Response Guided Therapy

I haven't written much lately for several reasons:
1) The "On Par for a Cure" golf tournament for the CFF was May 11th, and was all consuming,
2) Nothing has changed with Brady, he is still holding steady at a level I would call "AWESOME," and I assume that people aren't super interested unless I have something important to say. 
3) My head has been a mess.   I want to preface this whole entry by saying: I am not a CF expert.  I am a stay-at-home mom of a 4 yr. old son with CF.  I happen to have a background in Chemistry and have learned a lot on my own about CFTR science.  This is all my opinion. 

Things are going great for Brady on Kalydeco.  What could I possibly have to worry about?
In some ways I am extremely happy.  I am on top of the world that Brady has Kalydeco and is doing as well as we had hoped, so why am I still laying awake at night?  Why do I feel so fortunate, yet so tortured at the same time?  I'm not going to dance around it and try to be politically correct, I'm just going to say it--THERE IS A MUCH LARGER POPULATION OF CFers THAT COULD BENEFIT FROM KALYDECO, BUT DON'T HAVE ACCESS TO IT.  Any CF patient who successfully transports any quantity of CFTR to their cell surface would respond to treatment with Kalydeco to some extent.  Researchers already know that this group includes:

*ALL gating mutations,
*Most Conductance mutations,
*Some splice mutations. 

The fact that the group of Kalydeco responders might soon be expanding is fantastic news!  I talk about mutation classes and what that means for CFTR transport in this blog: http://luckycfmom.blogspot.com/2011/11/mutation-matters.html Yet, all of us are painfully aware that Kalydeco has only been approved for G551D ages 6+ and it is extremely difficult or next to impossible to get insurance coverage for this super expensive drug "off-label." Furthermore, there is a growing body of evidence showing that in some cases, Kalydeco has been beneficial for patients who shouldn't theoretically show any response to the drug such as:

1)Heterozygous patients with class 1 and 2 mutations
Theoretically, From what we know about these mutations individually, there should be no CFTR on the cell surface and these patients shouldn't show a response to Kalydeco. 
In reality, I know of several cases of patients obtaining a script and coverage for Kalydeco "off-label," trying it, and showing reduction in sweat chloride and improvement in lung function.  I think some patients are having some CFTR reach the surface when their two CF mutations interact with one another through a process called Transcomplementation: http://luckycfmom.blogspot.com/2012/03/calling-all-heterozygotes.html

2)DDF508
Almost everything you read about the DDF508 response to Kalydeco is that it DOES NOT work for this group. I want to very cautiously put this out there. 
Theoretically, there should be no surface CFTR to potentiate.  The vast majority of patients showed no significant response. 
In reality, a very small subset of DDF508 showed some response to Kalydeco in trials.  We are talking about 1 in 112 patients.  The scary thing is that they (researchers) have no idea how to identify one of these responders.  What makes them different from any other DDF508?? Still, right on the insert in every Kalydeco bottle it states that the drug is "not effective in patients with CF who are homozygous for the F508del mutations in the CFTR gene."  Is 1 in 112 patients statistically significant?  No.  Does that extremely rare DDF508 responder deserve the chance to find out if Kalydeco could help them?  Yes.

3)Who else?
The thing is, the biochemical reactions that take place within your body are as unique to you as your fingerprint.  We know that there is wide variability in the severity of CF, even between siblings or twins with identical genotype and similar environment.  There are other factors at play that influence CFTR.  I think Peter Mueller from Vertex was on to something amazing when he discussed idea this a few months ago. 
http://iom.edu/~/media/Files/Activity%20Files/Research/GenomicBasedResearch/2012-MAR-21/3%20-%20Peter%20Mueller.pdf  Take particular note of slides 31-37.  Doesn't that just blow your mind?  How awesome would it be to receive your own "Trial in a Box" from Vertex to track your body's response to Kalydeco and make a treatment decision based on the results?!  **This is not an official trial, or registered with clinicaltrials.gov.  This is an idea that is being talked about by those in the know...Vertex is definitely NOT recruiting for this right now.  It is just being discussed at a preliminary level.  The cooperation of the FDA and insurance industry would be of the utmost importance. 

Disclaimer --I just want to clarify that I am not suggesting that Kalydeco would work in every CF patient.  There are many CF patients that don't successfully transport any CFTR to the cell surface, and would not respond to treatment.  The point that I want to drive home is that:  NO ONE KNOWS FOR SURE IF IT WILL WORK IN AN INDIVIDUAL UNTIL IT IS TESTED IN THAT INDIVIDUAL.   

Response Guided Therapy
In an ideal world, when a drug like Kalydeco is discovered and found to be safe, people would be free to decide if they want to try it, and see if they feel better, or their sweat chloride drops.  If you show a response, then you would remain on the therapy.  If you didn't, they would know that you have no surface CFTR and you would stop and wait for the corrector + potentiator combo moving down the pipeline.  I mean, wouldn't this be revolutionary!  The problem is that this "trial in a box/trial of 1" design is not something that the FDA would look at as a valid statistical measure for approval.  That is why it is extremely important that the CF community continue to support the EXPERRT Act, which allows the FDA to bring in disease specialists for rare conditions like CF to best determine the endpoints for trials, etc...  The CF Foundation is truly blazing the trail toward a new generation of individualized, gene based medicine.  You can imagine that there are a few "norms" that we are going to have to challenge along the way.  Both Vertex and the CFF are legally bound to stay out of any off-label use because they are focued on obtaining wider regulatory approval in the U.S. and of course for our friends in Europe and Australia.  Waiting sucks.  I'm sure that Vertex would love nothing more than to fill thousands more Kalydeco orders and the CFF would love to see its community live longer and feel better.  Unfortunately, they have to play by the rules. 

I can't underestimate the importance of seeing the EXPERRT Act pass and become law because it would allow us to slightly change the rules and persue more individualized approaches to treatment.  The repercussions for CF patients could be phenomenal.  Visit the CFF's advocacy tookit to read about the EXPERRT Act, and quickly and easily email your elected officials asking for their support.  We need to educate the FDA about the new ways we are individualizing treatment for CF patients and this will allow us to be heard!  Personalize your letter for the greatest impact!  http://www.cff.org/GetInvolved/Advocate/AdvocacyToolkit/EXPERRTAct/

Off-label Documentation
Brady is part of the National CF Registry and we have documented in detail the benefits of Kalydeco through both office exams and lab work.  Every off-label approval and documented success of Kalydeco will tilt the odds a little more in our favor for additional insurance companies to approve it for others off-label.  Remember when Pulmozyme was first approved by the FDA?  It was only trialed in kids age 6 and older.  Of course, Dr.'s soon saw its benefits and began prescribing to younger patients.  At first, the insurance industry pushed back, but after seeing it routinely prescribed and accepted by other insurance companies, everyone eventually just began covering it for younger kids also--OFF-LABEL! Even insurance companies can see that PREVENTING problems in CF is cheaper than FIXING problems once they have already occured and caused potentially permanent damage.   I realize that Kalydeco is dangerously high priced.  It raises an automatic red flag for insurance companies.  Our insurance told us that it happens for anything costing over $10K per month in their system.  They automatically required the "letter of medical necessity" from Brady's Dr. and a "pre-authorization."  I live with constant fear that our insurance company will change their mind about covering Kalydeco for Brady, so we have been seeing the Dr. frequently, doing lots of lab work, and making sure there is NO DOUBT that it is working wonders for him.  I order his 5th bottle on Monday!  I can hardly believe it! 

Back to why I can't sleep
The image from Breck's thoughtful and well-written blog just after Kalydeco was approved has never left my mind. http://bennettgamel.blogspot.com/2012/01/will-helicopters-return-in-time-for-us.html Everyone waiting...stranded on that rooftop with the floodwaters rising around them.  She said it so brilliantly.  This is how I feel as I see how Kalydeco has positively affected Brady, and also having the knowledge that it could be helping many more.

Scene Setting

The whole CF community is on a deserted island in the middle of the ocean.  We have run out of food and we are all starving and ill, especially our children.  We see a helicopter in the distance and all scream with hope and delight!  Help arrives directly over my head and drops down a message for me,

"Here is the food you will need to sustain your family for the next 4 years. I am going back to the mainland to build a boat.  I will sail here and rescue everyone in a few years.  There is one condition--you cannot share any of this mountain of nourishment with anyone else on the island. You must only feed your own family. We have a videocamera on the island and if you are caught sharing, all your food will be taken back."

Then they fly away into the distance.  Everyone is staring at me asking what the note says.  When they will be back?  What the hell??  Why did they send help specifically to you?  Do you know them?   I read everyone the note and they digest the news of several more years of waiting.  In the meantime, I can't help but feel relieved as I feed my starving child what he needs to survive.  BUT--If I look just a bit further, I'll see another child suffering and feel another Mother's heart breaking.  It feels so extremely gluttonous to have access to Kalydeco while others don't. It has been such a lifechanging miracle for us.  It just makes me sick to know that we live in a world where money determines whether people live or die.  Because it doesn't matter how well the drug might work in you.  What matters right now seems to be technicalities like: what mutation you have, how old you are, what country you live in, what type of insurance coverage you have, etc... NOOOOOOOOOOOO!!!  It just doesn't feel right.  I don't know how I'll ever rest.

I hope everyone writes in to their representatives in support of the EXPERRT ACT!  I want to see the day when the "trial in a box" is more than an idea...it is a reality!   So what do I do now?  Since my family has the nourishment it needs, we can work to build shelters for the others, care for them in their weakest hours, and relentlessly keep the rescue fire burning, in the hopes of attracting a less idiotic helicopter pilot.  I may not be able to share my nourishment, but I can share my energy and love.  In Breck's version, my family flies away on the helicopter to safety, leaving the rest behind.  In my version, and in my heart, I will never leave the CF Community.  The rescue fire will never go out on my watch. 

 

Many Hands Make Light Work

Fundraising season is in full swing and I want to share a few of the ways that the CFF has impacted our lives.  I also want to get my local community involved as much as I can--to continue moving toward a cure or control for everyone with CF.  The science and technology to treat CF are moving forward fast...let's make sure that the CFF never has to slow down or hit the brakes because of a lack of money!  There are so many little ways you can help.

Here is more info about those upcoming local events:

April 21st--Community Yard Sale to benefit the CFF at the Kooskia IOOF hall from 8-5.  My Mom and Dad have been working hard on this and we are looking forward to helping raise some cash for CF this weekend! 

April 25th--Sip and Dip for CF at the Melting Pot Spokane, http://sipanddipforcf.weebly.com/

May 11th--On Par for a Cure Golf Tournament, http://www.onparforacure.weebly.com

June 2nd--Great Strides Walk (Spokane or Boise), Join "Brady's Buddies" and walk with us!  You can also make a donation of any size on my fundraising page, http://www.cff.org/Great_Strides/dsp_DonationPage.cfm?walkid=7873&idUser=286719

June 23rd--Hair Studio in Emmett, ID will be holding their 2nd Annual "Cut-a-thon" event to benefit the CFF!  A wonderful friend of mine took it upon herself to organize this great event last year and I feel so humbled that she is doing it again this year! The ladies at Hair Studio cut hair all day, and donate the money to the CFF!  I believe they will be selling pulled pork sandwiches also!  You will learn more about this event as we move closer!!  I can't thank my friend Heidi Smith enough for going above and beyond to organize this!  It means so much to us! 

A New Brand of Cystic Fibrosis

We had an appt. with Brady’s CF Dr. this morning.  It has been 2 whole months since he began Kalydeco (took first dose Feb. 10^th).  Before I get to all the juicy details of our visit, I just want to mention how much different I feel about going to clinic now, vs. pre-Kalydeco.  Most CF parents can probably relate to the idea that clinic can be a scary place.  Besides the risk of cross-infection from other patients, for me--there was always the fear of what I might learn about the progression of his disease.  Is the throat culture going to show a new bug causing problems?  What new meds will we be adding this time?  Is a hospital visit in our near future?  The list of potential CF complications is seemingly endless.  I’ve always had a lot of anxiety and fear surrounding clinic visits, but everything feels different now.  Before, I would spend the week before clinic pacing the floor, not getting much sleep, and trying to manage my fear.  I’m not going to lie…I’m still not getting any sleep, but it isn’t because of the fear and worry.  It is because I’m so freaking excited.  It is because I CAN’T WAIT to see the clinic team and discuss all the positive changes we have seen in Brady’s health.  It is because the game has changed, and I don’t know all the new rules yet, and my mind has just been racing with possibilities for the future. 

Clinic Visit: Day 62 of Kaydeco for my 4 1/2 yr. old with G551D and DF508

Weight: 48 lbs.  His weight was the same today as it was 1 month ago.  We feel totally fine with that because he is still close to the 90^th percentile weigh-for-age.  Also, we have been adjusting his diet (not covering everything he eats in butter, ½ n ½ etc...).  I’m sure that his intake of fruits and veggies has gone up, while intake of pure delicious fat has gone down.  We will continue to work with the dietician to figure out how to manage his caloric needs moving forward.

Pancreatic Function: One of the things we discussed with both the Dr. and Dietician is the potential enzyme dosage adjustments that might be needed with the addition of Kalydeco.  We very slightly reduced his Zenpep dosage after he first began Kalydeco, but have been holding steady with 2 pills with snacks, and 3 with big meals since then.  Of course, those familiar with CF know that the poo is the window to digestive function.  Brady’s bowel movements have definitely changed since he began Kalydeco—reduced to once per day, less stinky, more formed, and always sink to bottom of toilet.  I think patients and Docs have both been pleasantly surprised with the increase in digestive function that Kalydeco seems to provide.  No one knows for sure, but there are a few theories about why Kalydeco is associated with weight gain in CF patients:

1)      For individuals with significant lung damage, breathing becomes a strenuous activity that burns a lot of calories.  For patients who see a big increase in lung function with Kalydeco, weight gain might be linked to the decreased caloric demands of less labored breathing. 

2)      Kalydeco decreases abnormal mucus production in all epithelial cells.  Decreased digestive/intestinal mucus might allow more effective absorption of nutrients and calories (ever change a snotty CF diaper?—mucus can cause problems in the guts, just as it does in the lungs).

3)      Pancreatic function might be improved with Kalydeco.  The Dr. was really curious about what is going on, if anything, with Brady’s actual pancreatic function--the ability to release digestive enzymes into the small intestine where they breakdown nutrients for absorption.  He explained that most people view pancreatic sufficiency as a black or white issue, when it really isn’t that simple.  Pancreatic damage likely occurs in a similar manner to CF lung damage in the respect that it might start out as mucus plugging and inflammation before it reaches the point of full blown dysfunctional scar tissue and completely blocked enzyme ducts.  The Dr. believes that pancreatic function is more accurately described on a continuum of function (for example, some patients might have partial function, but still need enzymes to keep stomache aches away.  Others might have enough function to digest without enzymes and don’t take them at all, but might still potentially benefit from a very small dose of Zenpep etc...)  There isn’t a clear line between pancreatic sufficiency and pancreatic insufficiency.  If this is the case, patients who are somewhere in the middle of that continuum might be able to clear out some of the mucus plugging and actually experience an increase in the amount of digestive enzymes their bodies can naturally release—thereby reducing their need for enzyme supplements like Zenpep. 

Again, these are all theories and individual patients will respond to Kalydeco in their own way anyhow.  Patients in the end stages of disease might see more of a weight bump from the increase in their lung function, while very young patients might see a weight increase linked to improved pancreatic function.  I know that I’ve read several accounts of individuals stopping enzymes all together after beginning Kalydeco.  I don’t see that happening for Brady.  His malabsorption issues began when he was 2 weeks old (even breast milk was running right through him), and he certainly has some permanent pancreatic damage at this point.  Still, there have been a couple times that I’ve become concerned that we might be OVERDOSING him a bit with enzymes now because he seems a little constipated and has complained a few times that his tummy hurts.  With the help of his dietician, our plan to figure out the correct enzyme dosage for Brady is to gradually and systematically reduce his dosage, while monitoring his stools and weight.  We are going to start by decreasing Zenpep from his normal dose of 3pills/ meal, down to 2.5 and from 2/snack down to 1.5.  We will do this dose for 7-10 days, monitor the poo, and then do another small decrease if he is still absorbing well. 

Chest CT Scan

At our March 8^th clinic visit, we discussed the need for a more detailed “roadmap” to guide us in moving forward with Brady’s care, so we decided to perform a low-dose chest CT scan.  CT scan is the most sensitive and detailed technology we have right now to measure structural lung disease.  Previously, Brady had undergone annual chest X-rays that had all presented “normal.”  He did a great job the day of the scan and even got to push all the buttons on this huge cool machine!  Brady’s nurse called us earlier this week with the results.  The Dr. and their favorite pediatric radiologist had both reviewed the results and agreed that there was absolutely NO VISIBLE DAMAGE.  His lungs look awesome!  Imagine me saying that last part with mascara streaked tears streaming down my ugly “cry face.”  Writing about it just doesn’t do justice to what an emotional basket case I’ve been for the last 2 months.   I’ve been dreaming about this possibility since I first heard of VX-770…and now it has happened.  My dream has come true.  His lungs are currently healthy and he has Kalydeco working like magic in his body to keep them that way.   Discussing the awesomeness of the CT scan with the Dr. led us right into our next topic—what do we do now?  How do we move forward with treatments and airway clearance for my little CFer, who has picture perfect lungs and suddenly functional CFTR?  Will he eventually be able to "control" CF by simply popping a magic blue pill twice a day?

Breathing Treatments and VEST

This is the conversation that gets my heart beating so loud that I can barely think over the noise.  My hands are sweating like mad just typing about it!  To recap, we requested to start Brady on Pulmozyme at age 6 mo. in the absence of symptoms in an attempt to prevent lung issues.  We requested and began HyperSal at 20 mo. for the same reason--still with no lung symptoms at all.  In the 4 ½ years that we have been doing these treatments, we have NEVER missed a single dose of ANY treatment.  I realize that I am nuts about it.  I don’t care what the circumstances are, treatments are non-negotiable.  One time, I thought I had forgotten to pack the Pulmozyme in the cooler for a weekend at my parents place…I think I had a small panic attack and was getting ready to drive 3 ½ hours back home to get it before Brock found it.  I mention this because the idea of reducing or removing any of his breathing treatments or VEST scares the crap out of me.  I hope no one assumes we are in any kind of hurry to see treatments go away, because in reality, I have an irrationally bonkers attitude about it!

We just want to do the right thing, so we hashed out all our questions and concerns with Brady's Doctor.  One of the things I love most about his CF specialist is that when he doesn’t know the answer, he will say so.  EVERYONE is clueless as to the most appropriate way to proceed with a case like Brady.  Before we even got involved with our discussion, the Dr. stepped out of the room to email some colleagues quickly, to get their opinion about what to do with this new brand of CF patient like Brady.  In his words, “Brady is a pioneer.  He is the ideal candidate for this.”  This is all new territory.  Dr. M has a very collaborative attitude…I like it.  Another thing I love about Brady’s Doc is that he always asks for our input and we decide TOGETHER how to best care for Brady.  We concluded that our next small step should be to further reduce his HyperSal treatments.  This sounds strange, but it seems to me like the Hypersal treatment has become more irritating for Brady now than it was before he started Kalydeco.   Pre-Kalydeco, he would sometimes cough once or twice during Hypersal, but often not at all.  He has always breezed right through it like no big deal.  He still isn’t coughing, but he is complaining of a sore throat afterward occasionally now.  He is just acting like it is bugging him a little, which he never did before.  HyperSal is used to temporarily restore some surface chloride, which in turn, increases the “airway surface liquid” (ASL) on the lining of the lungs.  This ASL allows those little cilia to beat--to move and clear particles.   I don’t think there is any doubt that this treatment is effective, but can be a little rough to take.  If Kalydeco is working like it is supposed to, his ASL is likely in very close to "normal" condition with Kalydeco alone.  We decided that if a treatment was to be eventually be eliminated all together--HyperSal would go before Pulmozyme because it works with a totally different mechanism of action in the lungs.  We think Brady might still receive more potential benefit from sticking with this drug for a longer time.  Pulmozyme works by chopping up the long strands of extracellular DNA that bind mucus together in CF lungs.  http://www.pulmozyme.com/how-pz-works.jsp

Baseline Feb. 10th: Brady used to do HyperSal (7%) twice a day. 

March 8^th: Last month, we dropped it down to HyperSal once a day. 

Today, April 12th:  We decided to move down to Hypersal 3X/week.  This doesn’t sound like much…but what it means to us is that tomorrow morning, for the first time in over 4 years, we are going to wake up and NOT DO ANY NEBULIZER TREATMENTS!!  He normally does albuterol to prep for HyperSal, so during the actual appt., I had it in my head that we would be stopping the HyperSal some days, but still continue doing albuterol.  On the ride home from clinic, it hit me that the Dr. may have actually meant no nebs at all those mornings so I called the clinic back and talked to his nurse.  She said “no need for the albuterol either” that it was just to prep him for the HyperSal.   I had her repeat it to me one more time just to be crystal clear and convince myself I was hearing correctly—no nebs at all in the morning on the 4 days he skips the HyperSal.   “You might need to find some new hobbies,” his Dr. told us.  We are going to do this for a month and see how it goes.  If all is well then…

The next step will be to decrease the VEST from 20 min. twice a day, down to 15 min. twice a day.  Baby steps.  We will re-evaluate again when we see the Dr. in 2 months.  My mind is so blown right now.  I swear I have been watching this happen in my head for years.  I have been visualizing this exact miracle that is playing out in front of me—intervene before irreversible damage has been done and give him an honest-to-goodness second chance at a long healthy life.  It is like I am watching a super awesome Lifetime Original movie starring MY FAMILY—a real tearjerker, but with a fantastic conclusion.  I’d like to say that having Kalydeco has calmed me down a bit, but on the contrary, I remain firmly perched on the edge of my seat.  Every change is so exciting.  Every test result has been so fantastic.  I’m just amazed time and time again. 

Other Oral Meds: Holding steady with current schedule

Sinuses: Still totally clear with no steroid rinses or oral prednisone!  The polyp growth seems to be a thing of the past! Amazing!!  No snoring or mouth breathing, and he is making lots of comments about smells. 

I feel so unnaturally lucky that I’ve begun having really irrational fears about other parts of my life.  Everything is so perfect, something has to give.  Is Brock going to get into a car accident??  Do I have cancer??  Where is the cat?? Kitty!!  You get the picture.  I’ve never denied that I am slightly off-balance, and it just doesn’t compute how or why this is happening to us.  I mean, treatments are one of the ways CF parents “take care” of their kids.  We wake up every day swinging because every day with CF is a fight…but what do you do when your enemy stops swinging back??  How long and how hard do we keep swinging when CF has retreated back to its corner of the ring?  The transition is hard.  Knowing the right thing to do is impossible and is driving me crazy.  But, as Brady’s Dr. said, “this is a great problem to have.” I am trying hard to live in the present and stay out of the swirling thoughts in my head (not very successfully, but I’m trying).  Kalydeco may have changed the way CF is affecting Brady’s body, but it hasn’t changed the fact that CF messes constantly with my mind!!  Brady honestly couldn’t care less about treatments because he gets to watch Puss in Boots and I massage his legs.  I have so much fear about backing down from treatments because it has always represented the path to health.  BUT KALYDECO IS A GAMECHANGER, and I also want to take full advantage of the opportunities that lie before us.  Spending all those hours sucking in meds and getting shaken silly might actually be totaI overkill for someone with perfectly healthy lungs and functional CFTR.  I don’t want to sentence my lovely son, who has already been through so much, to unnecessary treatment time because of my fears.  I will be calling into the clinic in a couple weeks to inquire about the responses the Dr. is getting from his colleagues in regard to Brady’s case. 

Lastly, I want to just “radio in” a message to my CF families still waiting on that rooftop, with the floodwaters rising around you, wondering if you will be rescued in time.  .  http://bennettgamel.blogspot.com/2012/01/will-helicopters-return-in-time-for-us.html I often imagine how painful it has to be watching another child receive a treatment like this while your own precious babies continue to fight CF.  My message to everyone still waiting is this: “WE HEAR YOU!  We will never forget where you are and we are working to get back to you as fast as we can!  DO NOT EVEN THINK ABOUT GIVING UP, WE ARE ALMOST THERE!”  Roger.

Calling All Heterozygotes!

I'm so happy to introduce my guest blogger, Sandy Castle del Conte BA, MS, who brought this research to my attention and produced the following explanation of something I didn't realize was possible... 

Reasons why Kalydeco may work for 'Class I and Class II' Cystic Fibrosis mutations

I read a comment made by someone on a social media website that went something like this: we don't know how Kalydeco could help someone with a Class I and a Class II Cystic Fibrosis mutation.  My thought was, well, some researchers have a pretty good idea of how it could happen, and I would like to share what I have learned about their research.

First and foremost, I have to caution that the research described here does not guarantee that Kalydeco will work for people carrying Class I and Class II mutations, nor anybody with a mutation different than G551D; I attempt to explain how CF-causing CFTR proteins could traffic to the cell surface, but even if they traffic to the surface, they still could be very unstable, and still may not be potentiated by Kalydeco. The research described below has only been conducted in laboratories, not in people. I do not intend to create high hopes and expectations, or guarantee results; I only want to provide a reasonable explanation of how it may happen. 

The data are pretty clear on what Kalydeco does; Vertex researchers have reported that in their laboratory studies, they have found that '[Kalydeco] has a similar effect on all [tested] CFTR forms with gating defects' (Yu et al., 2012). Also, they have found Kalydeco potentiates CFTR from Classes II through V in the laboratory, including F508del, as well as 'multiple unclassified CFTR mutant forms' (Van Goor et al., 2010). Kalydeco has been able to potentiate a multitude of mutated CFTR proteins that make it to the cell surface.

CFTR proteins currently categorized within Class I and II cystic fibrosis mutations are described as usually not trafficking from the endoplasmic reticulum (ER) of the cell to the cell surface. These categorizations, however, do not take into consideration the interaction between mutant CFTR proteins.

Many people with cystic fibrosis are heterozygous; two different CFTR proteins are co-expressed in their cells.

There are many laboratory studies demonstrating that when two different CFTR mutant proteins are co-expressed, mutant CFTR proteins move to the cell surface that would not traffic when expressed alone because of transcomplementation between the mutant proteins. 

Transcomplementation has been shown to occur in the laboratory, and researchers are continuing to study it as a form of gene therapy. I have found no scientific reports of transcomplementation occurring  naturally (in vivo), but it is possible that in at least some CF heterozygotes, transcomplementation is occurring, resulting in CFTR proteins at the cell surface.

CFTR mutants that have been demonstrated to be transcomplemented, resulting in maturation, and thus  trafficking of CFTR proteins, include: F508del (Cebotaru et al., Cormet-Boyaka et al., 2004, 2008, 2009, 2011, Owsianik et al, 2003, Sun et al., 2008), A455E (Cebotaru et al., 2009), and H1085R (Cormet-Boyaka et al., 2004). Even trafficking of wild-type (normal, non CF-causing) CFTR has been shown to increase due to transcomplementation with mutant proteins (Cebotaru et al., 2006, 2008).  These CFTR proteins have been transcomplemented by a number of different proteins: wild-type and mutant CFTR proteins truncated (cut/missing sections) at the beginning, middle, or end, as well as truncated and full length proteins with amino acid deletions or substitutions.

The way that CFTR proteins interact and transcomplement is not entirely understood and seems to differ among CFTR mutations.  It seems that some CFTR mutants are targeted by and occupy the ER quality control system, allowing the second CFTR protein to escape to the cell surface (Sun et al., 2008), while other mutants actually associate with each other, 'most likely via a bimolecular interaction' (Cebotaru et al., 2011), altering and creating a protein that can traffic to the surface.

There is more to the story, but we'll save the rest for another day.

Many thanks go to Rebecca, for collaborating with me to 'translate' the following information, and for agreeing to post this on her blog.

Much appreciation also goes to Dr. Kevin Kirk, Professor and Vice Chair for the Department of Cell, Developmental and Integrative Biology, at University of Alabama at Birmingham, for thoroughly and clearly answering the many questions I have had for him, promptly answering my emails, conducting and supporting research on cystic fibrosis, and for giving me the citation to the first transcomplementation paper I ever read.

Sandy Castle del Conte, BA, MS

Side Notes: 

If you are interested in looking at mutations in detail, the Cystic Fibrosis Mutation Database has information on the currently known CFTR mutations (http://www.genet.sickkids.on.ca/cftr/MRnaPolypeptideSequencePage.html). Please note that the numbering of nucleotides and amino acids indicated in the papers cited below is slightly different from that found on the Cystic Fibrosis Mutation Database. The c.DNA name is the most accurate way to find the location of mutations on this website.

A tidbit of data I found interesting is: CFTR under 'constant stimulation' is degraded faster (Lewarchik et al., 2008).

Rebecca's Take on Transcomplementation

Is your head spinning yet?  I realize this is very technical information, but an extremely interesting line of research.  Especially since we now have an FDA approved drug like Kalydeco, which has been shown in the lab to have the ability to potentiate (open the gate) for any CFTR that succeeds at arriving to the cell surface.  Getting that protein to the cell surface is now an important goal in research and the reason why drugs like VX-809 and VX-661 are being studied right now.  The concept of “transcomplementation” represents an alternate process by which some CFTR might successfully reach the cell surface for some CF heterozygotes (2 different mutations). 

To shed a little light on this complicated process, an analogy is in order.  In a previous blog, I referred to CFTR as a piece of genetic origami.  For the purposes of this explanation, let’s envision the CFTR protein like a jigsaw puzzle.  There is a factory inside epithelial cells that produces jigsaw puzzles (CFTR proteins).  The jigsaw puzzles are churned out and sent to quality control (the endoplasmic reticulum).  Quality control ensures that all the pieces are present and fit together properly before each puzzle is shipped out to the customer (the cell surface).    In healthy individuals, this process happens smoothly.  The puzzles have all their pieces, pass quality control, and are shipped out to the customer.  In individuals with cystic fibrosis, some of the pieces of the puzzle are missing.  Each mutation of cystic fibrosis causes a different piece of the puzzle to be missing.  Let’s say that, for example, all delta F508 mutations are missing the upper right hand corner of the puzzle.  All delta 264 are missing the middle piece, etc…  Transcomplementation refers to an interaction that can occur when two different mutations (puzzles) exist in the cell (heterozygous).  In other words, if a puzzle missing the upper right hand corner gets together with a puzzle that HAS the upper right hand corner but is missing the middle piece…they might share pieces until they come up with a single complete puzzle that could successfully pass through quality control and get shipped.  It is essential that the missing piece from one puzzle be present in the other puzzle (mutation) for transcomplementation to occur.  This explains why this phenomenon doesn’t happen with homozygous mutations.  If the mutations are the same, all the puzzles in the cell would be missing the same piece--so sharing wouldn’t get you any closer to a complete puzzle!        

Another theory is that when two different CF mutations are present, it is possible for quality control to become somewhat distracted while counting and sorting all the pieces of the first screwed up puzzle.  While quality control has it’s back turned, dealing with the first mutation, some of the second mutation can potentially sneak through the endoplasmic reticulum without even being checked for quality, and successfully reach the cell membrane. 

Again, the idea is that once CFTR reaches the cell membrane, we now have a drug, Kalydeco, which can “turn on” the action of that protein.  I’ve read of a few cases of off-label use of Kalydeco in mutations outside of Class III (gating), that have described improvement, when according to our current classification, they shouldn’t have any available CFTR to potentiate (http://saltyspark.blogspot.com/).  The idea I want to put out there is that, while some CFTR mutations aren’t technically SUPPOSED to produce any protein on the cell surface, sometimes there may actually be a small amount because of processes like transcomplementation.  The more I learn about the genetics of cystic fibrosis, the more I realize that this disease is as individual to each patient as their fingerprint.  It may be very difficult to predict what is happening within the cells of a CF patient, because some people spontaneously have interactions like “transcomplementation” occurring, that are new concepts to the world of CF science.  I was very excited when Sandy approached me with this research.

The therapeutic implications of transcomplementation are that fragments of genes with the correct missing puzzle pieces might be able to be inserted into the mix, to allow a person’s body to produce complete proteins that fully “mature” and reach the cell surface.  Also, there is the potential that the pool of patients that could actually receive some benefit from Kalydeco, might be much larger than originally anticipated.  Again, this is certainly NO GUARANTEE that Kalydeco would work for you just because you are heterozygous with a Class I or II mutation…but it certainly brings to light the idea that it is possible under certain circumstances.  That is what this blog is all about!  Possibilities!  I want to thank Sandy for this wonderful piece of work and dozens of useful references(bottom of page).  I look forward to working with her again in the future as we delve even deeper into this topic.

Lastly, my blog wouldn’t be complete without a quick update on Brady.  He is doing fantastic!  Sinuses are still clear, he seems to be feeling amazing, full of energy, and gaining weight.  I haven’t been giving updates as frequently, but only because there is nothing new to report!  In the CF world, nothing new= good news!  He honestly seems like a new kid since beginning Kalydeco.   We are looking forward to the Chest CT scan in a few weeks and will give a full report on the results!

References

Carroll, T. P., Marcelo M. Morales, Stephanie B. Fulmer, Sandra S. Allen, Terence R. Flotte, Garry R. Cutting and William B. Guggino. Alternate Translation Initiation Codons Can Create Functional Forms of Cystic Fibrosis Transmembrane Conductance Regulator. J Biol Chem. 1995 May 19;270(20):11941-6. http://www.jbc.org/content/270/20/11941.long

Cebotaru, L., Terence R. Flotte and William B. Guggino. AAV [Delta]264CFTR Enhances Maturation of [Delta]F508CFTR and wt CFTR Expression. Molecular Therapy (2006) 13, S193. http://www.nature.com/mt/journal/v13/n1s/abs/mt2006639a.html

Cebotaru L, Vij N, Ciobanu I, Wright J, Flotte T, Guggino WB. Cystic fibrosis transmembrane regulator missing the first four transmembrane segments increases wild type and DeltaF508 processing. J Biol Chem. 2008 Aug 8;283(32):21926-33.

http://www.jbc.org/content/283/32/21926.long

Cebotaru, L., and William Guggino. Rescue of A455E CFTR by temperature, small molecule correctors and transcomplementation. Journal of Cystic Fibrosis. June 2009, 8, Supplement 2, pg. S17-S17. http://journals2.scholarsportal.info/details.xqy?uri=/15691993/v8inone_s2/s17_roacbtsmcat.xml

Cebotaru, L.; Woodward, O.; Guggino, W.B. A truncation mutant of CFTR, ∆27-264-CFTR, rescues  both trafficking and chloride channel function of ∆F508 CFTR by transcomplementation. Pediatric Pulmonology. October 2011. Volume 46, Issue S34, Page 214. http://onlinelibrary.wiley.com/doi/10.1002/ppul.21581/pdf

Cormet-Boyaka, E., Michael Jablonsky, Anjaparavanda P. Naren, Patricia L. Jackson, Donald D. Muccio, and Kevin L. Kirk. Rescuing cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by transcomplementation. Proc Natl Acad Sci U S A. 2004 May 25; 101(21): 8221–8226. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419584/?tool=pmcentrez

Cormet-Boyaka, E., Jeong S. Hong, Bakhram K. Berdiev, James A. Fortenberry, Jessica Rennolds, J. P. Clancy, Dale J. Benos, Prosper N. Boyaka, and Eric J. Sorscher. A truncated CFTR protein rescues endogenous ΔF508-CFTR and corrects chloride transport in mice. The FASEB Journal. 2009 November; 23(11): 3743–3751. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775001/?tool=pubmed

Fischer AC, Smith CI, Cebotaru L, Zhang X, Askin FB, Wright J, Guggino SE, Adams RJ, Flotte T, Guggino WB. Expression of a truncated cystic fibrosis transmembrane conductance regulator with an AAV5-pseudotyped vector in primates. Mol Ther. 2007 Apr;15(4):756-63.  http://www.ncbi.nlm.nih.gov/pubmed/17299412

Flume, P.A.; Borowitz, D.; Liou, T.; Li, H.; Yen, K.; Ordoñez, C.; Geller, D.E.5VX-770 in Subjects with CF and Homozygous for the F508DEL-CFTR Mutation. Pediatric Pulmonology.  October 2011. Volume 46, Issue S34. Pp 284 – 285. http://onlinelibrary.wiley.com/doi/10.1002/ppul.v46.34s/issuetoc

Flume, Patrick A., MD (flumepa@musc.edu), Theodore G. Liou, MD (ted.liou@utah.edu), Drucy S. Borowitz, MD (dborowitz@upa.chob.edu), Haihong Li (haihong_li@vrtx.com), Karl Yen, MD (karl_yen@vrtx.com), Claudia L. Ordoñez, MD (claudia_ordonez@vrtx.com), David E. Geller, MD (dgeller@nemours.org) and for the VX08-770-104 Study Group. Ivacaftor in Subjects with Cystic Fibrosis who are Homozygous for the F508del-CFTR Mutation. Chest. March 2012. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/22383668

Lewarchik, C. M., Kathryn W. Peters, Juanjuan Qi, and Raymond A. Frizzell. Regulation of CFTR Trafficking by Its R Domain. J Biol Chem. 2008 October 17; 283(42): 28401–28412. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2568940/?tool=pubmed

Owsianik G, Cao L, Nilius B. Rescue of functional DeltaF508-CFTR channels by co-expression with truncated CFTR constructs in COS-1 cells. FEBS Lett. 2003 Nov 6;554(1-2):173-8. http://www.ncbi.nlm.nih.gov/pubmed/14596935

Ramalho AS, Lewandowska MA, Farinha CM, Mendes F, Gonçalves J, Barreto C, Harris A, Amaral MD. Deletion of CFTR translation start site reveals functional isoforms of the protein in CF patients. Cell Physiol Biochem. 2009;24(5-6):335-46. http://www.ncbi.nlm.nih.gov/pubmed/19910674

Roxo-Rosa M, Xu Z, Schmidt A, Neto M, Cai Z, Soares CM, Sheppard DN, Amaral MD. Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanisms. Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17891-6. http://www.ncbi.nlm.nih.gov/pubmed?term=revertant%20mutants%20g550e

Sun, F., Zhibao Mi, Steven B. Condliffe, Carol A. Bertrand, Xiaoyan Gong, Xiaoli Lu, Ruilin Zhang, Joseph D. Latoche, Joseph M. Pilewski, Paul D. Robbins and Raymond A. Frizzell. Chaperone displacement from mutant cystic fibrosis transmembrane conductance regulator restores its function in human airway epithelia. The FASEB Journal. 2008;22:3255-3263. http://www.fasebj.org/content/22/9/3255.full?sid=082b0103-33c5-4615-b6af-1d1521726804

Van Goor, F.; Yu, H.; Burton, B. The investigational CFTR potentiator, VX-770, potentiated multiple CFTR forms in vitro. Journal of Cystic Fibrosis. 2010. Volume 9, S14. http://discover-decouvrir.cisti-icist.nrc-cnrc.gc.ca/eng/article/?aid=17408771

Yu, H., Bill Burton, Chien-Jung Huang, Jennings Worley, Dong Cao, James P. Johnson Jr., Art Urrutia, John Joubran, Sheila Seepersaud, Katherine Sussky, Beth J. Hoffman, Fredrick Van Goor. Ivacaftor potentiation of multiple CFTR channels with gating mutations. Journal of Cystic Fibrosis. Available online 30 January 2012. http://www.ncbi.nlm.nih.gov/pubmed/22293084

CF lung disease: Does symptomless = safe?

Everything is going along great.  Brady seems to be breathing well, sleeping well, and has lots of energy.  At his last CF Clinic appointment, his nurse performed a “throat culture” to check for infections growing in his lungs.  We got the call that his culture came back with “normal flora.”  Good news, but what does this information actually mean?  We also discussed that Brady will undergo a chest CT scan in a few weeks to better assess his lung health and determine whether it will be safe to pull him off of some of his breathing treatments now that he has begun Kalydeco. With this in mind, I can’t stop thinking about this talk I attended at the NACFC entitled: Early CF Lung Disease—No Time to Waste.  I consider it the most shocking information I learned about CF at the Conference and be warned that it might rattle you too.  I wrote about it briefly at the Conference, but have been avoiding summarizing it in detail because it is kind of scary and I try to keep my blog both optimistic and informative.  The last thing I want to do is scare people with this entry…but there is no doubt that this is important information and let’s be honest—MANY things you learn about CF are less than pleasant, so here goes. 

Early CF Lung Disease—No Time to Waste, Stephen Stick, Perth, University of Western Australia presented the data from his project AREST CF, which commenced in 2005.

AREST CF: Australian Respiratory Early Surveillance Team for Cystic Fibrosis.  “Arest CF seeks to improve the detection, prevention, and treatment of early respiratory disease in young children with cystic fibrosis in order to improve clinical outcomes and quality of life for patients and their families.”  This study was funded in large part by the U.S. Cystic Fibrosis Foundation.    

Dr. Stick then went on to use several different types of data to illustrate the importance of the period of time between birth and 6 years of age for cystic fibrosis patients.  He compared FEV1 data collected from the U.S. national Registry in 1990 to data from 2008 to show that “while FEV1 has increased in general over time, after about 12 years of age, the lines become parallel.  Furthermore, although there has been an improvement in the adult FEV1, most of the improvement is already evident by 6 years of age.”  This data prompted them to start looking more closely at what was happening to the CF lung in the early years of life, to examine whether the current protocol of detection and treatment is the best path.  Basically, they wanted to use the most sophisticated techniques available today to look as closely as possible at a group of children over the course of 6 years in Australia to see what is structurally going on inside the CF lung beginning at birth.

First, Dr. Stick describes the methods they used in their study and why these methods were chosen over commonly used throat culture and FEV1 measurements. 

--Based on data from an earlier study, Dr. Stick’s group determined that a technique called “Bronchoalveolar lavage” is a more sensitive method of detecting lung infections than the commonly used oropharyngeal swab (throat culture).  Bronchoalveolar lavage or BAL is a medical procedure where a bronchoscope is inserted into the lung via the nose or mouth and a liquid is squirted into a portion of the lung and then recollected for examination.  The term lavage means “to wash.”  By rinsing the lining of the lung and culturing that liquid, imagine how much more information could be found about active lung infections than by swabbing the back of the throat.  It makes sense that this technique would be more sensitive; the downside is that it is not nearly as simple to perform on patients.

--Dr. Stick also cites several studies about why they chose to employ CT scans rather than FEV1 as a means of tracking lung health in these young children (Fred Long, Journal of Pediatrics. 2004, Pim de Jong Thorax 2006).  These and more emerging studies show the ability of CT scan to detect dilatation of the airways, mucus plugging, gas trapping, and bronchiectasis in young children, even in the presence of normal FEV1 scores.  In Dr. Stick’s words, “FEV1 actually was a poor surrogate for what was happening in the lungs in terms of structural lung disease.” 

The AREST CF study commenced in 2005 was designed to examine the following criteria on children at age 3 mo., 1 yr., and then annually to 6 years.

·         Clinical Progress

·         Infant Lung Function

·         Chest CT Scan

·         Bronchoalveolar Lavage

·         Epithelial Samples

Dr. Stick briefly goes into how they performed/measured each of these outcomes, but puts the focus of the remainder of the talk mainly on the CT scan data in relation to development of structural lung disease.  These scans were performed under general anesthesia, and were “volume controlled” to give data on both inspiration and expiration. 

Detectable Structural Lung Disease

The major surprise on CT scans in young children with CF was the prevalence of bronchiectasis.  Bronchiectasis is defined as irreversible localized dilation/destruction of the airways and is “clearly visible as widening of the airway” in CT scans.  The data showed an increasing prevalence of bronchiectasis in the children studied—with over 80% exhibiting bronchiectasis visible in CT scan by age 6.  Once bronchiectasis was detected via CT, the majority of cases persisted or worsened by the time of the next CT—showing that this is a progression of disease, rather than just a transient phenomenon.

Summary of findings:

Prevalence of bronchiectasis in children, detected via volumetric CT scan

Age 1: 20% of children scanned exhibited bronchiectasis

Age 2: approximately 40%

Age 3: just over 50%

Age 4: 60%

Age 5: 70%

Age 6: over 80%

Air trapping and mucus plugging are also visible on CT in increasing prevalence as children approach age 6. 

Bronchoalveolar Lavage Data

Inflammation

Researchers can obtain information about the inflammatory response in the lungs by measuring the “neutrophil elastase” in the BAL fluid.  An elevated level of neutrophil elastase in the BAL fluid indicates greater inflammation in the lungs.  This inflammation marker was increased in children showing bronchial dilatation on their CT scan.  Children whose lungs harbored infection by one or multiple organisms also had higher neutrophil elastase levels.   

 Infection

Dr. Stick doesn’t believe the “throat culture” method is an effective way to detect lung infections.  Their BAL results showed much greater rates of infection than were revealed through throat swab.  According to their data, and in Dr. Stick’s words, “All of the organisms that we associate with CF have been found in the first BAL at 3 months, from pseudomonas right through to more unusual ones like Stenotrophomonas.”  This means that even if when patients receive “normal flora” results from a throat culture, there still may be many organisms growing within the CF lung detectable only through more sensitive techniques like BAL.  This doesn’t mean that every child with CF has ALL these organisms actively growing in their lungs.   It simply means that in their cohort of sampled children, ALL of the bad bugs associated with CF had been found in some children by 3 months of age.  In other words, very young children are susceptible to CF infections from birth.  This is seen as evidence that the disease progression begins very early in life, and often in the absence of symptoms.   

“The Salutory Lesson”

On the slide entitled “The Salutory Lesson,” Dr. Stick presents CT data from a completely asymptomatic 3 month old that has a “normal” throat culture.  Using prevalent methods of clinical analysis (throat culture and FEV1), this child would not raise any red flags in terms of progression of lung disease...BUT

The CT scan for this asymptomatic child revealed bronchiectasis and the bronchoalveolar lavage revealed infection with pseudomonas. 

Important Messages

Dr. Stick reiterates the most important findings from the AREST CF study:

-“Bronchiectasis is present in 20% of infants by age 1.  It persists in 100% of infants and progresses (worsens) in over 90% of infants.”

-“There is a window of approximately 6 mo. after birth where lung function is maintained” relatively well.

-“Must intervene at diagnosis to prevent lung disease and maintain normal lung function”

Dr. Stick concludes his discussion by showing the small amount of CF research spending that occurs for children under 6.  He believes that the FDA approved endpoints for clinical studies in CF (spirometry, quality of life, and pulmonary exacerbation) are neither feasible, nor appropriate for children under 6.   

“Essentially, infants are being excluded from trials of these potentially disease modifying drugs that may well be coming to market in the next 5-10 years.  I think it is time we actually got our heads out of the sand, in particular the FDA, and realize that if disease modifying therapies are available…then it may be fiscally irresponsible, morally unacceptable, and medically inappropriate to have infants on lifelong therapy with drugs that have only been demonstrated to show small changes in FEV1 in adults or older children.” 

Hopefully this sheds some light on why I walked out of this talk at the Conference feeling pretty freaked out, why I wanted Brady on Kalydeco a.s.a.p., and why I am anxious about Brady’s upcoming CT scan.    Brady is “symptomless” and has normal throat culture result, but does that mean anything??  We shall soon see.  There is no denying that this is extremely relevant information to parents of young kids with CF.  The reason I felt the need to share this summary is that, even though it was difficult for me to hear, I’m glad I know…and I think others should know.  This is the most detailed information ever collected on the early progression of CF in actual human lungs and Dr. Stick is promoting CT scan as the new “gold standard” of lung disease detection in CF!      

It is important to remember that there are plenty of adult role models in the CF community who have proven that you can have a positive impact on lung health at ANY POINT during life with choices like: adherence to treatments, regular exercise, and good nutrition.  This entry is not meant to be about doom and gloom.  My aim is simply to share information.  I have heard some criticism within the CF community about putting children under 6 on Kalydeco “off-label,” as we have done with Brady.  This research made a big impression on me at the NACFC and has certainly factored into our benefit vs. risk analysis of beginning Kalydeco right now as opposed to waiting.  There are going to be more and more studies featuring CT scan data as a way to measure CF lung disease and I think that this new information is going to change the protocol of treatment for the CF infant/child, even “symptomless” ones, to include more early preventative treatments.  This is just my opinion.  While Dr. Stick did not give the breathing treatment schedule of the monitored children in the study, he did remark that the use of Pulmozyme is currently regulated by the Australian government and is limited to children ages 5+.  Brady’s first CT scan is coming up in about 2 weeks.  Look for a detailed report!  I'm feeling optimistic, but also anxious.  According to Dr. Stick, most of the data we have collected about Brady's lung health really doesn't mean much...so you never know what we are going to find on the CT! 

Brady 2.0

Brady saw his CF specialist again this morning.  It has been one month since he began Kalydeco.  We repeated blood work and the sweat test last week, so we could discuss the results with his Dr. today.  KREM2 news came with us to the appointment also, to get some footage of the Dr. examining Brady and ask him a few questions about Kalydeco and CF.   It is ALWAYS a busy day in the CF clinic and they were all very accommodating to the news crew.  We brought treats and coffee for the clinic team to try and balance out how annoying we can be sometimes…Anyway, I want to revisit Brady’s health statistics and see how things have changed in the last month.  The entire “Baseline” entry is here: http://luckycfmom.blogspot.com/2012/02/baseline.html

Cough Day 1: None.

Cough Day 27: None.  We honestly haven’t noticed any lung clearance, which to me is a good sign that his lungs actually ARE in good shape. 

Chest X-ray: His last chest X-ray looked totally normal, but was taken several months ago. 

Day 27: We’ve decided, with Brady’s Dr., to do a “low dose” chest CT scan on Brady in one month to best assess his lung health.  Brady’s Dr. said that since Kalydeco is preventative in nature, that he would feel most comfortable “challenging” Brady’s lungs by removing some of his breathing treatments and VEST if he also had a CT scan showing minimal permanent damage in the smaller airways, that are tougher to see on a regular X-ray.  I’m anxious about this because I attended a talk at the NACFC about how much damage CT scans can reveal on INFANTS with CF.  Cystic fibrosis can progress in the smaller airways in the absence of symptoms.  This silent progression is the reason that we elected to begin Pulmozyme and Hypertonic Saline so young with Brady.  I hope it has gone a long way toward helping him maintain healthy airways.  Of course, I will report back the results of the CT scan in 1 more month.  Brady’s lungs sounded clear today.

Sweat Chloride Day 1: 105mmol/L

Sweat Chloride Day 20: 48 mmol/L  Brady’s Dr. is pretty mild mannered, but he was excited to talk about this!  We discussed the average drops in the trial and then agreed that even if these huge drops are expected…it doesn’t make it any less amazing when you see it with your own eyes!

Liver Enzymes Day 1: AST—36, ALT—37

Liver Enzymes Day 22: AST—37, ALT—34  We are so relieved to see these numbers holding steady within the normal range.  Elevated liver enzymes were one of the more serious side effects of Kalydeco in trials, so we are checking Brady’s numbers monthly for 2 more months.  These numbers indicate that we aren’t overdosing him and that his liver is processing this medicine without issues. 

Weight Day 1: 47 lbs

Weight Day 27: 48 lbs  Brady is over the 90^th percentile for weight-for-age  today.  This is fantastic news.  I see some changes to Brady’s diet on the horizon. 

Height Day 1: 42 ½ in.

Height Day 27: 43 in.

Blood Oxygen Sat Day 1: 99%

Blood Oxygen Sat Day 27: 100%

Sinuses Day 1: Aggressive Polyp growth.  We were doing an irrigation treatment with a steroid solution (Betamethasone) 3 times a day to keep the inflammation down as much as we could. 

Sinuses Day 27: Clear Sinuses!  Within 3 days of beginning Kalydeco, he was breathing freely through his nose, not snoring at night, and making comments about smells.  Under the direction of Brady’s Ear/Nose/Throat specialist, we reduced the sinus rinses to 2X/day and then to once a day before stopping altogether.  He has now gone over 2 weeks without a steroid rinse and is still breathing freely through his nose!  This has been the most remarkable change for Brady since beginning Kalydeco. Oral Prednisone is the only thing that has ever worked to shrink his polyps down to the point that he could breathe like this through his nose in the past.  Brady sort of hated doing his “Nasatouch” machine and still makes comments to me that he “doesn’t want to do his nose medicine today.”  Let me tell you that it is so awesome to be able to respond, “We don’t need to do it today.  Don’t worry.  Go play.” 

Pancreatic Function Day 1: 3 Zenpep per meal, 2 per snack

Pancreatic Function Day 27: 3 Zenpep per meal, 2 per snack.  We have stopped giving him any extra beads with meals, and give him the “snack” dose more often now.  His poo has been really “normal” looking and is less stinky.  He is also down to 1-2 bowel movements a day from 2-3.  He seems to be absorbing his calories and nutrients better even though he still needs enzymes.  Getting rid of the thick sticky mucus in the GI tract must be helping him gain weight.

Breathing treatments and Airway Clearance Day 1: Morning--Albuterol and Hypersal via nebulizer followed by 20 minutes on his VEST. Evening--Albuterol, Pulmozyme, and Hypersal via neb. followed by 20 minutes in the VEST.

Breathing Treatments and Airway Clearance Day 27: Morning--Albuterol and Hypersal via nebulizer followed by 20 minutes on his VEST. Evening—Albuterol and Pulmozyme via neb. followed by 20 minutes in the VEST.  *Just today we have decided with his Dr. to omit the evening Hypersal treatment and do Pulmozyme only in the evening.  This may seem like a small reduction…but any reduction in breathing treatments is so awesome in the CF world!  Typically treatments are added continually as patients age with CF…dropping treatments is a new concept!  I also directly asked Brady’s Dr. if he felt like there was potential to no longer need any breathing treatments or VEST treatments at some point in the near future and he said he thought it was a “reasonable goal.” 

Meds Day 1: Source CF vitamins, Prevacid, Singulair, Ursodiol, Periactin, Zenpep, and started Kalydeco!

Meds Day 27: Same.  The only change we have made to his regular meds is that we no longer give him Miralax.  We used to give him around a ¼ cap or so daily to keep him from getting blockages. 

Forehead Lick Day 1: Salty

Forehead Lick Day 27: Not nearly as salty.  We noticed this change about 3 days after he began taking Kalydeco.  His sweat chloride data backs me up on this! 

Overall, we couldn’t be more pleased with the results we have seen so far and have not noticed any negative side effects.  Brady seems to be a ball of energy since beginning Kalydeco.  He has always been energetic…but he just has a little extra zip.  It might have something to do with the fact that he is sleeping better at night.  He used to struggle to breathe through his nose at night and would snore and snort himself awake several times a night.  Now his breathing is completely silent and effortless at night.  Several times I’ve had to touch his chest to make sure he was breathing AT ALL because it was so quiet. This is such a dream come true.  I almost started crying during the Dr. appointment today when we discussed the future of stepping him down from breathing treatments.  Dropping just one saline treatment a day seems so awesome to us.  His Dr. also mentioned that he thought it would be safer to test out how his lungs respond to dropping treatments when we get a little further from the cold and flu season.  There are a lot of bad bugs going around right now and we are not in the habit of taking risks!  We are more than happy to hold steady with this small drop in treatments for another month and then do the chest CT scan and go from there.  It feels like every day that passes, we get a little closer to realizing the dream of healthy breathing without machines and meds.  What an absolute dream come true!  I’m really excited to finish the interview with KREM2 and see what kind of news piece they put together.  Brady’s Dr. gave them some really optimistic, positive material to work with!!  I talked a lot about our upcoming local CF events and think the reporter might even cover some of those on the news so that is great!  More exciting updates to come!