August 12, 2024 • 42 mins
Dr. Rupeena Purewal welcomes Dr. Thomas Duchaine , Director of the McGill Center for RNA Sciences, to discuss mRNA.
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Thanks for joining us at the Canadian Breakpoint, a Canadian infectious diseases podcast by
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Canadian infectious diseases physicians.
I'm Summer Stewart, back with Dr. Rupeena Purewal, pediatric infectious diseases physician
in Saskatoon.
Today we welcome Dr. Thomas Duchaine, founding director for the McGill Centre for RNA Sciences,
to discuss mRNA.
Dr. Purewal.
Thank you everyone for joining us on another episode of our podcast, the Canadian Breakpoint.
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So today we have a very special guest with us and we're going to be talking about a
lot about mRNA technologies, which we actually haven't done an episode on.
So I am actually super excited to learn a lot from Dr. Duchesne.
So Dr. Duchesne is a professor and chair of the Department of Biochemistry at McGill University.
For more than 28 years, his research elucidated the genetic and molecular basis for the functions
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of mRNAs and non-coding RNAs in the control of gene expression across a diversity of physiological
contexts and in cancer.
A renowned expert on mRNA biochemistry and molecular genetics, his research program currently
details how three prime untranslated regions of mRNAs and their interacting cofactors dictate
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mRNA translation, stability and decay.
He mentored more than 40 trainees over the years, most of which later led careers as
independent researchers or scientists in academia, as clinicians and in RNA related careers in
industry.
In most recent years, Dr. Duchesne led initiatives to translate deep expertise on RNA at McGill
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and in Quebec towards industry and clinical applications, among others by founding the
McGill Center for RNA Sciences, which he currently directs.
So thank you so much, Dr. Duchesne, for joining us today.
We are super excited.
We're going to talk a lot about mRNA.
Yeah, I'm always ready for that.
Of course.
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So just as a background, our listeners are healthcare professionals.
We have nurses, physicians, trainees.
So a lot of people, and I think just general audience that are interested in science and
technology.
So for background, can we maybe give our audience a bit of history on when mRNA was really introduced
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into medical therapeutics?
Oh, yeah.
I can give you a bit of a breakdown for this.
For the common people and most of us out there, whether it's in the clinics or I know our
daily lives all over the planet, RNA messenger RNA based therapeutics really became visible
with the COVID-19 vaccines introduced, approved by the FDA in 2020.
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But for that form of prophylactic, like for many other therapies or treatments, you really
have to look way back to really trace how this emerged.
As a matter of fact, messenger RNA based therapeutics have been in the works for nearly 60 years.
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Since its very discovery in, I think it's 1961 actually, the messenger RNAs, people
quickly realized the potential for their treatment, for the user's treatment.
So really what we saw emerge in recent years is really the tip of the iceberg for about
60 years of hard work by dedicated researchers.
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In Canada, just in Canada, for example, in our own backyard, there's the work, for example,
Naomi Sunderberg and Jerry Peltier.
McGill made us understand how messenger RNAs could be translated and used as tools.
People like K.K.
Ogilvie made the first chemically synthesized RNA, but also at UBC, for example, and this
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is a huge contribution directly applicable to the vaccines was the work of Peter Collis
and his team at UBC on lipids, really, fatty acids that are so important to make those
little bubbles of fatty acids that can bring RNA into cells.
And when he presents his data, it's like 40 years of hard work where you had a hard time
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getting funded for that research, but that really is so important.
But that was also in the US, as was celebrated with the novel in October, the work of Kathleen
Carrico and Drew Wiseman, which really was a cornerstone of use of RNA as a vaccine.
So Kathleen, actually, when she talks about in her novel lectures, she speaks of how hard
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it was to be funded on that research when nobody believed that RNA could be used as
a vaccine.
And Drew actually and Dr. Wiseman supporting her for believing in her vision for so long
that led in 2005 really at the major breakthrough that allowed messenger RNAs from exogenous
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sources to be translated into cells.
I'll talk a little bit more about this, but it's really a visionary contribution that
allowed messenger RNAs to be used as vaccines.
Beyond that, also, there's other major contributions that happened in most recent years.
And in the background, people don't know about this, but there was Moderna working really
hard on using RNA as a vaccine against cancer.
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Pre-COVID, this was going on.
They were working on treatments of cancer based on messenger RNAs, vaccines against
cancers, right?
We would imagine for several years.
And there are also other forms of RNA therapeutics that allowed this treatment that was going
on.
The RNA based therapy RNA LNP formulation was approved by FDA in 2018.
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It's another messenger RNA, but it is a RNA.
And it was the work of the RNA Therapeutic Institute at UMass Medical School with a drug
call on Trapel.
And this really was, I would say, one of the cornerstones, stepping stones that the vaccine
that we saw emerge.
So for most of us, we say, hey, where did that come from?
And how come it came to save so many people in the world?
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Did people just become a genius where they ignored this potential before?
But it actually is the fruit of so much basic and discovery work.
And people have really fought the hard fight for many years.
I'm saying people, but it's also companies like Moderna and BioNTech that carried that
ball for so many years in the shadow.
But now we see it emerge.
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Being in the medical community during COVID, like you said, even myself coming up with
mRNA vaccines, I think that was kind of our first exposure.
And I mean, we learn about mRNA, of course, like in medicine, but never really translated
how this could be kind of the future of some of the technologies that we, you know, mRNA
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based therapies.
And so definitely, like myself, wasn't very familiar with it.
So obviously, we've known about it for a long time, that these are the technologies.
Is there any other reasons why we wouldn't have been able to bring about therapies or
why are other companies, you know, like why was what was the difficulty with mRNA as opposed
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to kind of our other conventional therapies and models?
Yeah, it's a very important question, because I think it's put the spotlight on how big
of a contribution these folks I just mentioned and many others have made.
I think it was on back burner for so long, because ARNI really, because of its chemical
properties and how it interacts with cells, you know, there were a lot of barriers to
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overcome in order to use it as a drug.
So there was so much time between the discovery of messenger ARNI and lipid nanoparticles
and its ancestors, right, that used to be called liposomes and whatnot.
There was so much delay that kind of fell on the back burner and some of these barriers
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really were overcome only in the recent years.
So I'm talking, for example, about the chemical properties of ARNI.
One of the key things is that I was different with DNA, it has a two prime hydroxyl group.
So chemically, it's really something that is a handle and over it reacts really easily,
it forms an intermediate that degrades the ARNI.
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So what my jargon essentially means that the ARNI is unstable.
It's not meant to last forever, right?
It's really a plan that you bring on the construction site.
You're not supposed to keep it forever, right?
It's something that's meant to be destroyed fast, right?
Another issue is that it's polar.
So you look at the chemical groups and that thing and there's no way it's going to enter
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the cell easily, right?
So membranes are not polar.
So ARNI really wasn't meant to be used as a drug at all.
And usually when a cell recruit receives these signals from the environment, it's usually
because you're in trouble.
You either have broken cells or you have viruses around and you certainly don't want to have
the virus ARNI getting into your cell.
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So there's a whole barrier also that the cell used to say, hey, this is not ours, right?
And it's self versus non-self.
So it's called innate immunity and there's several cascades, there are genetic programs
that make sure that ARNI floating around doesn't get translated in your cells.
So this is the discovery really that Keryco, Kathleen Keryco did in Wiseman.
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They figured out a way to change, use chemical modification on the ARNI to hide it from the
innate immunity.
So, and that's only 2005, right?
That's a recent breakthrough.
But the other challenge in distribution where we do overcome with the lipid nanoparticles,
which is packaging these messenger ARNI's inside those lipid bubbles and making sure
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that it gets inside cells through routes that the cell use.
You have many, many vesicles and lipoproteins that are uptaken naturally inside the cell
and those LNPs use some of the machineries that those routes naturally use.
So we started harnessing essentially those pathways to get stealth ARNI inside the cell,
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hide it from the immune system and this allowed the messenger ARNI to do its job inside the
cell.
So overcoming those barriers took a long time.
And I think that that's why when these people were fighting the good fight, it kind of fell
in the back burner in spite of the potential to a point where people like Keryco couldn't
get funded and you really had the visionaries getting at it.
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So as to why we haven't heard about it until recently, I think it also was because the
need to kind of just say that if you look at the so-called imbalance in death, it's
about 20 million people that this vaccine saved.
Not even mentioning getting back to work after the pandemic when we very understood the coronavirus
and everybody was scared at home.
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This really came about quickly because there was a need.
In a way, Rupina, I think about this and I think the most amazing thing about it is how
fast and how well the humanity falls together and works together to overcome major challenges.
They happen key points in humanity and we really can overcome major threats like this
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when we work together.
And it's not only people, like I said, it's companies, it's university work, it's academia
and industry and people and companies.
It's just amazing how we can find solutions to huge demands like this.
To me, it's another lesson of how people can collaborate to come up with solutions that
impact the whole planet.
And honestly, I mean, it's years and years of research, right?
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So it's not all of a sudden that these things come up like from what you're saying even
now is that you have to work.
If anybody's done research, they know that there's hurdles.
There's a lot of ups and downs that you can have, but you really have to keep working
at it because there is certain technologies and certain methods that over time you can
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excel at and fine tune.
That's the key point.
That's the key point, Rupina, and it's time, right?
You need to keep your eyes on the long game and that's what research is about, biomedical
research and discovery research.
It takes a long time and it's not that and the application research.
You need both, right?
So otherwise you end up really quickly out of steam for innovation and not even mentioning
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the fact that you are outcompeted by other countries that do it properly.
So what you're saying is exactly right.
It's a matter of when you need things in the short term, you can mobilize, you can translate
knowledge, but you need that depth of knowledge, quality of knowledge, and that comes with
research.
So you really should have both.
Yeah.
And so you mentioned some limitations, obviously, of the mRNA-based methods.
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Being unstable, you need money, funding to work it up and to also build these technologies.
So what are some of the strengths that some of the mRNA-based methods provide compared
to conventional methods that we use in other therapies?
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Yeah.
So there are really two key points about RNA messenger RNA therapeutics that people should
have in mind.
And I think they reflect really, really well how they are disruptive and transformative
for the whole drugs or therapeutics or prophylactic ecosystem.
The most important point is that this is a new kind of drug, a new kind of treatment.
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It's an information drug.
RNA in itself encodes things.
It's information, right?
So if you change the sequence of that RNA, you have a new drug.
So chemically, it's the same thing.
It's the same chemistry, the same RNA molecule.
You're just changing that plan, what's written in their changes, and that changes in the
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case of a vaccine will have a new antigen.
So you'll have a new target for a new virus, for example, just by shuffling the sequence
to something that you want the immune system to target.
But you can also encode other forms of messenger RNAs that have other purpose, so-called modalities,
right?
So you could, for example, program cells, the T cells, which is one of the modality
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called T cells.
So you can essentially harness other forms of the immune system and direct it, let's
say, to treat the heart disease.
And we saw, for example, application like this last year in Nature, where they repurposed
a lot of messenger RNA really close to the formulation that was used in the COVID vaccine.
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Messenger RNA and LNP was reformulated to program CAR-Ts, and they used it to treat
overscarring issues in the heart disease and improve heart capacity after heart failure
in the mouse system.
So by changing the RNA sequence, not only do you have a new target for your immune system,
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you can even change a type of drug.
It's extremely versatile, extremely powerful, because before when you develop a drug, you
were limited to receptors and enzymes.
And every time you develop a new small molecule, it took forever.
You had to go through clinical trials and whatnot.
So what I'm saying is that you have more targets also.
You have far more therapeutic targets, not only for immunization, but also as potential
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drugs.
And also, you fasten, you accelerate the process, because every time you have a successful vaccine
or a successful RNA messenger RNA modality that works in the clinic, you de-risk the
next innovation wave.
So this ultimately, I think, is going to accelerate or at least change the game in clinical trials.
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I don't think it's going to happen right now, because these are new drugs and people are
worried and they want to make sure they're safe.
But I expect this to change the process of clinical trials, I think, in the mid-run.
Of course, when you have new technologies, you want to play everything safe, make sure
that people, it's acceptable.
And you cannot make mistakes when you have this transformative kind of drugs.
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And I know companies like Modera, for example, are aware of this.
And they're extremely careful in their clinical trials now.
But I think at the mid to long run, we'll have to reinvent how those clinical trials
are run financially and also in terms of also choice of disease.
You have disease that are we call so-called orphan disease, because the courts are so
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here.
There's so few people that have access to those clinical trials, because their clinical
trial is expensive, but you also need large cohorts.
And you can easily imagine how such a versatility and how easily you can repurpose them in the
risk trials that you'll have cohorts and people that were equity seeking, just couldn't enter
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in clinical trials and just weren't the right subtype to favor the economics for the development
of those drugs now having access to those therapies.
So I give you three advantages.
One of them is it's an information drug.
You just change the sequence.
You change the target, you change the modality.
The repurposing that the risks, the clinical trials.
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And finally, I told you that some people or disease could not have access to the traditional
form of clinical trials now, maybe gaining access to treatments that are based.
Those are just three of them.
But you can see how important this is going to be in the landscape for economics, for
example, of pharmacistics and whatnot.
This huge game changer.
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Yeah, very scalable, which is, I think, a huge advantage of an mRNA based method as
opposed to, like you mentioned, having to change the entire framework of the therapeutic
modality.
Right.
So instead of reinventing the wheel and going through the whole de-risking from A to Z,
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you build on previous success to de-risk the next step.
Because it's what we call it drug repurposing, right?
The greatest, I would say, level.
And also as being in the medical community, first having scalability, that's really important
because we're always looking for novel agents, especially as new diseases are coming up.
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Like you mentioned, there's rare diseases.
And sometimes we're, because we have a lot of diagnostic testing, I think, that overall
can find rare diseases now.
But when we come to therapy, so even if you can diagnose them, if you don't have a therapy
for them, it becomes challenging, right?
When you're a clinician.
That's right.
And so it's all the concept of precision medicine, right?
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It was all the concept of precision medicine.
You can stratify your disease, say, hey, you have this subtype of disease, this subtype
of what do you do if you have nothing to treat it?
Right.
So you start a clinical trial for that rare subtypes, it's going to take forever.
Nobody's going to get in a clinical trial.
So it's pretty sad, right?
So where you die, you have the wrong subtype, let's say cancer, the wrong subtype of cancer,
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and you're sorry out of luck.
But with this now, you can have much smaller scale trials just because you can, on one
hand, design a drug or vaccine against that type of cancer by just changing the sequence.
And second, you have a lot of prior clinical trials to de-risk even smaller cohorts.
And that's the key point, right?
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Because a lot of the fear and the scare comes from not knowing what the molecule is like
and how we can utilize it.
And so I think that's where if you have that information from other trials, that's the
majority of what we do with research and as base or even when clinicians are using therapies,
we look back at those research trials for assistance because we want to see how often
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did this therapy work, right?
Because it's obviously, it's usually you're using it outside of the norm or not really
off label per se, because it's probably, once Health Canada goes through the approvals,
et cetera, then you have an indication for it, but you still have to resort back to clinical
trials.
So I think the research aspect is huge.
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The key thing though that you referred to, I think, affects also the general public,
not only the clinicians.
That's how fast this happens, right?
How fast they emerge and we're just catching up to those new realities.
So clinicians have science and they can refer to clinical trials, right?
Even though it exploded in recent years, in 2020, I think there were a handful of those
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in the first year and now we're about 3,000 clinical trials that are MS and JARN based
about, I think it's about 700 of them are against cancer.
Cancer vaccine clinical trials, that's something that is completely new, you wouldn't think
would be possible.
Since 2020, now we have 700 clinical trials going on and I look at the data for these
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and they're very, very promising.
Things like pancreatic cancer, for example, melanoma and sometimes that usually won't
work now are actually within the range of those therapies.
Concepts like new antigens are being used, for example, to make new types of vaccines
against those diseases.
It's currently exploding and both clinicians and I would say the general public have a
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hard time catching up and this will rightfully, I would say, raise some concerns or at least
need to get access to the right information.
I think, Rupina, that's why your podcast is so important because you're bridging that
science with not only clinicians but general public.
So thanks for doing what you do today.
We still have a lot of catch-up, both clinicians, which would be called trial data, but also
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with the general public because when they're sitting at home and they're being told, now
show your arm, right?
And for the injection, you have something, you get injected in there, but now show me
your children's arm.
Show me your kid's arm so that we can inject those new technologies.
We really do as scientists and caregivers and also I would say our policy makers have
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to listen, we have to hear, we have to listen from what's happening on the field and we
have to understand those concerns so we can address them.
We also need to educate ourselves to the science underneath and also the limitations of this
science, not promising anything magical here.
Anytime you put something foreign in an arm for injection, whether it's a vaccine or not,
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there are risks.
There are risks.
So, yeah, so the right question to ask is it perfectly safe?
The right question to ask is, is it less risky than having a viral infection from a coronavirus
that can kill?
Another good question is, is it safer than what we currently have, for example, at the
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vaccines?
The answer to those questions is by far yes, right?
It was tested that the planet wide, you know, during the pandemic and these formulations
of RNA and vaccines now we know are perfectly, not perfectly, but there's much safer than
the prior modalities that we were using and far safer than being infected by this coronavirus,
right, that the planet hadn't seen before.
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So I guess my point is about social acceptability, Rupina, not only for clinicians to use the
full toolkit and understand and be able to answer questions to patients, but also in
general, right?
If you're not careful about this and you don't listen, you know, people will be worried and
they will actually respond, right, by not accepting the treatment and you may have patients
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that end up suffering because they rejected that treatment or you'll get people on your
parliament hill with trucks, with horns, because the policies, you know, weren't explained
or the general public is not ready to accept something moving so fast.
So it's a lot of words, but I think, you know, I'm touching upon the speed how these are
implemented and I think there's an important challenge there following up on the strengths
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of these and potential of these therapies.
Some of the weaknesses clearly have to do with social acceptability.
Yeah, and I think we all face this, you know, whether it was from a professional or personal
standpoint, you know, you always thought when the pandemic hit, I think it was everything,
there was a lot of anxiety, there was a lot of, everything was very fast paced, right?
So new disease, new learning environment, whether it was thinking about yourself getting
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the vaccine or giving it to others, like a lot of us clinicians became vaccine administrators
at that time too, because that was just the, you know, and really weighing out the risks
versus benefit, like you mentioned, right?
And so that was the key point.
Yeah.
As a scientist, you're there, you go, you look at the papers and you read the papers
and you say, oh, okay, that's what they know, that's what they're shooting in my arm.
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Oh, I see the chemistry here as a clinician say, okay, well, then, you know, they've had
some prior trials, they can, you see on travels, you see, oh, this LNP is not really new.
It's a messenger and so we have it, but the general public who doesn't have that science,
right?
They're blindfolded, they're blindsided and we're being asked to trust the government,
right?
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In a really angst generating period with the pandemic.
So yeah, you know, if you put yourself in their shoes, there's a lot of education to
be had, right?
With those technologies.
I can tell you though, in my mind, there's absolutely no doubt that these technologies
will just accelerate, right?
They're talking about replacing the influenza vaccine that we get yearly, for example.
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This is going on.
I mean, right now, you know, it's not very efficient.
It's peptide based or I think it's, I don't know, virus based.
So they're going to shift to Arnie.
So it's just the start.
So for the, you know, on one hand, we'll have messenger on the vaccines for things that
we were exposed to before.
But when there's a new pandemic, because there will be other pandemics upcoming, there's
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coronavirus and bats, you know, in Southeast Asia, there's going to be more that incubator
and population is more mobile and we travel a lot.
And we're more dense than ever.
People are concentrated in cities more than ever.
So and there's poverty and there's also, you know, all spectrum of, I would say, the cultural
and practice that will affect distribution of those viruses.
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It's going to happen again.
And guess to what they're going to turn next.
They're not going to go backward with the technologies that, you know, were supplanted
by the messenger Arnie vaccines.
Rincon is going to turn to messenger Arnie's because it's faster, it's cheaper and it's
versatile and you can reprogram and repurpose the modalities that were reliable before.
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So it's here to stay and it's going to replace and supplant many of the technologies.
It's really, when you think about it, disruptive technology in the, you know, the meaningful
sense of the word and the better we know about those as clinicians and scientists, the better
we are to answer questions by mom, daughter, cousin, but also our patients as well.
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Right.
And make them understand to the extent that we know, because we don't know everything
about those still.
Right.
What are the risks and what are the advantages?
And which is science.
Right.
So that is the evolution.
Yep.
And that is, and that's not only based on mRNA.
That's anything.
So we over time, and that's kind of why there's many steps of there's when you're doing a
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project, whether it's a small scale project or a large scale project, there's many milestones
that you reach during the process.
And then once it's out in the market, you also do a lot of post-market surveillance.
And so I think that's kind of where the focus has been for my practice in my area with counseling
is really, really letting people know that understanding that this is years and years
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of knowledge that's coming together.
And not only that, we're still watching it.
So there's an evolution.
So I can guarantee that what I know today is what I'm going to know in 10 years, because
that's not how science works.
Science is always about knowledge and learning.
Right.
And so we're reflecting on this ongoing.
And so what we know today about mRNA is probably much, much different than we knew about 40,
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50 years ago.
So it's just fantastic.
Absolutely.
And there's a good system of checks and balance in science, but also in clinical applications
and in therapy development.
We really keep those with checks and balance.
It's not to say it's a perfect system, but if there's flaws, they will be seen sooner
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than later.
But this being said, I think that we need to keep an eye on those new technologies,
that's for sure, and change whatever we need as soon as we capture any evidence of flaws.
And I guess just to touch on that safety aspect, I always get questions around because this
molecule is very unstable and we can change it in so many ways.
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Does it actually affect my own genetic makeup when I'm taking these vaccines or these treatments?
And so what's your thoughts on that?
Yeah, it's a question that I hear a lot.
And I think it's very important for people to have a satisfying answer to that one.
RNA is not like DNA.
I know it's only one letter as an acronym, but fundamentally, chemically speaking and
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biologically, there's millions and millions, hundreds of millions of years of evolution
made sure that RNA really had different purpose, a different biological purpose than DNA.
DNA is something that you want to keep as a hard drive memory of who you are as a species
and transmitted to next generation.
Because RNA is really a blueprint, something transient and degradable.
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So RNA is, messenger RNAs anyway, are really meant to be read, used as a blueprint on site
and then destroyed.
It's actually on purpose that it's destroyable with that special chemistry.
So when you inject a messenger RNA in the cell, it's not going to last very, very long.
So keep in mind that there's about 400,000 messenger RNA in every single one of your
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cells right now.
Every single one of your cells have 400,000 of messenger RNAs doing their job.
They're not going back in your genome.
They're actually read and destroyed and they're constantly produced from DNA.
DNA's job is the memory.
The messenger RNA's job is to be transient, read and destroyed.
And it's very chemistry is make sure that it doesn't.
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There are really, really rare cases where RNA, and maybe that's part of the confusion,
RNA can be reverse transcribed and inserted in genomes.
And that's a job of rare viruses we call retroviruses.
But that's because RNA can be also modified to play weird tricks.
But that's not the messenger RNA's job.
That's not what the chemistry and the biology of messenger RNAs do.
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And the ones that we use, the formulation or types of messenger RNAs that we use with
its chemistry is really the product of about 60 years of intense study by millions of people
worldwide.
And there's groups working on the RNA in labs since the event, its discovery in 1961.
So we know about messenger RNAs.
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They're not going back into your genome.
It's really something that it doesn't do.
And I think it's important for people to know that.
And so we talked a little bit about the, obviously we're using mRNA based methods and prevention
in vaccines.
But you also mentioned that in treatment of diseases, for example, cancer would be a common
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theme.
Are there specific diseases or like you mentioned for prevention, I think vaccines is kind of
the key player there and influenza for the future.
Are there other current modalities that are current therapies that are using mRNA based
technologies that you'd like to mention to our audience today?
Yeah.
So I'm super excited about the cancer vaccines and what's cool about it, it's not only as
(32:14):
prophylactic.
We talk about vaccine as if they're prophylactic to prevent, but actually some of the clinical
trials right now use cancer vaccines as a treatment.
So there's one actually that was published in Nature in May, 2023, where, and that's
actually really promising, there's a couple of others in parallel where what they did
(32:37):
is they took the tumors, the patient's tumor, and they identified bits that are unique to
the tumor and absent from the patient.
So it's called neoantigens.
So cancer shuffled the cards in a way that you can find bits of information there in
the tumors that are not present in the rest of the patient.
So you take this information and because RNA is so flexible and you can really generate
(33:01):
a vaccine so fast, you generate a bank, a library of messenger nes that would immunize
against those very same neoantigen.
So you actually identify the Achilles heel of the tumor, you immunize while the patient
is ongoing clinical trials, you immunize against its very own neoantigen and you can treat
(33:24):
it this way.
So it's not really the traditional prophylactic use of those, right?
But eventually, what my understanding is eventually they will find some neoantigens that are common.
That's in pancreatic cancer, you will find neoantigens that are multiple of those cancers
and they may use it as a prophylactic as well.
(33:44):
You were referring to other use of messenger netherpethics.
There's for example, the self-programmable form of cells that we call CAR T. So they're
essentially, yeah, you probably heard about this.
They're cell-based messenger netherpethics and the idea there is to program the immune
system to redirect it to serve different purposes.
(34:06):
There's huge potential for messenger netherpethics there as well.
It's another so-called modality and it can go and treat things like heart disease, for
example, just to name one of them.
So the different modalities are based on messenger netherpethics are quite diverse and there's
also flavors of messenger netherpethics that are in development, things like self-implifying
(34:27):
messenger RNAs.
So you add a bit of information, the RNA so that it stays longer, you amplify the messenger
RNAs or circular RNAs that are messenger RNA linear, you have a 5' and 3' and it's part
of its behavior but you can also make it a circle and the RNA lasts longer this way.
There are many, many uses for the different forms of RNAs.
(34:48):
They're apparent to messenger RNAs but there are different modalities I would say that
are emerging that can modify the pharmacokinetics and pharmacodynamics but also the types of
targets that you can challenge with those therapeutics.
All of this is different level of development but I think the first essay, the self-amplifying
RNA was just approved by FDA a few weeks ago as a matter of fact.
(35:11):
So all these are different stages of development but they will emerge in therapeutics soon.
Okay.
So the vast majority of indications definitely when we're looking at kind of what we're targeting
and also what these modalities will be eventually be used for.
So a lot of ongoing research.
Yeah.
That's awesome.
Yeah.
Well, there's a lot of other modalities also.
(35:32):
There's the SI RNA base.
They're not messenger RNAs but they're RNA base like CRISPR for example where you engineer
the genome and can change your cells forever but there's also lots of cool research done
in chemical biology, new modifications of RNA, adding bits of sequence to the RNA so
that we decide where and when the RNA is expressed.
You know, I work on true prune untranslated regions.
(35:53):
Those bits of information decide where the messenger RNA works really.
And there's a lot of cool stuff done on lipid nanoparticles and other nanoparticles.
Again, the delivery of the RNA is a huge challenge and you know, not only from microkinetics,
from microdynamics to which tissues it goes, how long it distributes, you can even change,
(36:13):
tweak the response of the immune system by changing the lipids and those particles for
example.
There are other challenges like, you know, many of people who did dealt with, you may
have dealt with those, the vaccines.
You need those special fridges to keep them minus 80 degrees Celsius, right?
It was a nightmare for distribution.
So there's solutions coming to make them more thermostable, right?
You have vaccines that you can keep at room temperature and that affects the whole distribution
(36:35):
and also ultimately how fast you can respond if something emerges and the availability
of the drugs in your practice.
So there's research and stability also of those vaccines going on as well.
It's going in overdrive.
It's very exciting to see this coming.
And to me, the most exciting part is disease that were out of reach before like cancer
(36:57):
now having options with those.
So it's a lot of hope for patients that, you know, had few options before.
And then I guess just for like my own knowledge because I deal with a lot of, you know, infections,
deficiencies, transplant, is there any talk with mRNA kind of in the immune deficiency
world or bone marrow transplant, stem cell transplant?
(37:20):
Is there any discussions around bringing mRNA technologies for treatment options there?
The intersect between messenger RNA based therapeutics or RNA therapeutics in that larger,
but messenger RNA therapeutics in particular and the immune system is a sweet spot.
That's where we're successful and there's going to be more and more uses there.
(37:42):
I'm not an expert to precisely answer your question.
I'm not an expert and I don't know really what's being done there.
What I can tell you though is that of all the clinical trials, most of them with messenger
RNAs, most of them have to do with the immune system.
And you could have things like chronic inflammation, the chronic disease, right, that are undergoing
autoimmunity.
(38:03):
I wouldn't be surprised if there's breakthroughs there with those therapies.
I don't know how fast it will come, but if I had a chunk of money to put on somewhere
where it's going to move fast, it's going to be on the intercept with the immune system,
whereas immunomodulation, you know, but also, you know, we see things like, for example,
(38:25):
combinatorial treatment with immunotherapy, for example, in cancer, right, the cancer
suppresses the immune system and you can modulate that with immunotherapies.
So there's a synergy between messenger RNA vaccines against the answer immunotherapy.
So you'll see those combinations of treatment in the clinic, for example.
So that's a hot space, I would say, to do research on.
(38:46):
And, Rupina, if you want to do some research, I think that would be grantable, I would say,
in the current period.
Yeah, no, that's fair.
Thank you so much, Dr. Tichane.
I think, I mean, I've learned a lot about mRNA technology and, you know, through everything
that we've spoken about today, doing a bit of my own research as well.
And I think this is, it's nice to see that there's novel techniques that are coming up
(39:10):
and we really have a future where we're not only diagnosing diseases, but we have treatment
options and really just a better understanding, right?
So we have experts like yourselves that can come on and talk to us about this.
And so I think this is very different from a few multiple decades ago, where a lot of
(39:31):
this information wasn't brought out to the public, wasn't brought out to clinicians and
other audiences.
So thank you so much for your wealth of knowledge today.
My pleasure.
It's what's exciting is that this is hope that's given from knowledge.
It's from solid knowledge, from very robust knowledge.
(39:51):
So it's a pleasure to be, you know, conveying this to clinicians and the general public.
Thank you for doing what you do.
Oh, of course.
Thank you for doing what you do.
I think you make my day job easier.
So it's perfect.
And so I think we're definitely, I'll reach back out to you at some point, because I think
(40:13):
there's a lot of future to mRNA-based methods and technology.
I know there's going to be a lot of research in this area.
And I know that the U and R Centre will definitely be on top of it.
And so I think it'll be nice to discuss kind of future, what the future really holds.
Is there anything from a last standpoint that we didn't talk about in mRNA that you were
(40:37):
hoping to share with our audience today?
I just think that what we're seeing is the beginning and that the potential is huge.
Technology is now awake to that potential.
And it's really a very important period to fund research in that area, basic and translational.
And you know, the potential now is absolutely clear and all the players are awake to it.
(41:03):
So I think I would like to close with an appeal for to support research, both basic discovery,
but also translational, so that we can start mobilizing this knowledge towards people,
patients that we need and have few options.
So that would be my last word.
Yeah, no, that's great.
That's fantastic.
(41:23):
Anybody who's a researcher would definitely would, I think, having support in their research
would be important, whether it's clinical, whether it's bioengineering.
There's so many phases.
So, yeah, I think both engineering, basic and applied, I think both need to work in
band and those, definitely.
(41:45):
We've seen it work really well with this.
That's fantastic.
Well, thank you so much for your time and we look forward to future episodes.
Thank you, Rupina.
Thank you, Dr. Duchesne, for the discussion on this interesting topic.
Have an episode suggestion?
Email thecanadianbreakpoint at gmail.com and be sure to follow us on x at cabreakpoint
(42:05):
for updates.
See you again soon at the Canadian Breakpoint.
Thanks for joining us at the Canadian Breakpoint, a Canadian infectious diseases podcast by
(00:13):
Canadian infectious diseases physicians.
I'm Summer Stewart, back with Dr. Rupeena Purewal, pediatric infectious diseases physician
in Saskatoon.
Today we welcome Dr. Thomas Duchaine, founding director for the McGill Centre for RNA Sciences,
to discuss mRNA.
Dr. Purewal.
Thank you everyone for joining us on another episode of our podcast, the Canadian Breakpoint.
(00:37):
So today we have a very special guest with us and we're going to be talking about a
lot about mRNA technologies, which we actually haven't done an episode on.
So I am actually super excited to learn a lot from Dr. Duchesne.
So Dr. Duchesne is a professor and chair of the Department of Biochemistry at McGill University.
For more than 28 years, his research elucidated the genetic and molecular basis for the functions
(01:01):
of mRNAs and non-coding RNAs in the control of gene expression across a diversity of physiological
contexts and in cancer.
A renowned expert on mRNA biochemistry and molecular genetics, his research program currently
details how three prime untranslated regions of mRNAs and their interacting cofactors dictate
(01:26):
mRNA translation, stability and decay.
He mentored more than 40 trainees over the years, most of which later led careers as
independent researchers or scientists in academia, as clinicians and in RNA related careers in
industry.
In most recent years, Dr. Duchesne led initiatives to translate deep expertise on RNA at McGill
(01:51):
and in Quebec towards industry and clinical applications, among others by founding the
McGill Center for RNA Sciences, which he currently directs.
So thank you so much, Dr. Duchesne, for joining us today.
We are super excited.
We're going to talk a lot about mRNA.
Yeah, I'm always ready for that.
Of course.
(02:15):
So just as a background, our listeners are healthcare professionals.
We have nurses, physicians, trainees.
So a lot of people, and I think just general audience that are interested in science and
technology.
So for background, can we maybe give our audience a bit of history on when mRNA was really introduced
(02:36):
into medical therapeutics?
Oh, yeah.
I can give you a bit of a breakdown for this.
For the common people and most of us out there, whether it's in the clinics or I know our
daily lives all over the planet, RNA messenger RNA based therapeutics really became visible
with the COVID-19 vaccines introduced, approved by the FDA in 2020.
(02:58):
But for that form of prophylactic, like for many other therapies or treatments, you really
have to look way back to really trace how this emerged.
As a matter of fact, messenger RNA based therapeutics have been in the works for nearly 60 years.
(03:18):
Since its very discovery in, I think it's 1961 actually, the messenger RNAs, people
quickly realized the potential for their treatment, for the user's treatment.
So really what we saw emerge in recent years is really the tip of the iceberg for about
60 years of hard work by dedicated researchers.
(03:41):
In Canada, just in Canada, for example, in our own backyard, there's the work, for example,
Naomi Sunderberg and Jerry Peltier.
McGill made us understand how messenger RNAs could be translated and used as tools.
People like K.K.
Ogilvie made the first chemically synthesized RNA, but also at UBC, for example, and this
(04:04):
is a huge contribution directly applicable to the vaccines was the work of Peter Collis
and his team at UBC on lipids, really, fatty acids that are so important to make those
little bubbles of fatty acids that can bring RNA into cells.
And when he presents his data, it's like 40 years of hard work where you had a hard time
(04:29):
getting funded for that research, but that really is so important.
But that was also in the US, as was celebrated with the novel in October, the work of Kathleen
Carrico and Drew Wiseman, which really was a cornerstone of use of RNA as a vaccine.
So Kathleen, actually, when she talks about in her novel lectures, she speaks of how hard
(04:51):
it was to be funded on that research when nobody believed that RNA could be used as
a vaccine.
And Drew actually and Dr. Wiseman supporting her for believing in her vision for so long
that led in 2005 really at the major breakthrough that allowed messenger RNAs from exogenous
(05:12):
sources to be translated into cells.
I'll talk a little bit more about this, but it's really a visionary contribution that
allowed messenger RNAs to be used as vaccines.
Beyond that, also, there's other major contributions that happened in most recent years.
And in the background, people don't know about this, but there was Moderna working really
hard on using RNA as a vaccine against cancer.
(05:35):
Pre-COVID, this was going on.
They were working on treatments of cancer based on messenger RNAs, vaccines against
cancers, right?
We would imagine for several years.
And there are also other forms of RNA therapeutics that allowed this treatment that was going
on.
The RNA based therapy RNA LNP formulation was approved by FDA in 2018.
(05:57):
It's another messenger RNA, but it is a RNA.
And it was the work of the RNA Therapeutic Institute at UMass Medical School with a drug
call on Trapel.
And this really was, I would say, one of the cornerstones, stepping stones that the vaccine
that we saw emerge.
So for most of us, we say, hey, where did that come from?
And how come it came to save so many people in the world?
(06:20):
Did people just become a genius where they ignored this potential before?
But it actually is the fruit of so much basic and discovery work.
And people have really fought the hard fight for many years.
I'm saying people, but it's also companies like Moderna and BioNTech that carried that
ball for so many years in the shadow.
But now we see it emerge.
(06:41):
Being in the medical community during COVID, like you said, even myself coming up with
mRNA vaccines, I think that was kind of our first exposure.
And I mean, we learn about mRNA, of course, like in medicine, but never really translated
how this could be kind of the future of some of the technologies that we, you know, mRNA
(07:05):
based therapies.
And so definitely, like myself, wasn't very familiar with it.
So obviously, we've known about it for a long time, that these are the technologies.
Is there any other reasons why we wouldn't have been able to bring about therapies or
why are other companies, you know, like why was what was the difficulty with mRNA as opposed
(07:28):
to kind of our other conventional therapies and models?
Yeah, it's a very important question, because I think it's put the spotlight on how big
of a contribution these folks I just mentioned and many others have made.
I think it was on back burner for so long, because ARNI really, because of its chemical
properties and how it interacts with cells, you know, there were a lot of barriers to
(07:52):
overcome in order to use it as a drug.
So there was so much time between the discovery of messenger ARNI and lipid nanoparticles
and its ancestors, right, that used to be called liposomes and whatnot.
There was so much delay that kind of fell on the back burner and some of these barriers
(08:12):
really were overcome only in the recent years.
So I'm talking, for example, about the chemical properties of ARNI.
One of the key things is that I was different with DNA, it has a two prime hydroxyl group.
So chemically, it's really something that is a handle and over it reacts really easily,
it forms an intermediate that degrades the ARNI.
(08:33):
So what my jargon essentially means that the ARNI is unstable.
It's not meant to last forever, right?
It's really a plan that you bring on the construction site.
You're not supposed to keep it forever, right?
It's something that's meant to be destroyed fast, right?
Another issue is that it's polar.
So you look at the chemical groups and that thing and there's no way it's going to enter
(08:53):
the cell easily, right?
So membranes are not polar.
So ARNI really wasn't meant to be used as a drug at all.
And usually when a cell recruit receives these signals from the environment, it's usually
because you're in trouble.
You either have broken cells or you have viruses around and you certainly don't want to have
the virus ARNI getting into your cell.
(09:14):
So there's a whole barrier also that the cell used to say, hey, this is not ours, right?
And it's self versus non-self.
So it's called innate immunity and there's several cascades, there are genetic programs
that make sure that ARNI floating around doesn't get translated in your cells.
So this is the discovery really that Keryco, Kathleen Keryco did in Wiseman.
(09:36):
They figured out a way to change, use chemical modification on the ARNI to hide it from the
innate immunity.
So, and that's only 2005, right?
That's a recent breakthrough.
But the other challenge in distribution where we do overcome with the lipid nanoparticles,
which is packaging these messenger ARNI's inside those lipid bubbles and making sure
(09:59):
that it gets inside cells through routes that the cell use.
You have many, many vesicles and lipoproteins that are uptaken naturally inside the cell
and those LNPs use some of the machineries that those routes naturally use.
So we started harnessing essentially those pathways to get stealth ARNI inside the cell,
(10:23):
hide it from the immune system and this allowed the messenger ARNI to do its job inside the
cell.
So overcoming those barriers took a long time.
And I think that that's why when these people were fighting the good fight, it kind of fell
in the back burner in spite of the potential to a point where people like Keryco couldn't
get funded and you really had the visionaries getting at it.
(10:47):
So as to why we haven't heard about it until recently, I think it also was because the
need to kind of just say that if you look at the so-called imbalance in death, it's
about 20 million people that this vaccine saved.
Not even mentioning getting back to work after the pandemic when we very understood the coronavirus
and everybody was scared at home.
(11:09):
This really came about quickly because there was a need.
In a way, Rupina, I think about this and I think the most amazing thing about it is how
fast and how well the humanity falls together and works together to overcome major challenges.
They happen key points in humanity and we really can overcome major threats like this
(11:29):
when we work together.
And it's not only people, like I said, it's companies, it's university work, it's academia
and industry and people and companies.
It's just amazing how we can find solutions to huge demands like this.
To me, it's another lesson of how people can collaborate to come up with solutions that
impact the whole planet.
And honestly, I mean, it's years and years of research, right?
(11:51):
So it's not all of a sudden that these things come up like from what you're saying even
now is that you have to work.
If anybody's done research, they know that there's hurdles.
There's a lot of ups and downs that you can have, but you really have to keep working
at it because there is certain technologies and certain methods that over time you can
(12:18):
excel at and fine tune.
That's the key point.
That's the key point, Rupina, and it's time, right?
You need to keep your eyes on the long game and that's what research is about, biomedical
research and discovery research.
It takes a long time and it's not that and the application research.
You need both, right?
So otherwise you end up really quickly out of steam for innovation and not even mentioning
(12:41):
the fact that you are outcompeted by other countries that do it properly.
So what you're saying is exactly right.
It's a matter of when you need things in the short term, you can mobilize, you can translate
knowledge, but you need that depth of knowledge, quality of knowledge, and that comes with
research.
So you really should have both.
Yeah.
And so you mentioned some limitations, obviously, of the mRNA-based methods.
(13:05):
Being unstable, you need money, funding to work it up and to also build these technologies.
So what are some of the strengths that some of the mRNA-based methods provide compared
to conventional methods that we use in other therapies?
(13:26):
Yeah.
So there are really two key points about RNA messenger RNA therapeutics that people should
have in mind.
And I think they reflect really, really well how they are disruptive and transformative
for the whole drugs or therapeutics or prophylactic ecosystem.
The most important point is that this is a new kind of drug, a new kind of treatment.
(13:49):
It's an information drug.
RNA in itself encodes things.
It's information, right?
So if you change the sequence of that RNA, you have a new drug.
So chemically, it's the same thing.
It's the same chemistry, the same RNA molecule.
You're just changing that plan, what's written in their changes, and that changes in the
(14:11):
case of a vaccine will have a new antigen.
So you'll have a new target for a new virus, for example, just by shuffling the sequence
to something that you want the immune system to target.
But you can also encode other forms of messenger RNAs that have other purpose, so-called modalities,
right?
So you could, for example, program cells, the T cells, which is one of the modality
(14:32):
called T cells.
So you can essentially harness other forms of the immune system and direct it, let's
say, to treat the heart disease.
And we saw, for example, application like this last year in Nature, where they repurposed
a lot of messenger RNA really close to the formulation that was used in the COVID vaccine.
(14:54):
Messenger RNA and LNP was reformulated to program CAR-Ts, and they used it to treat
overscarring issues in the heart disease and improve heart capacity after heart failure
in the mouse system.
So by changing the RNA sequence, not only do you have a new target for your immune system,
(15:14):
you can even change a type of drug.
It's extremely versatile, extremely powerful, because before when you develop a drug, you
were limited to receptors and enzymes.
And every time you develop a new small molecule, it took forever.
You had to go through clinical trials and whatnot.
So what I'm saying is that you have more targets also.
You have far more therapeutic targets, not only for immunization, but also as potential
(15:39):
drugs.
And also, you fasten, you accelerate the process, because every time you have a successful vaccine
or a successful RNA messenger RNA modality that works in the clinic, you de-risk the
next innovation wave.
So this ultimately, I think, is going to accelerate or at least change the game in clinical trials.
(16:02):
I don't think it's going to happen right now, because these are new drugs and people are
worried and they want to make sure they're safe.
But I expect this to change the process of clinical trials, I think, in the mid-run.
Of course, when you have new technologies, you want to play everything safe, make sure
that people, it's acceptable.
And you cannot make mistakes when you have this transformative kind of drugs.
(16:25):
And I know companies like Modera, for example, are aware of this.
And they're extremely careful in their clinical trials now.
But I think at the mid to long run, we'll have to reinvent how those clinical trials
are run financially and also in terms of also choice of disease.
You have disease that are we call so-called orphan disease, because the courts are so
(16:46):
here.
There's so few people that have access to those clinical trials, because their clinical
trial is expensive, but you also need large cohorts.
And you can easily imagine how such a versatility and how easily you can repurpose them in the
risk trials that you'll have cohorts and people that were equity seeking, just couldn't enter
(17:08):
in clinical trials and just weren't the right subtype to favor the economics for the development
of those drugs now having access to those therapies.
So I give you three advantages.
One of them is it's an information drug.
You just change the sequence.
You change the target, you change the modality.
The repurposing that the risks, the clinical trials.
(17:28):
And finally, I told you that some people or disease could not have access to the traditional
form of clinical trials now, maybe gaining access to treatments that are based.
Those are just three of them.
But you can see how important this is going to be in the landscape for economics, for
example, of pharmacistics and whatnot.
This huge game changer.
(17:49):
Yeah, very scalable, which is, I think, a huge advantage of an mRNA based method as
opposed to, like you mentioned, having to change the entire framework of the therapeutic
modality.
Right.
So instead of reinventing the wheel and going through the whole de-risking from A to Z,
(18:12):
you build on previous success to de-risk the next step.
Because it's what we call it drug repurposing, right?
The greatest, I would say, level.
And also as being in the medical community, first having scalability, that's really important
because we're always looking for novel agents, especially as new diseases are coming up.
(18:34):
Like you mentioned, there's rare diseases.
And sometimes we're, because we have a lot of diagnostic testing, I think, that overall
can find rare diseases now.
But when we come to therapy, so even if you can diagnose them, if you don't have a therapy
for them, it becomes challenging, right?
When you're a clinician.
That's right.
And so it's all the concept of precision medicine, right?
(18:56):
It was all the concept of precision medicine.
You can stratify your disease, say, hey, you have this subtype of disease, this subtype
of what do you do if you have nothing to treat it?
Right.
So you start a clinical trial for that rare subtypes, it's going to take forever.
Nobody's going to get in a clinical trial.
So it's pretty sad, right?
So where you die, you have the wrong subtype, let's say cancer, the wrong subtype of cancer,
(19:17):
and you're sorry out of luck.
But with this now, you can have much smaller scale trials just because you can, on one
hand, design a drug or vaccine against that type of cancer by just changing the sequence.
And second, you have a lot of prior clinical trials to de-risk even smaller cohorts.
And that's the key point, right?
(19:38):
Because a lot of the fear and the scare comes from not knowing what the molecule is like
and how we can utilize it.
And so I think that's where if you have that information from other trials, that's the
majority of what we do with research and as base or even when clinicians are using therapies,
we look back at those research trials for assistance because we want to see how often
(20:03):
did this therapy work, right?
Because it's obviously, it's usually you're using it outside of the norm or not really
off label per se, because it's probably, once Health Canada goes through the approvals,
et cetera, then you have an indication for it, but you still have to resort back to clinical
trials.
So I think the research aspect is huge.
(20:26):
The key thing though that you referred to, I think, affects also the general public,
not only the clinicians.
That's how fast this happens, right?
How fast they emerge and we're just catching up to those new realities.
So clinicians have science and they can refer to clinical trials, right?
Even though it exploded in recent years, in 2020, I think there were a handful of those
(20:48):
in the first year and now we're about 3,000 clinical trials that are MS and JARN based
about, I think it's about 700 of them are against cancer.
Cancer vaccine clinical trials, that's something that is completely new, you wouldn't think
would be possible.
Since 2020, now we have 700 clinical trials going on and I look at the data for these
(21:11):
and they're very, very promising.
Things like pancreatic cancer, for example, melanoma and sometimes that usually won't
work now are actually within the range of those therapies.
Concepts like new antigens are being used, for example, to make new types of vaccines
against those diseases.
It's currently exploding and both clinicians and I would say the general public have a
(21:35):
hard time catching up and this will rightfully, I would say, raise some concerns or at least
need to get access to the right information.
I think, Rupina, that's why your podcast is so important because you're bridging that
science with not only clinicians but general public.
So thanks for doing what you do today.
We still have a lot of catch-up, both clinicians, which would be called trial data, but also
(21:59):
with the general public because when they're sitting at home and they're being told, now
show your arm, right?
And for the injection, you have something, you get injected in there, but now show me
your children's arm.
Show me your kid's arm so that we can inject those new technologies.
We really do as scientists and caregivers and also I would say our policy makers have
(22:21):
to listen, we have to hear, we have to listen from what's happening on the field and we
have to understand those concerns so we can address them.
We also need to educate ourselves to the science underneath and also the limitations of this
science, not promising anything magical here.
Anytime you put something foreign in an arm for injection, whether it's a vaccine or not,
(22:43):
there are risks.
There are risks.
So, yeah, so the right question to ask is it perfectly safe?
The right question to ask is, is it less risky than having a viral infection from a coronavirus
that can kill?
Another good question is, is it safer than what we currently have, for example, at the
(23:06):
vaccines?
The answer to those questions is by far yes, right?
It was tested that the planet wide, you know, during the pandemic and these formulations
of RNA and vaccines now we know are perfectly, not perfectly, but there's much safer than
the prior modalities that we were using and far safer than being infected by this coronavirus,
right, that the planet hadn't seen before.
(23:29):
So I guess my point is about social acceptability, Rupina, not only for clinicians to use the
full toolkit and understand and be able to answer questions to patients, but also in
general, right?
If you're not careful about this and you don't listen, you know, people will be worried and
they will actually respond, right, by not accepting the treatment and you may have patients
(23:51):
that end up suffering because they rejected that treatment or you'll get people on your
parliament hill with trucks, with horns, because the policies, you know, weren't explained
or the general public is not ready to accept something moving so fast.
So it's a lot of words, but I think, you know, I'm touching upon the speed how these are
implemented and I think there's an important challenge there following up on the strengths
(24:14):
of these and potential of these therapies.
Some of the weaknesses clearly have to do with social acceptability.
Yeah, and I think we all face this, you know, whether it was from a professional or personal
standpoint, you know, you always thought when the pandemic hit, I think it was everything,
there was a lot of anxiety, there was a lot of, everything was very fast paced, right?
So new disease, new learning environment, whether it was thinking about yourself getting
(24:39):
the vaccine or giving it to others, like a lot of us clinicians became vaccine administrators
at that time too, because that was just the, you know, and really weighing out the risks
versus benefit, like you mentioned, right?
And so that was the key point.
Yeah.
As a scientist, you're there, you go, you look at the papers and you read the papers
and you say, oh, okay, that's what they know, that's what they're shooting in my arm.
(25:02):
Oh, I see the chemistry here as a clinician say, okay, well, then, you know, they've had
some prior trials, they can, you see on travels, you see, oh, this LNP is not really new.
It's a messenger and so we have it, but the general public who doesn't have that science,
right?
They're blindfolded, they're blindsided and we're being asked to trust the government,
right?
(25:22):
In a really angst generating period with the pandemic.
So yeah, you know, if you put yourself in their shoes, there's a lot of education to
be had, right?
With those technologies.
I can tell you though, in my mind, there's absolutely no doubt that these technologies
will just accelerate, right?
They're talking about replacing the influenza vaccine that we get yearly, for example.
(25:45):
This is going on.
I mean, right now, you know, it's not very efficient.
It's peptide based or I think it's, I don't know, virus based.
So they're going to shift to Arnie.
So it's just the start.
So for the, you know, on one hand, we'll have messenger on the vaccines for things that
we were exposed to before.
But when there's a new pandemic, because there will be other pandemics upcoming, there's
(26:08):
coronavirus and bats, you know, in Southeast Asia, there's going to be more that incubator
and population is more mobile and we travel a lot.
And we're more dense than ever.
People are concentrated in cities more than ever.
So and there's poverty and there's also, you know, all spectrum of, I would say, the cultural
and practice that will affect distribution of those viruses.
(26:31):
It's going to happen again.
And guess to what they're going to turn next.
They're not going to go backward with the technologies that, you know, were supplanted
by the messenger Arnie vaccines.
Rincon is going to turn to messenger Arnie's because it's faster, it's cheaper and it's
versatile and you can reprogram and repurpose the modalities that were reliable before.
(26:51):
So it's here to stay and it's going to replace and supplant many of the technologies.
It's really, when you think about it, disruptive technology in the, you know, the meaningful
sense of the word and the better we know about those as clinicians and scientists, the better
we are to answer questions by mom, daughter, cousin, but also our patients as well.
(27:13):
Right.
And make them understand to the extent that we know, because we don't know everything
about those still.
Right.
What are the risks and what are the advantages?
And which is science.
Right.
So that is the evolution.
Yep.
And that is, and that's not only based on mRNA.
That's anything.
So we over time, and that's kind of why there's many steps of there's when you're doing a
(27:38):
project, whether it's a small scale project or a large scale project, there's many milestones
that you reach during the process.
And then once it's out in the market, you also do a lot of post-market surveillance.
And so I think that's kind of where the focus has been for my practice in my area with counseling
is really, really letting people know that understanding that this is years and years
(27:59):
of knowledge that's coming together.
And not only that, we're still watching it.
So there's an evolution.
So I can guarantee that what I know today is what I'm going to know in 10 years, because
that's not how science works.
Science is always about knowledge and learning.
Right.
And so we're reflecting on this ongoing.
And so what we know today about mRNA is probably much, much different than we knew about 40,
(28:24):
50 years ago.
So it's just fantastic.
Absolutely.
And there's a good system of checks and balance in science, but also in clinical applications
and in therapy development.
We really keep those with checks and balance.
It's not to say it's a perfect system, but if there's flaws, they will be seen sooner
(28:46):
than later.
But this being said, I think that we need to keep an eye on those new technologies,
that's for sure, and change whatever we need as soon as we capture any evidence of flaws.
And I guess just to touch on that safety aspect, I always get questions around because this
molecule is very unstable and we can change it in so many ways.
(29:08):
Does it actually affect my own genetic makeup when I'm taking these vaccines or these treatments?
And so what's your thoughts on that?
Yeah, it's a question that I hear a lot.
And I think it's very important for people to have a satisfying answer to that one.
RNA is not like DNA.
I know it's only one letter as an acronym, but fundamentally, chemically speaking and
(29:32):
biologically, there's millions and millions, hundreds of millions of years of evolution
made sure that RNA really had different purpose, a different biological purpose than DNA.
DNA is something that you want to keep as a hard drive memory of who you are as a species
and transmitted to next generation.
Because RNA is really a blueprint, something transient and degradable.
(29:57):
So RNA is, messenger RNAs anyway, are really meant to be read, used as a blueprint on site
and then destroyed.
It's actually on purpose that it's destroyable with that special chemistry.
So when you inject a messenger RNA in the cell, it's not going to last very, very long.
So keep in mind that there's about 400,000 messenger RNA in every single one of your
(30:20):
cells right now.
Every single one of your cells have 400,000 of messenger RNAs doing their job.
They're not going back in your genome.
They're actually read and destroyed and they're constantly produced from DNA.
DNA's job is the memory.
The messenger RNA's job is to be transient, read and destroyed.
And it's very chemistry is make sure that it doesn't.
(30:43):
There are really, really rare cases where RNA, and maybe that's part of the confusion,
RNA can be reverse transcribed and inserted in genomes.
And that's a job of rare viruses we call retroviruses.
But that's because RNA can be also modified to play weird tricks.
But that's not the messenger RNA's job.
That's not what the chemistry and the biology of messenger RNAs do.
(31:07):
And the ones that we use, the formulation or types of messenger RNAs that we use with
its chemistry is really the product of about 60 years of intense study by millions of people
worldwide.
And there's groups working on the RNA in labs since the event, its discovery in 1961.
So we know about messenger RNAs.
(31:28):
They're not going back into your genome.
It's really something that it doesn't do.
And I think it's important for people to know that.
And so we talked a little bit about the, obviously we're using mRNA based methods and prevention
in vaccines.
But you also mentioned that in treatment of diseases, for example, cancer would be a common
(31:49):
theme.
Are there specific diseases or like you mentioned for prevention, I think vaccines is kind of
the key player there and influenza for the future.
Are there other current modalities that are current therapies that are using mRNA based
technologies that you'd like to mention to our audience today?
Yeah.
So I'm super excited about the cancer vaccines and what's cool about it, it's not only as
(32:14):
prophylactic.
We talk about vaccine as if they're prophylactic to prevent, but actually some of the clinical
trials right now use cancer vaccines as a treatment.
So there's one actually that was published in Nature in May, 2023, where, and that's
actually really promising, there's a couple of others in parallel where what they did
(32:37):
is they took the tumors, the patient's tumor, and they identified bits that are unique to
the tumor and absent from the patient.
So it's called neoantigens.
So cancer shuffled the cards in a way that you can find bits of information there in
the tumors that are not present in the rest of the patient.
So you take this information and because RNA is so flexible and you can really generate
(33:01):
a vaccine so fast, you generate a bank, a library of messenger nes that would immunize
against those very same neoantigen.
So you actually identify the Achilles heel of the tumor, you immunize while the patient
is ongoing clinical trials, you immunize against its very own neoantigen and you can treat
(33:24):
it this way.
So it's not really the traditional prophylactic use of those, right?
But eventually, what my understanding is eventually they will find some neoantigens that are common.
That's in pancreatic cancer, you will find neoantigens that are multiple of those cancers
and they may use it as a prophylactic as well.
(33:44):
You were referring to other use of messenger netherpethics.
There's for example, the self-programmable form of cells that we call CAR T. So they're
essentially, yeah, you probably heard about this.
They're cell-based messenger netherpethics and the idea there is to program the immune
system to redirect it to serve different purposes.
(34:06):
There's huge potential for messenger netherpethics there as well.
It's another so-called modality and it can go and treat things like heart disease, for
example, just to name one of them.
So the different modalities are based on messenger netherpethics are quite diverse and there's
also flavors of messenger netherpethics that are in development, things like self-implifying
(34:27):
messenger RNAs.
So you add a bit of information, the RNA so that it stays longer, you amplify the messenger
RNAs or circular RNAs that are messenger RNA linear, you have a 5' and 3' and it's part
of its behavior but you can also make it a circle and the RNA lasts longer this way.
There are many, many uses for the different forms of RNAs.
(34:48):
They're apparent to messenger RNAs but there are different modalities I would say that
are emerging that can modify the pharmacokinetics and pharmacodynamics but also the types of
targets that you can challenge with those therapeutics.
All of this is different level of development but I think the first essay, the self-amplifying
RNA was just approved by FDA a few weeks ago as a matter of fact.
(35:11):
So all these are different stages of development but they will emerge in therapeutics soon.
Okay.
So the vast majority of indications definitely when we're looking at kind of what we're targeting
and also what these modalities will be eventually be used for.
So a lot of ongoing research.
Yeah.
That's awesome.
Yeah.
Well, there's a lot of other modalities also.
(35:32):
There's the SI RNA base.
They're not messenger RNAs but they're RNA base like CRISPR for example where you engineer
the genome and can change your cells forever but there's also lots of cool research done
in chemical biology, new modifications of RNA, adding bits of sequence to the RNA so
that we decide where and when the RNA is expressed.
You know, I work on true prune untranslated regions.
(35:53):
Those bits of information decide where the messenger RNA works really.
And there's a lot of cool stuff done on lipid nanoparticles and other nanoparticles.
Again, the delivery of the RNA is a huge challenge and you know, not only from microkinetics,
from microdynamics to which tissues it goes, how long it distributes, you can even change,
(36:13):
tweak the response of the immune system by changing the lipids and those particles for
example.
There are other challenges like, you know, many of people who did dealt with, you may
have dealt with those, the vaccines.
You need those special fridges to keep them minus 80 degrees Celsius, right?
It was a nightmare for distribution.
So there's solutions coming to make them more thermostable, right?
You have vaccines that you can keep at room temperature and that affects the whole distribution
(36:35):
and also ultimately how fast you can respond if something emerges and the availability
of the drugs in your practice.
So there's research and stability also of those vaccines going on as well.
It's going in overdrive.
It's very exciting to see this coming.
And to me, the most exciting part is disease that were out of reach before like cancer
(36:57):
now having options with those.
So it's a lot of hope for patients that, you know, had few options before.
And then I guess just for like my own knowledge because I deal with a lot of, you know, infections,
deficiencies, transplant, is there any talk with mRNA kind of in the immune deficiency
world or bone marrow transplant, stem cell transplant?
(37:20):
Is there any discussions around bringing mRNA technologies for treatment options there?
The intersect between messenger RNA based therapeutics or RNA therapeutics in that larger,
but messenger RNA therapeutics in particular and the immune system is a sweet spot.
That's where we're successful and there's going to be more and more uses there.
(37:42):
I'm not an expert to precisely answer your question.
I'm not an expert and I don't know really what's being done there.
What I can tell you though is that of all the clinical trials, most of them with messenger
RNAs, most of them have to do with the immune system.
And you could have things like chronic inflammation, the chronic disease, right, that are undergoing
autoimmunity.
(38:03):
I wouldn't be surprised if there's breakthroughs there with those therapies.
I don't know how fast it will come, but if I had a chunk of money to put on somewhere
where it's going to move fast, it's going to be on the intercept with the immune system,
whereas immunomodulation, you know, but also, you know, we see things like, for example,
(38:25):
combinatorial treatment with immunotherapy, for example, in cancer, right, the cancer
suppresses the immune system and you can modulate that with immunotherapies.
So there's a synergy between messenger RNA vaccines against the answer immunotherapy.
So you'll see those combinations of treatment in the clinic, for example.
So that's a hot space, I would say, to do research on.
(38:46):
And, Rupina, if you want to do some research, I think that would be grantable, I would say,
in the current period.
Yeah, no, that's fair.
Thank you so much, Dr. Tichane.
I think, I mean, I've learned a lot about mRNA technology and, you know, through everything
that we've spoken about today, doing a bit of my own research as well.
And I think this is, it's nice to see that there's novel techniques that are coming up
(39:10):
and we really have a future where we're not only diagnosing diseases, but we have treatment
options and really just a better understanding, right?
So we have experts like yourselves that can come on and talk to us about this.
And so I think this is very different from a few multiple decades ago, where a lot of
(39:31):
this information wasn't brought out to the public, wasn't brought out to clinicians and
other audiences.
So thank you so much for your wealth of knowledge today.
My pleasure.
It's what's exciting is that this is hope that's given from knowledge.
It's from solid knowledge, from very robust knowledge.
(39:51):
So it's a pleasure to be, you know, conveying this to clinicians and the general public.
Thank you for doing what you do.
Oh, of course.
Thank you for doing what you do.
I think you make my day job easier.
So it's perfect.
And so I think we're definitely, I'll reach back out to you at some point, because I think
(40:13):
there's a lot of future to mRNA-based methods and technology.
I know there's going to be a lot of research in this area.
And I know that the U and R Centre will definitely be on top of it.
And so I think it'll be nice to discuss kind of future, what the future really holds.
Is there anything from a last standpoint that we didn't talk about in mRNA that you were
(40:37):
hoping to share with our audience today?
I just think that what we're seeing is the beginning and that the potential is huge.
Technology is now awake to that potential.
And it's really a very important period to fund research in that area, basic and translational.
And you know, the potential now is absolutely clear and all the players are awake to it.
(41:03):
So I think I would like to close with an appeal for to support research, both basic discovery,
but also translational, so that we can start mobilizing this knowledge towards people,
patients that we need and have few options.
So that would be my last word.
Yeah, no, that's great.
That's fantastic.
(41:23):
Anybody who's a researcher would definitely would, I think, having support in their research
would be important, whether it's clinical, whether it's bioengineering.
There's so many phases.
So, yeah, I think both engineering, basic and applied, I think both need to work in
band and those, definitely.
(41:45):
We've seen it work really well with this.
That's fantastic.
Well, thank you so much for your time and we look forward to future episodes.
Thank you, Rupina.
Thank you, Dr. Duchesne, for the discussion on this interesting topic.
Have an episode suggestion?
Email thecanadianbreakpoint at gmail.com and be sure to follow us on x at cabreakpoint
(42:05):
for updates.
See you again soon at the Canadian Breakpoint.
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