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!