Gene Therapy -- The time is now: Nick Leschly at TEDxBoston

Summary

The 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

00:00

😢 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.

05:01

🛠️ 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.

10:03

🧬 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.

15:06

🤔 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.

Keywords

💡Gene Therapy

Gene therapy refers to the use of genes to treat or prevent diseases. In the context of the video, it is a revolutionary medical approach that aims to cure or transform the life of a child with a genetic disorder. The script describes gene therapy as a 'Buck Rogers kind of medicine,' highlighting its futuristic and transformative nature. It is used to treat conditions like Adrenoleukodystrophy (ALD) by modifying blood stem cells to produce a functional gene that was previously non-functional.

💡Adrenoleukodystrophy (ALD)

Adrenoleukodystrophy, abbreviated as ALD, is a genetic disorder that affects the brain and adrenal glands. The script describes ALD as a 'genetic death sentence' for children, causing a buildup of very long-chain fatty acids in the brain, leading to severe neurological damage. The video emphasizes the devastating impact of ALD, as illustrated by the tragic story of Ethan, a young boy affected by the disease.

💡Blood Stem Cell

A blood stem cell is a type of cell found in bone marrow that has the potential to develop into various types of blood cells. In the video, the blood stem cell is referred to as 'The Mighty Mouse of all cells' due to its ability to transform into different cell types, including the microglial cells affected in ALD. The script discusses the process of either replacing these cells or fixing them through gene therapy.

💡Microglial Cell

Microglial cells are immune cells found in the brain and spinal cord. The script mentions that in ALD, the microglial cells have a problem clearing very long-chain fatty acids, leading to their accumulation in the brain. This buildup is visually represented in the video by a brain scan where white areas indicate the presence of these harmful lipids.

💡Hematopics

The term 'hematopics' seems to be a mispronunciation or a specific term used in the script to refer to hematopoietic stem cells, which are responsible for producing all types of blood cells. The script uses the term to emphasize the importance of these cells in the process of gene therapy, where they are either replaced or modified to treat diseases like ALD.

💡Virus Vector

A virus vector is a modified virus used to deliver genetic material into cells. In the context of the video, the virus vector is described as a 'Trojan horse' that carries the therapeutic gene into the blood stem cells. The script explains the process of creating this vector in cellular manufacturing plants and its role in gene therapy.

💡RNA

RNA, or ribonucleic acid, is a molecule involved in coding, decoding, regulation, and expression of genes. In the script, RNA is mentioned as a critical component in the gene therapy process, where it encodes for the broken gene that needs to be fixed in the blood stem cell. The therapeutic RNA is packaged into the virus vector for delivery into the cells.

💡Integrate

In the context of gene therapy discussed in the video, 'integrate' refers to the process where the therapeutic DNA integrates itself into the DNA of the blood stem cell. This integration is crucial as it allows the modified cells to produce the therapeutic gene, correcting the genetic defect and potentially curing the disease.

💡Payers

Payers in the healthcare system are entities that provide coverage or reimbursement for medical services and treatments. The script discusses the challenges faced by payers in evaluating the value and cost of gene therapy, which may provide a one-time treatment with long-term benefits, unlike traditional drugs that require ongoing administration.

💡Regulatory Hurdles

Regulatory hurdles refer to the obstacles or requirements set by regulatory agencies that must be met before a new treatment can be approved and marketed. The script mentions these hurdles as a potential challenge for gene therapy, suggesting that the current regulatory framework may not be fully equipped to evaluate and approve such transformative treatments.

💡Barcode

In the script, a 'barcode' is used metaphorically to describe a unique identifier for the virus used in gene therapy. This identifier allows scientists to track every single blood molecule produced by the modified cells, providing a way to measure the effectiveness of the treatment and understand the patient's response to the therapy.

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

[Music]

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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]