at the Conference was how many other correctors already exist and are being tested.  We aren't just talking about the Vertex compounds here.  They have already discovered many (probably tens or hundreds) of compounds that make those initial small blips.  In some of the talks, I would see a slide present 10 correctors I had never ever heard of and how they are working(or not) to fix those two F808 misfolding problems I mentioned in an earlier blog.  They are also in the process of screening already existing drugs to see how they act on mutations. They have found some compounds that exibit corrector action for F508.  This is directly from something presented at the conference:

"We constructed a novel high throughput cell based assay to test the ability of small molecules to restore F508 CFTR trafficking to the plasma membrane.  In a screen of known drugs we identified the non-steroidal anti-inflammatory (NSAID) drug Ibuprofen.  Ibuprofen has previously been reported in small-scale clinical trials to improve the symptoms of CF and prolong lung function in CF.  However, this is the first report of ibuprofen being a corrector for CFTR.  Ibuprofen increased the cell signal up to 27% of wild-type signal." **Disclaimer-Talk to your damn Dr. before you run out and start an ibu regimen!  This is a trial!

Also remarkable is that they are finding a wide variance in how people with F508 respond to corrector compounds.  They will have a population of double F508 having a wide range of responses...some very good, indicating that there might be other genetic markers at work, making it more therapeutic for that subgroup.  So what I'm trying to say is that even if the VX-809/VX-770 combo isn't the magic bullet, it might be for another small subpopulation of F508 that have other genetic markers that enable it to work better in them.  What I'm saying is that if VX-809 doesn't work, there may be another compound already approved like ibuprofen that might be able to be combined with a potentiator and shave years off the clinical trial process.  I'm saying any one of those little blips might be tweaked just right and shoot the efficacy through the roof.  I'm screaming that the combo of two corrector compounds working synergistically on the two misfolding sites for F508 has been shown in the lab to restore up to 60-70% function in some cases(that is above and beyond how well VX-770 works for G551D)!!  I'm reminding you that with big time companies like Pfizer getting involved, they are bringing with them the databases of compounds that they own to be scanned for previously undiscovered treasures.  I believe with all my being that there is more hope about fixing this than you can shake a stick at!  I read one question the other day that prompted this blog and it was something like, "Someone tell me if there is any hope for F508 and I need a simple answer."  All I could think was, well do you want an answer or not, because it is not simple any way you slice it.  I realize that trying to understand the research can be daunting, but it is impossible if you don't even try.  I guess I just think it is worth it because the place (in my head) where I live now is where I wish you all could be. I'm not trying to sugar coat this or string anyone along.  This is something I believe with all my heart. You know, when VX-770 was in early development, everyone thought I was crazy for believing it could work.  I don't think I need to tell you who got the last laugh.   I cannot wait until next year's Conference in Orlando to see where they have taken this...I have no doubt that there will some failures, but more importantly...there will be some successes!  I think they are so far ahead of where many of the families seem to think. 

Just for fun, I'm posting a picture of a model of the CFTR protein.  It looks complicated, doesn't it?  My recommendation to you is that you join me in hope.  Please join me in believing.  I realize not everyone loves chemistry as much as I do, but isn't it worth sitting though a few lousy science classes if it gives you a ticket to that place in your head where you believe everything is alright??  And I hope I've made it clear that I'm happy to help/translate with this kind of info or help find someone else who can if I don't get it either.  It isn't simple...but WOW is it worth it!


  1. I wish I could just give you a giant hug for reassuring me past my wildest dreams that my son will get this miracle drug <3

  2. Thank you Rebecca for giving and explaining all this Information! Especially As our doctor here in Germany is always trying to tell us Not to get too excited...
    I always hated Chemistry, but I try to follow and understand as much as I can. And Yes! I am very excited! My daughter with CF is now almost 5 month old and I am sure She will fully Benefit from the drugs that will Be out there! :-)

  3. Great post! Thank you so much for sharing! I also have a 4 yr old with CF.

  4. You are truly amazing! Thanks once again for the wonderful info and for reassuring us that our hope is REAL!

  5. Thank you so much for posting all this information. While we are not 551's (del508) we are so happy for you. My license plate looks similar to yours but it's from Maine and it says "CURENCF". Can't wait until it says "CUREDCF."

    Trevor is 12 and we're hoping things change fast!

  6. Thanks for this breakdown!!! And thanks for the honesty!! :)

  7. Hi.
    I just had my two boys (26 and 2 months old) diagnosed 8 days ago. And yesterday we had the unbelievable news that they both have G551D. What a rollercoaster week.

    Do you have any more info about the infant trial? I am based in Europe, but the 2 trials were conducted in Ireland, which would work for us.