Tackling the Cause of Cystic Fibrosis One Mutation at a Time

This little molecule is changing how some cystic fibrosis patients are treated. And how new drugs may be made in the future.

This little molecule is changing how some cystic fibrosis patients are treated. And how new drugs may be made in the future.

There was big news in the cystic fibrosis (CF) field recently: a new CF drug called ivacaftor (or VX-770 or Kalydeco) has been approved that does more than target the symptoms of CF. It actually works to get the broken gene working again.

The good news is that this is the first treatment that has the potential to cure this genetic disease (as long as the patients keep taking their medicine). The bad news is that it is only approved for around 4-5% of people with CF. This last bit of news may get a lot better in the near future but ivacaftor will never help every CF sufferer.

The reason for this has to do with the fact that there is more than one way to break the main gene involved in CF — the CFTR gene — and that there is more than one class of CFTR break.

The CFTR gene has the instructions for making the CFTR protein. This protein needs to get made and sent to the membrane so it can do its job of shuttling chloride ions back and forth. If you have a slight difference* in the gene that disrupts any step, then you can end up with CF. (Although not every slight difference leads to CF — not by a long shot!)

There are many ways to keep this protein from working. Each way may need a different medicine.

So some CF-causing differences in the CFTR gene will keep the protein from being made while others will keep it from making it to the membrane. Still others will keep the channel from opening wide enough to let the chloride ions pass through. Ivacaftor helps people in this last category.

These folks have a mutation in their gene called G551D. As you might recall, genes are written in a simple language that just has four letters—A, G, C, and T. These letters are all grouped together in a gene to form three letter words.

With the exception of three words that act like a period at the end of a sentence, each of these words corresponds to one of twenty different amino acids. So a gene is really just the instructions for stringing together certain amino acids in a certain order.

The CFTR protein is made up of 1470 of these three letter words. The people helped by ivacaftor have a letter change that causes the cell to read the 551st word as a D instead of a G. This is enough to cause the protein to have trouble letting the chloride ions through.

Ivacaftor enhances CFTR’s ability to open up. So it makes sense that it would help people with the G551D variation. But it also makes sense why it won’t help for other CF patients.

For example, around 10% of people with CF have what is called a nonsense mutation in their CFTR gene. What happens in these cases is that a word that normally corresponds to an amino acid is mutated so that it now codes for a period. The cell stops reading the gene too soon and so you end up with only a part of the protein. Usually these “truncated” proteins can’t do much of anything.

Giving one of these patients a drug that helps the full length protein open wider isn’t going to be of much help. No, you need a drug that will ignore the period and make at least some functional CFTR. And there is a drug in the pipeline called PTC-124 that just might be able to pull this off. Of course PTC-124 will be of little use for people with the G551D variant!

Now having said this, ivacaftor may be more than a one trick pony. In fact, it may be able to help the majority of people with CF in the near future.

Our genetic uniqueness will make finding cures more difficult.

Most people with CF have a certain mutation called delta508. Basically the 508th word has gone missing in their CFTR gene.

What happens in these cases is that most of the CFTR protein gets lost on its way to the membrane. But a tiny bit does make it to the right place and ivacaftor might be able to boost that little bit enough to help these patients.

Ivacaftor is currently in Phase 2 clinical trials to see if it can help patients with the delta508 variant. The results are promising so far.

These treatments for CF are showing how we may have to deal with genetic diseases in the future. As I talked about in my last blog, we are all unique genetically. This means that even simple genetic diseases are going to be like CF and come in many different classes that will all have to be treated differently. It also means that new drugs may only help a relatively small number of patients.

This last point will require a paradigm shift in how drugs are developed too. Most big pharma companies won’t touch drugs that treat so few people. Ivacaftor is showing us the way here too.

The Cystic Fibrosis Foundation provided big pharma with a sizeable chunk of change to get this drug through clinical trials and to the market. The new paradigm may be that interested patient groups collaborate with big pharma to get these “boutique” drugs to market.

It’ll be interesting to see if this is a viable business model. But at least for now a minority of CF patients can have real hope.

*These DNA differences go by lots of different names: variant, SNP, mutation, mistake, etc.

Tackling the Cause of Cystic Fibrosis One Mutation at a Time 21 June,2012Dr. Barry Starr

  • this story compliments well with the other story on this blog about pesonalized medicine! – Gabriel Roybal

  • CF_Mum_in_Oz

    Here’s hoping one day soon CF will stand for Cure Found 🙂
    FDA approves Kalydeco to treat rare form of cystic fibrosis
    Breakthrough therapy targets defective protein

    The U.S. Food and Drug Administration today approved Kalydeco (ivacaftor) for the treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm289633.htm

  • CF_Mum_in_Oz

    Shares of Vertex Pharmaceuticals Inc. plunged Tuesday after the company said it made a mistake in calculating results from a clinical trial of two cystic fibrosis drugs.

    The Cambridge, Mass., company said the combination of its drug Kalydeco and an experimental medication called VX-809 did not work as well as it had initially reported. The original trial results suggested that Kalydeco and VX-809 were more effective at improving lung function in patients with the common type of cystic fibrosis


    • Barry

      I guess that doesn’t surprise me…the delta 508 protein is pretty messed up. Still, what a great deal for G551 folks and what great promise that 508 people may find something similar one day.

      • CF_Mum_in_Oz

        we can only hope hey Barry
        I’m finding the results with Kaly a bit disappointing, OK it only targets 1 gene mutation, but it’s only helping about 1/3rd of them
        I guess for that 1/3rd it’s great
        and what follows on from this could be huge
        we can only hope
        there’s only roughly 3,000 in Australia
        compared to 30,000 in US
        so of the roughly 120 predicted, which has turned out to be 150 in Oz with G551D
        50 people could get help
        that is better than nothing
        I recently found out this drug is 300,00 a year per person

  • CF_Mum_in_Oz

    I’m so glad I found your website
    I have enjoyed reading many pages today
    not just about CF either
    fascinating info Thankyou 🙂

  • LMB

    This was the best explanation of what goes wrong in the CFTR gene and also why it has taken so long to be able to find a treatment that actually works on the basic defect. Thank you so much for your work. Perhaps a cure is actually in sight.

    • Barry

      I’m glad you found it useful…comments like yours keep me writing so thanks! Also, probably a cure is a long way away but treatments that go after the cause and so greatly improve the symptoms and longevity of people with CF will hopefully be here much sooner.

  • MPink

    I was curious if you were still checking this? My four year old had genetic testing for cf and the report is so confusing. Any help would be so greatly appreciated! We’ve been waiting six weeks for treat results that no one can agree on.

  • Sarah Onstead Guagliardo

    My one month old son was just diagnosed with CF and his doctor said he is heterozygous for the G551 variant if I’m not mistaken. Would this drug be able to help him then? I’m still learning how all of this works…


Dr. Barry Starr

Dr. Barry Starr (@geneticsboy) is a Geneticist-in-Residence at The Tech Museum of Innovation in San Jose, CA and runs their Stanford at The Tech program. The program is part of an ongoing collaboration between the Stanford Department of Genetics and The Tech Museum of Innovation. Together these two partners created the Genetics: Technology with a Twist exhibition.

You can also see additional posts by Barry at KQED Science, and read his previous contributions to QUEST, a project dedicated to exploring the Science of Sustainability.

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