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The Tragedy of the Cystic Fibrosis Cure
The Tragedy of the Cystic Fibrosis Cure
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0:00
"Woe to the child who tastes salty from a kiss on the brow,
0:04
for he is cursed and soon will die."
0:06
That ominous piece of folklore dates back at least to medieval times,
0:11
and we now know that it likely referred to children with cystic fibrosis.
0:15
For most of human history, cystic fibrosis was a death sentence.
0:19
But in the last few years, scientists have developed drugs
0:23
so effective that for some, they basically reverse the disease.
0:27
These new treatments have dramatically improved
0:29
the lives of 90 percent of patients with the disease.
0:33
Maybe you can see the problem, though.
0:35
About 10 percent of cystic fibrosis patients have genetic
0:39
mutations that these miracle drugs do nothing to fix.
0:42
So scientists are hunting for a solution
0:44
that will make up the difference.
0:46
Here’s what the future might hold for these salty babies.
0:49
[♪INTRO]
0:53
While cystic fibrosis has been around for centuries,
0:56
it only got its name in the 1930s, when pathologists observed
1:00
fibrous cysts in pancreas samples taken
1:03
from children sick with a then-undefined illness.
1:06
And while it was first noticed in the pancreas,
1:09
cystic fibrosis causes problems pretty much everywhere in the body.
1:13
The disease is caused by mutations in the gene that makes
1:16
a certain protein in the outside membrane of your epithelial cells.
1:20
And it’s a very important protein, because it
1:23
controls salt and water levels in those cells.
1:25
When that protein doesn’t work the way it should,
1:28
your cells can’t hold onto the salt they need
1:30
and it just kinda leaks out, hence the salty babies.
1:33
This is very, very bad.
1:36
People with cystic fibrosis have issues with electrolyte balance,
1:39
staying hydrated, and crucially, they have really messed up mucus.
1:43
You probably don’t think about your
1:45
mucus very much unless you’ve got a cold.
1:47
But you have it all over the place in your body,
1:49
and it plays a major role in the function of a lot of organs.
1:53
Including our lungs.
1:54
You have a nice layer of mucus coating the inside of your lungs,
1:58
where it helps trap pathogens and particles before they can damage
2:01
the lungs and be absorbed into your bloodstream,
2:04
and then you can cough it out.
2:05
But crucially, that mucus needs to be thin enough
2:08
that it won’t clog up the works, so to speak.
2:10
People with cystic fibrosis have mucus that’s thick and tar-like,
2:14
and they basically can’t expel it from their lungs at all.
2:17
So all those pathogenic baddies that get stuck in the mucus just…
2:21
stay there, which means that people with
2:23
cystic fibrosis often get really nasty lung infections.
2:28
And if you have all these infectious bacteria trapped in your lungs,
2:32
you’re pretty darn contagious, and these infections are most
2:36
dangerous if they spread to other people with cystic fibrosis.
2:40
Which means that cystic fibrosis patients
2:42
have been social distancing before it was cool –
2:44
they’ve had to, so they don’t make each other sicker.
2:47
Because the lungs can’t clear out the excess mucus on their own,
2:51
one long-term cystic fibrosis treatment is manual percussion therapy,
2:55
AKA pounding on the chest to try and knock this mucus loose.
2:59
Every day. Several times a day.
3:01
But remember, you have mucus in more places than just your lungs.
3:05
It’s in lots of other organs too, including the pancreas,
3:08
as we saw with those first documented cases in the 1930s.
3:12
That too-thick mucus blocks up the pancreas,
3:15
which stops the enzymes made there from getting into
3:18
your small intestine, meaning that digestion gets all messed up.
3:21
So people with cystic fibrosis need to take
3:24
medications with digestive enzymes to correct this.
3:27
It can even cause fertility issues, because again,
3:30
mucus is everywhere, including the lining of the cervix.
3:34
And cystic fibrosis is caused by a mutation in just a single gene,
3:38
which was identified in 1989. Scientists called it cystic fibrosis
3:42
transmembrane conductance regulator gene, or CFTR for short.
3:46
Even if your CFTR gene is mutated,
3:49
your body still reads it out, and makes the protein it encodes.
3:53
It’s just probably going to be a messed-up version of the protein.
3:56
But not all mutations affect the protein in the same way.
3:59
And the way the gene is broken is just as important as the fact
4:03
that it’s broken, because some of these mutations result
4:06
in much more severe cases of cystic fibrosis than others.
4:10
Like, some mutations can make shortened,
4:12
non-functional versions of the CFTR ion pump.
4:15
Other mutations impact the protein’s stability,
4:18
so it breaks down too quickly to be useful.
4:20
So if it’s just one problem gene, that may sound
4:23
like gene editing therapies would be a simple fix.
4:26
But there are at least 1,200 known mutations in CFTR
4:31
that cause disease, and to effectively use gene editing,
4:35
you’d basically need a custom treatment for each one.
4:38
The most common mutation is F508del,
4:42
which about 85% of people with cystic fibrosis in the US have.
4:46
The F508del mutation causes a single amino acid to be
4:50
missing from the final protein, and that causes chaos.
4:54
The resulting CFTR protein is badly folded, breaks down quickly,
4:58
and the few that make it to the surface are really bad at their jobs.
5:02
There are a few medications that try to boost the proteins that
5:05
the bodies of cystic fibrosis patients are already making.
5:09
The first one’s called Ivacaftor, a drug that helps make
5:12
existing CFTR proteins more effective at ion transport.
5:16
This is great if your mutation means your
5:18
ion pumps aren’t super effective, but it doesn’t do much for
5:21
cells without enough CFTRs already on the cell surface.
5:25
Ivacaftor was tailored to a mutation that
5:28
about 4% of CF patients have, called G551D,
5:32
where the CFTR channel is stable and where it should be,
5:36
but doesn’t let salt ions flow through like it’s supposed to.
5:39
Basically, it’s like CFTR is a gate,
5:41
and with the G551D mutation, the gate isn’t opening.
5:45
When Ivacaftor binds to those damaged proteins,
5:48
it acts like a key, unlocking the gate so ions can flow through.
5:52
But for the F508del variant, you have to fix the ion channel and
5:56
stop it from breaking down, so Ivacaftor was only part of the solution.
6:01
Mutated CFTR proteins break down faster because they’re misfolded,
6:05
and that means they often deteriorate
6:07
before they even get transported to the surface.
6:09
So the next step in treating cystic fibrosis was to find
6:12
drugs that help mutated CFTR fold correctly.
6:15
Enter: Tezacaftor and elexacaftor.
6:18
Both of these drugs bind to F508del CFTR proteins
6:22
and help fix the folding issue, meaning they are nice and stable
6:26
and can be transported to the cell surface to be unlocked by Ivacaftor.
6:30
Tezacaftor and elexacaftor each bind to a different spot on the protein,
6:34
meaning they improve the odds of each protein folding up properly,
6:38
and getting to the cell surface so that
6:40
Ivacaftor can do its job of opening the ion gate.
6:43
In 2019, these three medications were approved in
6:46
a combination medicine called Trikafta, and from the
6:50
minute patients started taking it, the effects were profound.
6:53
It starts with what people with cystic fibrosis call the Purge.
6:57
And in this case, it’s not a day where laws stop counting.
7:01
This purge has a lot more phlegm.
7:03
Once a patient takes their first dose of Trikafta,
7:06
they start to cough up all the thick mucus in their lungs,
7:09
usually within 24 hours. Once it’s out, they can just breathe.
7:14
Some people have reported being able to run up hills
7:16
when previously they could barely walk up stairs,
7:20
and others started training for marathons.
7:22
Some people with cystic fibrosis even started
7:24
being able to get pregnant, since CFTR everywhere
7:27
was functioning normally, including in the cervix.
7:30
Lung infections have gone down too, which means people with
7:33
cystic fibrosis who are on Trikafta no longer need to socially distance.
7:38
In the time that it’s been available on the market,
7:40
this treatment has radically changed how people view cystic fibrosis.
7:44
Before Trikafta, the lifespan of someone with cystic fibrosis varied,
7:48
but few patients lived past their 40s.
7:50
Now doctors estimate that a patient who stays on Trikafta
7:54
can expect to have a normal life expectancy.
7:56
Like, it’s so survivable that children with cystic fibrosis
8:00
also no longer automatically qualify for the Make-a-Wish program,
8:04
because it’s no longer a given that
8:06
the condition will be life threatening.
8:08
They still can qualify, it’s just that their case needs
8:11
to be reviewed first, where before, it was like
8:13
“Oh, you have cystic fibrosis? Welcome to Make-A-Wish!”
8:16
This drastic improvement in the prognosis for cystic fibrosis has
8:20
been described as similar to the AIDS epidemic after
8:23
the pharmaceutical breakthroughs of the ‘90s.
8:25
One new medication turned a death
8:27
sentence into a manageable illness.
8:29
Doctors suddenly needed to learn how to care for
8:32
patients who weren’t dying, and some patients even struggled
8:35
with the reality that they were here for the long haul after all.
8:38
Imagine realizing you’re going to need a retirement plan when for
8:42
most of your life you didn’t know if you’d live long enough to retire.
8:45
Trikafta isn’t a true cure for cystic fibrosis,
8:49
because patients need to keep taking it twice daily to stay healthy.
8:52
But staying on it keeps the tar-like mucus at bay, which is great news.
8:56
That said, there are also some downsides to the treatment.
9:00
But before we get into those, all research needs funding,
9:03
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9:07
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9:10
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9:14
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9:57
One major downside of this new medication is that some people
10:01
have severe side effects, including cataracts, liver issues,
10:05
and various neurological and neuropsychiatric issues, like insomnia.
10:09
For some patients, the side effects are bad
10:11
enough that they’ve had to stop taking it.
10:13
Another issue is the money.
10:15
In the US, a year’s supply of Trikafta costs over $300,000 annually
10:20
before insurance, even though it costs about $6,000 to produce.
10:25
That’s partially because drug companies have to recoup the
10:28
cost of developing the drug and getting it through clinical trials.
10:32
But also, for-profit healthcare sucks
10:34
when it’s the patients staring at their medical bills.
10:36
It also means that in many lower income nations,
10:39
Trikafta is basically impossible to get.
10:42
Some generic versions have been manufactured,
10:44
and are available at a fraction of the price.
10:46
They’re still $12,000, but hey, that’s only
10:49
4% of the name-brand sticker price.
10:51
And there’s still a massive demand for these medications.
10:54
There are some workarounds, including developing novel
10:58
ways to get more bang out of smaller doses of the drug.
11:01
Scientists in South Africa have shown that it could
11:04
be possible to reduce the dose of Trikafta required,
11:07
if patients also took medication to slow
11:10
down how quickly they metabolized the drugs.
11:13
But the biggest limitation is that not everyone can take Trikafta,
11:17
and not just because of side effects or access.
11:21
It just doesn’t work for all the possible
11:23
mutations that lead to cystic fibrosis.
11:25
More recent research has found that Trikafta works on some of the
11:29
other cystic fibrosis mutations besides the all-too-common F508del,
11:34
but that list is short, only about 270 additional mutations.
11:38
All in all, about 90% of people with cystic fibrosis can take it,
11:42
but that leaves the other 10% on the outside looking in.
11:45
Although the F508del mutation is the most common cause of
11:49
cystic fibrosis in North America and West Europe,
11:52
in other populations, it’s a much rarer cause
11:55
of cystic fibrosis than other mutations.
11:58
So the usefulness of Trikafta varies by country
12:01
depending on what mutations are common.
12:03
Vertex, the company that makes Trikafta,
12:06
has released another combo cystic fibrosis medicine called Alyftrek,
12:10
but this is taken once-a-day instead of every twelve hours like Trikafta.
12:14
Alyftrek also primarily targets F508del mutations, but like Trikafta,
12:20
it seems to help with some non-F508del mutations too,
12:24
and maybe even more of them than Trikafta can hit.
12:27
And aside from the clinical and medical side of things,
12:30
we haven’t even gotten into the social change.
12:32
As more people are functionally cured, the support communities
12:36
for cystic fibrosis patients are shrinking, leaving an ever-smaller
12:40
group of people that are still drowning in their own lungs.
12:43
There’s no guidebook for how to cope with the idea that most of your
12:47
friends that share your disease can feel better, but you’re still sick.
12:51
Fixing the mutations that can’t be treated with
12:53
Trikafta or Alyftrek may require a totally different strategy,
12:58
like the gene therapy we mentioned earlier.
13:00
And in 2024, researchers were able to develop a
13:03
CRISPR-based gene therapy that they tested in lab mice.
13:07
These mice had a CFTR mutation resulting
13:09
in a shortened version of the protein.
13:11
So, the gene editing package went in and corrected the mutation
13:15
so cells could make full-length CFTR. And it worked pretty well!
13:19
The downside is that this strategy needs to be bespoke to
13:22
the patient’s particular mutation, and as we mentioned
13:25
there are more than 1,000 known, so it’s not broadly applicable.
13:30
But the good news is that there may be another way.
13:32
Instead of editing whatever mutations are present in
13:35
an existing CFTR gene, scientists have found a way
13:38
to add a brand-new, full-length, fully-functional CFTR gene to cells.
13:44
It doesn’t matter if the cells make some janky CFTR proteins,
13:47
because they can make the right ones, too.
13:49
This therapy is still at the cells-in-a-dish stage,
13:52
but it could be a game-changer.
13:54
Other genetic tools are being developed too,
13:56
with some in clinical trials.
13:58
Trikafta has been revolutionary for many people with cystic fibrosis.
14:02
They can now live practically normal lives.
14:05
The story isn’t over though, since there are still many people
14:08
with cystic fibrosis for whom Trikafta isn’t an option.
14:12
So scientists continue to work on these problems in the hopes
14:15
that some day soon, cystic fibrosis will be a thing of the past.
14:23
[♪OUTRO]
