Gene Therapy -- The time is now: Nick Leschly at TEDxBoston
Summary
TLDRThe speaker shares a deeply personal journey in the field of gene therapy, starting with the heart-wrenching story of Ethan, a young boy with a fatal genetic disorder called ALD. He transitions to the innovative strides in gene therapy, using stem cells to combat diseases like ALD and hemophilia, demonstrating the potential to cure or transform lives. The talk concludes with a call to action, urging stakeholders to address the challenges in regulatory approval and payer perspectives to ensure life-saving treatments reach patients in need.
Takeaways
- 🌟 The speaker starts with an introduction that highlights the inspiration behind his work, emphasizing the joy of family and the dream of transforming lives through gene therapy.
- 🏥 The narrative focuses on a disease called Adrenoleukodystrophy (ALD), which is portrayed as a genetic death sentence for children, with a deeply emotional story about a child named Ethan.
- 🧬 The script explains the role of a specific cell in the brain, the microglial cell, which is affected in ALD and leads to the accumulation of very long-chain fatty acids, causing severe neurological issues.
- 💉 The speaker discusses the concept of gene therapy, aiming to cure or transform the lives of children with genetic disorders, using a 'Buck Rogers' futuristic analogy.
- 🛠️ The process of gene therapy is described in detail, involving the creation of a virus to deliver a therapeutic gene into blood stem cells, which can then produce the necessary proteins to combat the disease.
- 🔬 The script introduces the audience to the scientific process of gene therapy, including the use of 293T cells to manufacture the components of the therapeutic virus.
- 🧪 The video shown during the talk illustrates the complex steps of gene therapy, from the creation of the virus to its interaction with blood stem cells outside the body.
- 🩺 The potential of gene therapy is demonstrated through the transformational effects on patients with ALD and other genetic disorders, such as hemophilia.
- 💼 The speaker raises concerns about the readiness of the regulatory system, payers, and the industry to embrace and support the development and application of gene therapies.
- 🤔 The script concludes with a call to action, urging stakeholders to find a balance between scientific advancement and the practical challenges of delivering gene therapies to patients.
- 🌱 The overarching message is one of hope and the potential for gene therapy to provide a 'bluebird day' for children suffering from previously untreatable genetic conditions.
Q & A
What is the speaker's motivation for starting his day with a smile?
-The speaker is motivated by two reasons: having a supportive family with an inspirational wife and five daughters, and working at Bluebird where he gets to work on a therapy that could potentially cure or transform the life of a child with a genetic disease.
What is the condition called Adrenoleukodystrophy (ALD)?
-Adrenoleukodystrophy (ALD) is a genetic disorder that affects the myelin sheath, which is the protective covering of nerve fibers in the brain. It can be life-threatening and was depicted in the movie 'Lorenzo's Oil'.
What is the significance of the brain scan shown in the script?
-The brain scan is of a seven-year-old child with ALD. The white areas in the scan indicate demyelination, which is the breakdown of the myelin sheath, and the buildup of very long-chain fatty acids, which are harmful to the brain.
Who is Ethan, and what is his connection to the speaker's story?
-Ethan was a nine-year-old boy, the son of a friend of the speaker and a fellow CEO in the industry. Ethan was diagnosed with ALD too late, and his story serves as a stark reminder of the urgency and importance of the work the speaker is involved in.
What is the role of the blood stem cell in gene therapy?
-The blood stem cell, also known as the 'Mother cell,' is crucial in gene therapy because it can turn into various types of cells, including the microglial cell affected in ALD. Gene therapy aims to either replace these cells or fix the genetic issue within them.
What is the process of creating a gene therapy treatment as described in the script?
-The process involves creating a viral vector in cellular manufacturing plant cells, which includes the therapeutic piece of RNA that encodes for the broken gene. This vector is then used to infect and modify the patient's blood stem cells outside the body, integrating the new gene into the cells' DNA, which are then reintroduced into the patient.
What is the challenge the speaker identifies in bringing gene therapy treatments to market?
-The challenge lies in balancing the readiness of the regulatory system, societal acceptance, and the understanding of value by payers. The current system may not be adequately prepared to handle the transformative nature of gene therapies and their long-term benefits.
What is the significance of the barcode on the virus in gene therapy?
-The barcode on the virus allows scientists to track every single blood molecule that is made with the therapy. This helps in understanding the effectiveness of the treatment and how it can be optimized for individual patients.
What is the speaker's view on the current balance between scientific advancement and stakeholder readiness?
-The speaker believes that the balance is skewed and not quite right. He suggests that there is a gap between the readiness of scientific advancements and the readiness of stakeholders, which could potentially lead to patients not receiving life-saving treatments in time.
What is the term 'bluebird day' and what does it represent?
-The term 'bluebird day' is used by the speaker's workplace to represent the ideal day for every child, emphasizing the goal of providing every child with the opportunity to have a day free from the burdens of their disease.
How does the speaker describe the impact of gene therapy on patients with genetic diseases?
-The speaker describes the impact as transformative, with the potential to cure or dramatically improve the quality of life for patients with genetic diseases. He cites examples of patients with ALD and other diseases who have seen significant improvements after gene therapy.
Outlines
😢 The Emotional Impact of Adrenoleukodystrophy (ALD)
The speaker begins with a deeply emotional narrative about the devastating effects of Adrenoleukodystrophy (ALD), a genetic disorder that leads to a progressive demyelination in the brain. The audience is asked to reflect on the experience of parents who discover their child has ALD, often at a young age, and the subsequent 'genetic death sentence' that follows. The speaker uses the heart-wrenching story of Ethan, a nine-year-old boy, to illustrate the rapid progression and tragic outcome of ALD, emphasizing the urgency and importance of finding a cure or transformative therapy for such conditions.
🛠️ The Promise of Gene Therapy: A Lego Analogy
Shifting from the sadness of ALD, the speaker introduces the concept of gene therapy with an analogy to Legos, highlighting the importance of hematopoietic stem cells, or 'Mighty Mouse' cells, which have the potential to transform into various other cells, including the microglial cells affected in ALD. The speaker explains the process of gene therapy, which involves creating a modified virus to deliver a healthy gene into the patient's blood stem cells. This process is intricately detailed, from the creation of the viral components in a cellular manufacturing plant to the packaging of the therapeutic RNA. The goal is to correct the genetic defect within the blood stem cells, which can then produce the necessary proteins to combat the disease.
🧬 Gene Therapy in Action: Transforming Lives
The speaker presents the tangible results of gene therapy, showing before-and-after brain scans of patients who have undergone treatment, demonstrating significant improvements in their condition. The narrative then broadens to include another disease, beta-thalassemia, where gene therapy has enabled a patient to produce their own hemoglobin, thereby reducing the need for blood transfusions. The speaker emphasizes the groundbreaking nature of these treatments and the profound impact they have on patients' lives, while also acknowledging the scientific ingenuity behind tracking the therapeutic effect at a molecular level.
🤔 The Challenge of Implementing Gene Therapy
The final paragraph addresses the challenges faced in bringing gene therapy to a wider patient population. The speaker identifies regulatory hurdles, payer perspectives on the value of one-time treatments that provide long-term benefits, and the financial risks for pharmaceutical companies in investing in such therapies. The speaker calls for a reevaluation of the current system to better accommodate the transformative potential of gene therapy, stressing the importance of aligning scientific advancements with the readiness of stakeholders to ensure that patients like Ethan do not fall through the cracks.
🌟 The Vision for a 'Bluebird Day' for Every Child
Concluding the speech, the speaker shares the vision of his workplace, Bluebird, where every child should have the opportunity for an 'ideal day.' The phrase 'Bluebird Day' encapsulates the hope for a future where children are not limited by genetic diseases and can live their lives to the fullest. The speaker's commitment to this vision is evident, as he thanks the audience for their attention and support.
Mindmap
Keywords
💡Gene Therapy
💡Adrenoleukodystrophy (ALD)
💡Blood Stem Cell
💡Microglial Cell
💡Hematopics
💡Virus Vector
💡RNA
💡Integrate
💡Payers
💡Regulatory Hurdles
💡Barcode
Highlights
Speaker wakes up with a smile due to family and working on a potentially life-transforming therapy at Bluebird.
The therapy aims to cure or dramatically improve the lives of children with genetic disorders.
Adrenoleukodystrophy (ALD) is a genetic disorder that leads to a 'genetic death sentence' for affected children.
ALD affects the microglial cells in the brain, leading to the accumulation of very long-chain fatty acids.
The impact of ALD is illustrated with brain scans showing the progression of the disease.
Personal story of Ethan, a 9-year-old boy diagnosed with ALD, who passed away at age 10.
Gene therapy offers hope as a method to treat genetic disorders like ALD.
The discovery of blood stem cells as a potential method for treating genetic disorders.
Blood stem cells can be either replaced or fixed to treat disorders like ALD.
Gene therapy involves inserting a gene into a blood stem cell to correct the genetic issue.
The process of creating a viral vector for gene therapy is detailed, including the use of 293T cells.
The viral vector is used to infect and modify the patient's blood stem cells outside the body.
Modified blood stem cells are reintroduced into the patient, where they produce the therapeutic gene.
Gene therapy has shown success in stabilizing the disease in some patients with ALD.
The potential of gene therapy is also discussed in the context of other genetic disorders like hemophilia.
Challenges in the adoption of gene therapy include regulatory hurdles, payer perspectives, and industry readiness.
The need for a balance between scientific innovation and stakeholder readiness for transformative treatments.
The ethical imperative to ensure every child has the opportunity for an 'ideal day' and a 'bluebird day'.
Transcripts
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that's a tough act to follow uh I think
both acts but literally I jump out of
the bed in the morning with a big smile
on my face and I do that for two reasons
one I have a spectacular family I have
an inspirational wife I have five
daughters so I'm looking for
sympathy between the ages of now get
this 6 and 11
yeah work with me here work with me but
the other reason I do it is I go to work
at Bluebird and I I live a dream I get
to work on a therapy that has a
potential to
cure or at least dramatically transform
the life of a child that's been handed a
genetic death
sentence so that to me is inspirational
and I'm going to tell you a story I'm
going to tell you your story in three
parts first one of great sadness and I
hope it makes everyone extremely
uncomfortable in the room then I'm going
to tell one of great hope that comes
back to gene therapy and what we're
trying to do and I actually had this
line planned which was I call it super
cool Buck Rogers kind of medicine and I
was going to pull it because someone
else had mentioned Buck Rogers and I
thought that was actually a little
strange but you'll hear an amazing piece
of science and medicine and then third
and the reason I think I'm up here is
there's actually a challenge a concern a
a a big dilemma that sits out in front
of us that I alone certainly can't solve
I hopefully can just push the envelope
so first I'm going to ask a question uh
all of those of you and the room who
have kids between the ages of 0 and 10
please raise your
hand okay how many of you in the
audience or in the car whoever is
listening have witnessed a child
somewhere below 10 or 12 years old die
from a
disease okay so everyone I think in here
should really pay attention to the next
few words because I do think we have an
opportunity to make a huge difference so
first great sadness there's a disease
called adrenal lucad distopy Al for
short it was captured in a movie called
Lorenzo's
Oil so some of you may be familiar with
it but imagine this imagine a child
between the ages of four 6 seven
somewhere in that range mom and usually
mom notices that something's not quite
right in school on the playground
somewhere and if she's smart which they
usually are bring them to the doctor and
if you're really lucky the doctor will
figure out in the first go round that
the child has a problem get the right
medical tests and then is handed a
diagnosis of Al what just happened in
that instant was that child was handed a
genetic death
sentence so what do you do in that
instance and what is Al interestingly
enough it's one problem it's one problem
with a cell in your brain called the
microa cell forget the details of all
the biology but that cell has a problem
that it can't clear something called a
very longchain fatty acids forget that
also just remember that when that builds
up in the brain you start to have a real
big problem and what you see on the
screen here in a minute right there is
on the far left hand side you see the
brain scan of a seven child
seven-year-old child and all you have to
know about this scan is white is bad you
can figure out the rest white equals
demonization of the brain white equals a
buildup of these very longchain fatty
acids and if you notice the time course
on this slide that's two years child on
the left is everyone's child all of our
children child on the right is a child
who's vegetative the only thing that
child and the only way that child stays
alive is When does Mom and Dad decide to
let
go horrifying situation now I think most
of you probably are captured now but let
me just needle this a little bit more
okay cuz I want to make this extremely
personal and so I'm going to make those
of you who aren't already uncomfortable
a little more uncomfortable I want you
to meet Ethan Ethan is now uh was a son
of a friend of mine was a fellow CEO in
the industry
Ethan about a year and a half too late
got to the doctor's office and
discovered he had Al he's a
nine-year-old boy in this picture with
braces thinking about the future
thinking about whatever a 90-year-old
should think about but in that instant
when they went to the doctor and in this
case a year too late they found already
he had
Al in this picture which was less than 6
months from left to right he's lying in
his bed and this was the last picture
ever taken of Ethan he died three months
after this picture at the ripe age of
10 so if you're not uncomfortable you're
not human and you should look at
somebody I take this picture everywhere
it's in my office my Cube It's in my car
it's at home I present this to my kids
and I'll walk them through it because
this is the Stark reminder why we
must address the challenge that I'm
going to get to you here but let me
shift gears on you a little bit just to
make sure you're not totally depressed
walking out of here so let's talk about
some great hope let's talk about gene
therapy but it starts with a game of
Legos I'm Danish I like Legos so let's
start with a big Lego piece first which
was discovery of something called the
hematopics forget that fancy word called
a blood stem cell if you don't like that
call The Mighty Mouse of all
cells okay this is an awesome cell my
kids actually call it the Mother cell
reason they do that is you see this cell
turns into all kinds of things and wears
all kinds of hats and does a spectacular
job at it it produces your immune system
it produces the cells in your blood
system it produces this the cells in
your CNS in your nervous system
including the micro Leo cell Bing
hopefully all of y'all made the
connection I'm not from the south I'm
not sure where that came from but you
made the connection the blood stem cell
turns into the micr Leo cell and that's
the magic that's where we figured out
that at that point in time you have two
choices you can either replace the blood
stem cells in your body or you can fix
them next piece in the Lego game was
let's try to replace them and they did
they took the cells out of the body of
the child they put the new ones in from
someone else and lo and behold some of
the cases it actually worked
the process worked there were some cells
that got in the brain but here's the
catch in a big percentage of the time
that treatment alone kills you and
another big percentage of the time you
don't even have access to that type of
treatment so I'm going to shift gears
and go to the Buck Rogers part here and
talk about gene therapy saying how do we
fix it how do we take that blood stem
cell and fix what's broken how do we
take a gene from the outside and put it
in that cell it sounds remarkably
complicated it's actually extremely
complicated I don't understand half of
it but I'll walk you through it here and
bear with me here there's a 3 minute and
51 second video I'm going to show you
because Ted folks are pretty specific
about their timings so I'm going to take
you through this video I'm going to talk
you through it because I think what you
have to figure out is we have to make
something that can penetrate a cell and
insert a piece of DNA so first we got to
make it what you see here is the
cellular manufacturing plant called 293t
cells for those of you who care what
they do and they're really good at is
making making things those little things
you see slipping around those are four
plasmas those are four parts to the
virus we're trying to make you put them
in there in parts and the cell
understands what to do inside the
nucleus it reads them as you can see
here it produces four pieces of RNA
three of them bug out of the
nucleus go out there and produce the
three components we need capsid a red
protein and the vsvg envelope again
forget all those fancy words but those
are the parts then here's the key piece
that therapeutic piece of RNA that's
what encodes for that broken Gene that's
in the blood stem cell in the case of Al
here you see it packaged and boom right
there that's your virus that's our
trojan horse that's the thing it's
actually an HIV derived virus that now
has been hacked up and has produced and
now millions of those are sitting in
this
vial cool but not that helpful unless
you have the other half which is you
need the blood stem cell from the
patient from Ethan and here what you're
visualizing is you're going into the
blood ban sorry you're going into the um
the marrow to pick out the blood stem
cells and you see these little red guys
popping into the bloodstream those are
the ones we capture it's fairly standard
procedure we stick billions of those or
as many as we can into a bag now next
step virus meets blood stem cell in the
bag outside the body so virus never goes
in the body what it then knows to do
is to infect the cells infected as many
times as we can as many of cells as we
can in that bag it goes into the first
the cytoplasm then it releases the
payload it then knows to and we're
certainly taking some scientific
Liberties here to make it a little more
simple but it explodes there right there
that's your money ship the RNA but for
those of you who remember your biology
class we got to do some gymnastics to
make sure that turns into DNA because we
have here up here it says revolutionary
ideas
well watch carefully here because as we
finish this gymnastics you're going to
visualize the Revolutionary idea this
gets moved and transported into the
blood stem cells compartment the nucleus
where the DNA exists and right here in a
little magic boom it integrates itself
into the
DNA now what you've just created is a
gene modified blood stem cell that stem
cell knows what to do the cells know
what to do it starts producing your
therapeutic Gene start producing a lot
of them you turn your red cell into blue
cell in this picture here bottom line
those are modified those now know how to
do what the problem was before we put it
back into the patient so picture Ethan
here we put it back in now these cells
see your marrow and they then start to
Pro daughter cells all those daughter
cells now know what to do they have a
functioning copy of this Gene that's
great how do it compare to to
Al Al as you remember in the brain had
this buildup of white matter or white or
demonization these very long chain fatty
acids so what happens now is some
percent of these blood stem cells as
they continue to produce turn into
macras that's this pretty cell once that
cell moves some percentage of those
cross the blood brain
barrier this is all pretty you know
seismic in science if you ask me and it
moves into the brain it then sits there
and acts like a sponge on these very
longchain fatty acids and what happens
is stabilizes the disease in not all the
cases but we certainly hope in many of
the cases depending on where the disease
is and you say Nick great great video
wonderful who cares it's a
video what you should care about is an
awesome PA Elin France patrico Borg and
Natalie K did exactly what I just
described what you see on the left- hand
side is an untreated patient we went
through that what you see on the right
is two patients that were treated over
five plus years
ago you don't have to look at a lot of
scans or be a radiologist to realize
that those two kids are doing pretty
well they're in the playground they're
at home they're in school pretty amazing
what's also really cool now let's zoom
out a little bit and say how does this
apply somewhere else well let me tell
you about another disease very quickly
it's called phemia This is a case where
you can't make hemoglobin if you don't
get hemoglobin from someone else you die
average age of seven if you do get it
from someone else you can survive to the
age of 30 40 years old perhaps with a a
very tough quality of life so what we do
there is instead of inserting the
transporter gene we insert the
hemoglobin Gene so this funy slide that
you have up here is the blood level in
this patient who at the age of four has
been tend dependent on someone else's
blood since the age of four and is now
was 18 years old we treated him one
time at that point in time red is good
in this picture we're now producing over
a third of his hemoglobin and we're out
five plus or four plus years now with
this p completely transformed life it's
never happened before in this disease
there's no way this is a spontaneous
treatment CU we can track every single
blood molecule that's made with our
virus has a barcode on it we can see it
and that was the genius of of uh Philip
labou our scientific founder to figure
that out because that's how we know
we're making a difference that's how we
know how to treat this patient
differently so that's great Nick this
all sounds good so what in the world is
the problem right what's the challenge
well I think the challenge at this
moment is that are we ready is the
system is society is the status quo
ready to receive a treatment like this
it's pretty transformational but here's
how it kind of blows up the system a
little let's take three viewpoints first
The Regulators you talk to The
Regulators what's the right balance what
are the right number of patients that
they should require for this how do they
handle this kind of treatment what are
the hurdles put in place those are
absolutely essential poal to folks like
me that's one piece of the equation and
I can tell you obviously my opinion is
that balance is not quite right that
balance is skewed it's a one-sized
fitall second stakeholder even more
confusing the payer they're great at
saying deliver a drug pay for the drug
here we delivered the drug one time the
body is now the enzyme replacement
system and every time that body delivers
drug it doesn't pay very well right what
do you do what's the value of that type
of treatment forget the price what's the
value of that treatment I describ to you
Ethan he had a battle for eight months
that battle cost over $ three and a.
half
million that's a big number so how do
you think about it from a payer point of
view and then thirdly from my point of
view an industry point of view bigger
companies smaller companies how do you
put all this together how do you think
about if The Regulators put up a lot of
hurdles and the payers don't understand
the value how do you justify spending
hundreds of millions of dollars to take
the science and medicine like this
forward the answer is it's complicated
the answer is we got to do a much better
job putting in context how we balance
the science and medicine that we're
bringing forward with the stakeholders
we need to rise above and figure out a
way to realize that that Gap that could
potentially exist between the time that
we're ready to deliver this to the
market and all these other therapies
we're bringing forward these
stakeholders better be ready because if
there's a gap patients die Ethan dies
and that's not acceptable to me I live
under the edict that every child has
should have the opportunity to have an
ideal day and what we say at the place I
work is every child should have the
right to have a bluebird day thank you
[Applause]
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