Keynote Lecturer Christine Seidman on Genetic Approaches to Cardiomyopathy


(mellow music) – Hello, I’m Beth McNally, and I’m a cardiologist and geneticist from Chicago, Illinois. And I’m here today with Cricket Seidman and Jil Tardiff. And we are at the Basic
Cardiovascular Sciences Meeting here in Boston, Massachusetts. We just had our keynote lecture, which was given by Doctor Seidman. And the topic of her talk today was around dilated cardiomyopathy and hypertrophic cardiomyopathy and the important sets of mutations that lead to these important
clinical disorders. Doctor Seidman has been
a leader in the field, and I’m going to let her
tell you a little bit about some of what she talked about today. – Well, thank you very much, Beth. I’m here joined by really
two very close colleagues who have contributed incredible amounts to this field, as well. But I think all of us would agree that understanding the genetic basis of heart disease has
been enormously impactful not only for making early
diagnosis of patients so that we can take better
care of them longitudinally, but also to that we can
really use that information to build models and
understand disease mechanisms. And from that approach, it allows us to really begin to not only dissect the pathways that are
perturbed by gene mutations but to begin to identify targets that can be candidates for
future drug development. Ultimately, that, we
hope, will really advance the not only diagnosis but treatment of dilated and hypertrophic
cardiomyopathy. – So Cricket, I have a question for you. So today you talked about
myosin mutations largely and one of the questions I had for you, is when thinking about
Mavacamten, for example, do you see, going forward, us developing different sorts of small
molecule inhibitors or activators depending on the mechanism involved, for different subsets of mutations? Because we can’t expect
that one size will fit all and you know, from my
perspective, I’ve always wondered whether we’re going to evolve this field such that we’re treating
HCM and possibly genetic DCM more like we treat heart failure. Where we’re sort of hitting
different components of the downstream activation
that causes, that is caused by these biophysical derangements. So do you have any opinion about that? – Yeah, Jill I totally agree with you. We know that the thick
and the thin filament work together, but they each have distinct and very important properties that can be perturbed by a mutation in one of the proteins of
the thin or thick filaments. And I think its very
unlikely that we’ll have the opportunity to have
one drug correct the whole biophysical properties or
abnormalities that occur in the sarcomeres. And being able to tease out the effects of altering the thin filament, as compared to thick filament, will be very important. And I think these ideas of developing small molecules that really modulate allow us, not only to understand
the biophysical properties, but to be able to see
what their influences are, in the context of a healthy heart and a mutant heart, a heart
with a mutation, that is. – Great – So, one of the things I’ve most enjoyed having been in this field for a long time and watching it is we spend a lot of time, earlier on using mouse models
for a lot of what we do, and you created some of the
most important mouse models for the field to be able to work on. But what’s so exciting now is to be able to see this happening with patient’s cells, and human cells, and the progress made with
doing things in isolated cells and then engineered heart tissues, and representing these diseases
actually using human cells. So maybe you can talk
about some of the findings that you’ve had with that because I thought the pictures
today were just fantastic, – Well, thank you. – Looking at some of the contraction. – It’s really pretty amazing genetic engineering of cell lines that we can then differentiate into relatively mature cardiomyocytes has allowed us to study heart disease truly in a dish. And it’s not mouse
hearts, it’s human hearts that really are beating in our dishes. And I think that really allows us, as you well know, the
opportunity to not have to assume what would be
happening in a human scenario and that is because, frankly, the expression of many
genes, as we all know, is very different between a heart from a mouse and a heart from a human. And so this ability to really go directly to those cell lines is very, very important. The other thing that’s really
opportune, in my opinion, is that we can then
begin to tweak a pathway using genetic approaches, again modulating a gene expression, without having off target effects of small molecules, and the like, to really begin to probe
so that complementary ability to tease out mechanisms from a genetic point of view is something that all of us
have been using for many years. And I think is very, very impactful. I think, as well, while
there’s a very large group of people who are
working on being able to make cells that will make embryoid bodies and actual living 3-dimensional tissues, that we have a ways to go yet. We know only some of the interacting effects that are important for actually getting 3-dimensional tissues. And while I am very hopeful
that that’ll go forward, there’s a lot more work that’s needed to be able to have a morphologic structure that we recognize as a ventricular, or indeed someday an
atrial piece of tissue. – But it is exciting, I mean to be able, I don’t know, every time we, – Yeah – Grow those cells in a dish, and if you show it to people, and to actually see the
contraction of cells in dish. – Yes – I think even in the
absence of our engineered heart tissues there’s
still a lot to be done, even with the cardiomyocytes, just as they grow. And when you’re trying to think about platforms for drug screening, sometimes the engineered heart tissues are a little more limited, just for throughput. – Yeah – And so I think, has that, I know the approach of
screening for small molecules has been reliant on purified proteins but then I assume there’s a second stage that is also involving using cells. – Yeah – For a lot of that screening – Certainly I think the ability to do high throughput
screens of cardiomyocytes, that are now human, IPS,
derived cardiomyocytes that carry, not only, this mutation, but the whole different
spectrum of different mutations really provides incredible fidelity of being able to see
the direct consequences. And as well, the opportunity to explore some off target effects, which
is clearly very important in terms of drug development. Whether we have enough
protein-protein interactions that occur between cells, I think really remains a work in progress. But it has completely revolutionized what we do in the laboratory. And I think made it more impactful, in terms of direct moving
towards patient care. – So, I know the small molecules, again, so, the work is
really taking small molecules and targeting the myosin directly. And with that is moving
towards a therapeutic, we hope. The data looked very
exciting at this point. But I know, I as a cardio-geneticist, I get asked all the time, about, what about gene editing? And so I’m just going to ask you that what are your thoughts about how realistic gene editing is for being able to actually treat some of these genetic disorders that we see all of the time in patients. – Gene editing, certainly
would be the ultimate therapy in fact one could
potentially use the word cure because you could correct
a fundamental gene defect. The question then is how
could we make that happen? And there are a number of barriers that I think we all recognize, and need to acknowledge. Certainly, if one corrects a mutation before the heart is formed at the embryo stage, very early embryo stage, you could have the
potential to prevent any heart disease from emerging
in that particular fetus, and ultimately individual. The problem is the off target effects – Yeah – And we don’t yet know
the scope of those, nor do we have a good way of monitoring if they are evolving over time. We can sequence cells, we can look for whether
there’s an off target hit that we had not intended to occur, or we can simply wait
and see what emerges. And both of those are
not very effective ways to know in advance what
might have gone wrong despite our best intention. The alternative approach
is been, obviously, to correct the adult heart
or the well-formed heart of an individual. And that raises another complexity, whereas we can certainly manipulate a cell in a cell culture dish or a group of cells in
a mice, a mouse rather, it’s much harder to be able to percolate that effective gene correction therapy across the entire myocardium. This is where, unfortunately, the hematologic system – [Beth] Advantages – A lot of advantages. Because you can correct a stem cell that then will repopulate
all the hematologic lineages that are ultimately being targeted. Whereas out heart cells fail to divide in any great extent throughout life and so we would have to
manipulate the genome of every one of those cardiomyocytes. Or a least a substantial
proportion of them. You know, that being said, the opportunities to
address these challenges have never been better. The models now exist to do it in cells, in small tissues, and, indeed, I’m sure in
organoids in short order. And I think that we will
be seeing advances in that opportunity, and that direction. There’s no question that the power of that is truly remarkable. The one other hiccup, I think that’s worth mentioning is that one of the things that human
genetics has taught all of us is that no two patients have
exactly the same mutation – [Beth] That’s true
– [Jil] That’s right – Even if the phenotype and the disease that we give it is exactly the same the precise nucleotide
difference is very different. And so the challenges for being able to execute this across populations will be, again, really quite substantial. That being said, I think it’s worth the effort, and I know many of us are trying. – Yes, indeed – Yeah – And I think also, the
other thing to remember is that incrementally,
we don’t have very many approaches, medical approaches, – Right – For these patients. So I think even any
incremental improvement has a lot of power, to really change the natural
history of the disease. Especially when we start treating people in a younger sample (mumbles) As opposed to, you know,
sort of end stage treatments, and so I think there’s a lot of, even these smaller incremental approaches are going to have a big impact. – Right, I would not in any way underplay these incremental advances. I think they’re very
important, and substantive. As you well know, we now, from understanding the
genetic substrate for diseases we recognize a pre-clinical phenotype. Abnormalities that are subtle that we would not cause disease, but we certainly can
recognize as not being what we would expect and usually
see in healthy individuals without those mutations. And so that really allows
us to be preemptive – [Jil] Exactly – In intervening, if we can do so without deleterious effects. The other real challenge,
I think, would be the opportunity to note at
what point does the heart turn from having a subtle
pre-clinical phenotype to what we know is then the emergence of overt disease. If we could target our
therapies right there we’d have the best of both worlds. – I agree with that. I think a lot of this is
the interesting aspect of the communication between
the basic and the clinical side – Yup – In terms of great
improvements in imaging and biomarkers, and allows
us actually stage the disease – Right – Which would really be
a great advance for us because we do now, with
the power of genetics, as you just said, we do get genotype positive phenotype negative – Yup – They’re young. We have a general idea of
what their prognosis may be based on their family history, and it’s really imperative. – Yes – For us to do do more than to stand by and wait for the phenotype to develop. – Absolutely – And I think this is in many ways in comparison, for example,
the heart failure field this is a gift that we have. We have this, we know who
had the predisposition. – Yes – And so learning how to
harness that to improve you know, long term care I think is right where we need to be. And I think that’s where
a lot of your work is just zeroing in on, is just really exciting. – I think it’s a lot of
our work quite honestly, but I would also say, the other thing, that allowing, knowing
when to intervene early. – [Jil] Umhmm – Probably will have more efficacy. – Absolutely – You know, if nothing, the better than the cancer
field has taught us, you know, early recognition of disease, and intervention before
there is end stage phenotypes is hugely impactful. Not only in the efficacy of treatments, but much more importantly, obviously, in the lives of people
who carry these disorders. So if we could really back
into knowing when to intervene and really have an effective
intervention at that point I think is great opportunity that we will reduce the burden of heart failure, and we may not need some
of the advance therapies that while hopeful, in terms of maintaining
some protracted life, are not cures by a long shot.
– [Jil] Long shot. – Right, I think it’s a
good point to think about, which is, we again, we
know these people are genetically predisposed to develop either dilated or hypertrophic, I think hypertrophic’s a
harder disease to treat, cause we don’t have really
great therapies for it, and that’s why your work is so important. For dilated, we do have – [Jil] Yeah
– [Cricket] Yeah – Some pretty darn therapies
available right now. – Yeah – In the form of guideline
directed therapy that that is really quite
efficacious in treating people with heart failure. And I think one of our
big questions right now is at what point do we
start those therapies for somebody whose genetically
predisposed for that? – Right – And so I think that will
be really good questions for us to be asking and
answering pretty, pretty soon. – Absolutely – Yeah – Absolutely – So with that, I’d like to thank Dr.
Tardiff and Dr. Seidman and we, this has been from the Basic Cardiovascular Sciences Meeting here in Boston, Massachusets. Thank you. – [Jil and Cricket] Thank you. (mellow music)

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