New Therapies to Treat Cystic Fibrosis

New Therapies to Treat Cystic Fibrosis


(upbeat music) – Hi. I’m Ali Ashare, and I’m a pulmonologist and
immunologist, and I moved to the upper valley about
nine years ago, and started, moved with my research program
to Dartmouth at that time, and my work really focuses
on finding new therapies to treat cystic fibrosis lung disease. I first became interested
in cystic fibrosis when I was a pulmonary fellow
at the University of Iowa, and I developed a bond
with a patient named Jack, we shared a pretty special bond because we had the same birthday, and I took care of him several
times during my fellowship. During one prolonged hospitalization during my second year of fellowship, he unfortunately didn’t get better, and he died of cystic
fibrosis lung disease. And this was a particularly
powerful moment in my career, as I sort of worked
around processing the fact that this young man, who
was my age, had died, and my life was really just beginning. And I’ve had a lot of
inspirational moments with patients with cystic
fibrosis throughout the years that have really kept me doing what I do, but I would say that was
really the one pivotal moment where CF really kind of
hijacked my professional life. So cystic fibrosis is
a multi-system disease, it affects multiple
organs, but most patients end up dying from
progressive lung disease. So patients have
overwhelming lung infections, and they develop
overwhelming inflammation, which causes lung damage, and they ultimately die of lung disease. In the normal lung, the cells of the lung are lined with a thin,
watery layer of liquid, and that layer of liquid is
really there to protect us so that when we’re all
walking around breathing, and we inhale bacteria, or viruses, or other debris, that
layer of watery liquid really protects the lining of the lung, or the cells of the lung. In patients with cystic fibrosis, that layer isn’t liquid
and watery anymore, instead it becomes
really thick and sticky, and it becomes an environment where bacteria can actually grow,
and live very happily. So my work really focuses
a lot on immune cells in the cystic fibrosis
lung, and in particular, I work on macrophages, and
macrophages are really important immune cells that live in the lung, and other places in the body. In the lung, both healthy and diseased, there are abundant
macrophages that live there, and their job is, when we inhale bacteria, or viruses, or other debris,
they take care of those. They sort of eat anything that we inhale, and they do it, generally, pretty quietly, and without causing much damage. If there is an infection,
like in pneumonia, in a healthy person, and
the macrophages sense that there is more bacteria
than they can handle, they change their response in two ways. And the first way is that they generate some inflammation on their own. And the second way is
they send out sort of a distress signal for
other immune cells to come, so if you think of it in other words, the macrophages are basically
making a 911 call, right, and if you think of the other immune cells as emergency responders, the
macrophages are calling them to come to the scene of the infection. And then once those cells come, and they start to fight the infection, the macrophages have a different role, and they switch their role to say, “Okay, we’re done here, and
this infection is taken care of, “you can stop,” and they tell those cells to shut off inflammation,
and then the macrophages kinda clean up the mess at the end, so that the lung can go back to normal. So in our work, we’ve found
that cystic fibrosis macrophages are abnormal in at least two ways. So first, they have an abnormal inflammatory response to
bacteria, they produce more inflammation than
a healthy macrophage. And the second thing is that
they’re unable to switch from “We need cells here
and we need inflammation” to “Turn off the
inflammation, we’re done.” So they don’t have that way to switch. And what we’ve found is that,
in order for a macrophage to switch from inflammation to
“Let’s resolve inflammation,” they have to change the way
that they produce energy. And so cells can produce energy in a couple of different ways, and if you think of energy
as the cell’s currency, say that one way of producing energy is that the cell does a lot of work to generate that currency, and that’s the inflammation generating currency. The other way would be that
the cell could tap into, like, its saving account and
generate currency that way, and the cystic fibrosis
macrophages are constantly in a workhorse mode, where
they generate inflammation, and they can’t switch to that
“Tap into my savings account, “I need to resolve inflammation” mode, and so the inflammation persists. So we’ve discovered two
potential targets in our work, where we’ve shown, in
our in vitro studies, using primary macrophages that we take out of the cystic fibrosis lung, that, if we target those two areas, we can actually have
the cells switch from a pro-inflammation, generate
lots of information phenotype, to a “Let’s resolve inflammation.” And we’re really hoping to be able to develop these therapies further, so that we can test them in patients, and so we’re looking for
support and additional funding to be able to design and develop a multi-center clinical
trial to test these therapies in patients with cystic fibrosis. We have a lot of antibiotics out there to treat patients with cystic fibrosis, but we really lack standard therapies to target the inflammation,
and if we could target the inflammation,
we really feel like we could prevent some of the progressive lung damage that happens. When I moved to Dartmouth nine years ago, one of the main reasons I came here was because of the innovative
and collegial research of the Lung Biology Center. The Lung Biology Center at
Geisel is run by Bruce Stanton, and it’s one of the
premier cystic fibrosis research programs in the country. It’s one of 10 Cystic
Fibrosis Foundation-designated research development
programs in the country, and the only one in the Northeast region. And that really signifies the excellent work that’s being done here. That’s a multidisciplinary group, where there’s lots of
different investigators who target different
aspects of cystic fibrosis, with the same goal of trying
to develop new therapies to make patients live longer. And so I work on inflammation, and I have colleagues who work on these complex bacterial infections,
and others who work on how the bacteria impacts the
host cell, or the patient cell. And there’s other colleagues who work on sort of the underlying
defect of cystic fibrosis, but all towards one goal,
and so our main goal, what we really want to do, is develop, is have additional funding to develop a cystic fibrosis research
center at Dartmouth that would allow us to really promote our most innovative scientists to do the work necessary
to develop novel therapies aimed at prolonging
life in cystic fibrosis. So I feel really privileged
to work with these patients with cystic fibrosis, they live with a lifelong chronic disease
that impacts them in ways that none of us could really
even begin to understand, and they inspire me every
day to keep doing what I do. When I was a fellow and I took
care of Jack in the hospital, the average survival for cystic fibrosis was only 20 years, or in the 20s. They’ve developed a lot of
new therapies since then, and patients are living longer, but the average survival is still only 40, and 40 is really not good enough. And we’d like to be able to
see newer therapies come out that target different
aspects of the disease so patients can live
into their 70s and 80s. 10 years ago, I went to a lot of patient funerals every year. Now, thankfully, my patients have more weddings and graduations,
and fewer funerals. And that’s a really nice thing, but I think we can do even better, and I think with additional support, Dartmouth can really
be on the map as being a pivotal center for developing
new and novel therapies to prolong the lives of patients with CF so they can live longer
and healthier lives. – You answered my question
about the potential to extend the life of CF patients, but how much of a commitment
do you think it would take to develop the center as you envision it to continue to produce
these new, novel therapies? – So I’ve thought a lot about that, and that’s a very good question, and I think that the
commitment that we would need to really develop a
center, and really promote our most innovative scientists,
would be $5 million. – Well, Dr. Ashare, you’re clearly devoted to these patients, who
really have a fairly devastating disease affecting
them and their families, so doing things to improve
their quality of life, prolong their life, really is impactful. I want to just drill down
a little bit on your work, and I understand it’s
done within the concept of the whole Lung Biology Center, and that’s what’s great,
because it’s so integrated, but your work is looking to find how you change the switch
on the macrophages, so that they function
in a more normal way, not in a constant inflammation. So are you looking at targets, are you developing drug therapies that are really specific
for these macrophages that have become abnormal
in patients with CF? – That’s a good question,
we’re not developing new drugs, we have found targets within
that metabolic switch, sort of the energy generating
switch within the cell, of medications that are
actually already FDA approved for other conditions that we can then use for a novel indication in cystic fibrosis, to switch the way the
macrophages function, and allow them to resolve inflammation, rather than generate more inflammation. – So taking advantage of existing drugs, but repurposing them for these patients. – Correct, exactly. – So that is innovative, and it’s actually a very efficient way to target,
to treat these patients. Well, thank you, thank you
for the work you’re doing, and the work that your
colleagues are doing to improve the lives of the
patients with cystic fibrosis.

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5 thoughts on “New Therapies to Treat Cystic Fibrosis”

  • Impressive. I found this video so interesting and i really wish i will have an opportunity to pay and gain some experience in this prestigious school.

  • Jack, my son, is 33 this year. Only two years ago, same year his daughter was born, he found out he had CF. Over the years doctors just said he had allergies, gave us some meds and sent him on his way. I of course feel guilty for, not fighting hard enough to find the actual cause to his problems when he was younger and for being half of the DNA reason his daughter will lose her daddy way too young. Is there work being done to go into the DNA and repair the gene on chromosome 7 which, IF I understand correctly, is where the mutation is that my son inherited from me?

  • What about the issue of selenium deficiency? A doctor in the 70s found the cure and it was suppressed. If you have cystic fibrosis keep digging and don’t just trust the status quo.

  • I’m a 15 year Sarcoidosis sufferer. The inflammation sounds very similar. Maybe there’s hope for the thousands of sarcoidosis patients as well.

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