Tackling the Cause of Cystic Fibrosis One Mutation at a Time

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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.