Gene editing is revolutionizing medicine, and Dr. Matthew Porteus, Professor of Pediatrics at Stanford University School of Medicine, is at the forefront of this transformation. Join us for a conversation with Dr. Porteus as he shares his insights on CRISPR technology and its potential to personalize therapies for rare genetic conditions, including sickle cell disease. Discover how this groundbreaking tool not only identifies the root causes of diseases but also paves the way for innovative treatments. As we discuss the challenges of translating gene editing into clinical practice, Dr. Porteus will highlight the ethical considerations and access issues that shape the future of healthcare. Don’t miss this opportunity to explore the promise of CRISPR and its impact on the lives of patients.
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Episode Transcript
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(00:00):
(bright music)
- Welcome to "Stanford Medcast,"
the podcast from Stanford CME
that brings you the latest insights
from the world's leadingphysicians and scientists.
If you're joining us for the first time,
be sure to subscribe on Apple Podcast,
(00:20):
Amazon Music, Spotify, or YouTube
to stay updated with our newest episodes.
I am your host, Dr. Ruth Adewuya.
Joining me today is Dr. Matthew Porteus,
who is a physician scientist
and a global leader infield of gene editing
and STEM biology.
He's currently the Sutardja Chuk
professor of definitiveand curative medicine
(00:42):
and professor of pediatrics
at Stanford University School of Medicine.
A pioneer in the field,
Dr. Porteus was the first todemonstrate the feasibility
of precise genome editing in human cells
using engineered nucleuses,
laying the foundation fortherapeutic gene correction.
His research focuses ondeveloping curative therapies
(01:03):
for genetic diseases,particularly sickle cell disease
and other blood disorders byediting hematopoetic stem cells
using CRISPR-based technologies.
He has played a central rolein translating genome editing
from the lab to the clinic,
and his team continues
to lead early phase clinical trials
designed to evaluate the safety, efficacy,
(01:26):
and scalability of thesegroundbreaking approaches.
Dr. Porteus, thank you somuch for chatting with me
on the podcast today.
- Thank you, Ruth.
Really glad to be here.
- For listeners who maynot be deeply familiar
with the science, couldyou walk us through
how CRISPR works, what itis, how it edits genes,
and why is it considered
(01:47):
to be such a breakthroughin molecular science?
- I'm gonna even stepback a bit before CRISPR.
As you're going through medical training,
we recognize that for certain diseases,
if one could just change a nucleotide
in the DNA of a cell or changethe DNA sequence precisely,
(02:08):
that you could address many diseases.
In the early 2000s, aspeople, including myself
started to figure out ways of doing
what we now call gene editing in cells.
The tools we had at the time
were tools called zinc finger nucleases
and TAL effector nucleases.
The way they worked isthat you design a nuclease,
(02:32):
a protein that makes a break in the DNA.
So it recognizes exactlywhere you want in the DNA.
It makes a break,
and then that triggers thecell to repair the break.
By allowing the breakto repair on its own,
you can create new mutationsat the site of the break,
and we'll get into why that's important.
(02:54):
Or if you provide what wecall a donor piece of DNA,
the cell will use, the homologousrecombination machinery
to make a copy of the undamaged donor
and paste it over thebreak to fix the break.
By designing the donorDNA in the right way,
we can now introduce those exactchanges to the DNA we want.
(03:15):
So this was all goingon in the late 1990s,
early 2000s, but thetools were hard to use.
What CRISPR did when it was discovered
that you could reprogramit to make a break
at a sequence very easily,
and then when it was shownthat this bacterial system
worked very well in human cells,
(03:38):
it totally changed the field.
Now, instead of havingto spend several years
to make a specialized protein,
you could spend several daysmaking a CRISPR nuclease.
The way the CRISPR system worksis it has two parts to it.
It has a protein part called Cas9.
That is the scissorsthat's gonna cut the DNA.
(03:59):
And then it has an RNA part
that gets abound by the Cas9 protein,
and it's the sequence of the RNA
that guides the molecular scissors
to the right site in thegenome to cut the DNA.
It's this very elegant two-part system
where the Cas9 is used all the time,
and by just changing 20nucleotides in the RNA,
(04:23):
you now can move the scissors
to different parts of the genome.
- It sounds like whatmakes CRISPR revolutionary
is its precision, flexibility,and accessibility.
And what you've said has set the stage
for everything else thatwe will be discussing
because it's really reshaping our ability
to intervene at the root cost of disease.
(04:45):
- That's right.
Genome editing is a processof changing the DNA of a cell
in a precise manner.
CRISPR is a tool to enable us to do that,
but CRISPR is not genome editing.
And we'll get into maybe a little later
that there are other differentgenome editing tools.
So you have a class and a tool.
(05:05):
- Yes, and we'll certainlytalk more about that later,
but one of the things
that I also wanted tostart our conversation with
is to center the impact of this work
because it becomes clearest
when we move from talkingabout molecules and genes
and all of that, and we move to people.
How has your experience as a clinician
(05:27):
informed your approach
to designing and translatinggene editing therapies
for real world use?
- I'll start with my personal story.
I was an MD PhD student here at Stanford,
and it was on my clinical rotations
in my third and fourthyears of medical school
that I met and took care of a young woman
with sickle cell disease whocame into the emergency room
(05:48):
with pain in her bones,
which is a commonmanifestation of the disease.
For the most part, the treatment of anyone
who has sickle cell disease
who goes into what we call a pain crisis
is depending on the severity of the pain.
In its most severe cases,they're admitted to the hospital,
they're given hydration,
and they're given opiate pain medicine,
(06:08):
and you'd wait for that paincrisis to resolve on its own.
What was striking to me and to many others
is that what we were doing clinically
to treat the pain crisiscaused by the variation
that causes sickle cell disease
compared to what we knew aboutit from a molecular biology
and genetics perspective.
One could argue the disease
(06:30):
that has taught us the mostabout how genetics interface
with human health.
It has always been apioneer in our understanding
of that really complicated
and industry relationship thatpermeates all of medicine.
Yet we had no good therapiesbased on that knowledge.
I came out of medical school idealistic.
(06:51):
We need to bridge the gapbetween the knowledge of genetics
and developing genetic therapies,
highly precise genetic therapies
to address the geneticbasis of the disease.
- It's incredibly powerful to hear
how a patient's experience
can directly shape scientific priorities
and a reminder of how important it is
(07:14):
to ground research in thereal world realities of care
and to stay connected to whatpatients are truly facing.
In what ways is genome editing
enabling a more personalizedapproach to care,
especially for patients with rare
or treatment resistant genetic conditions?
- That is a problem thatwe're still working on.
(07:36):
Sickle cell disease is unique
among serious genetic diseases
in that every patient has the same,
and I use variant not mutation
because if you have onecopy of the sickle cell gene
and one copy of the A gene, so your SA,
you're actually resistant to malaria.
(07:56):
So it's beneficial to have one S and one A
if you get malaria.
It is only detrimentalif you get two S genes.
So I don't like to thinkof it as good or bad.
It's all contextual.
But every person with sickle cell disease
has that same S gene,
which means that if youdesigned an approach
(08:17):
for one patient, you could treat them all.
Most genetic diseasesdon't have that feature.
Instead, there might behotspots that cause the disease,
but there are mutations thatcause the genetic disease
that are scattered throughout the genome.
A CRISPR system
that could treat a onesize fits all mutation
(08:38):
for any given genetic disease.
My lab and other labs have worked on that.
It's a specific genetictherapy for one disease.
What was exciting two weeksago was the announcement
that was designed to correctthat patient's mutation
and only that patient's mutation,
and that was so super personalized.
(08:59):
Six months in multimilliondollars of work,
they only worked for thatone patient and that boy,
who's been publicly described as baby KJ,
had a super severe metabolicdisease of the liver,
and now his disease issignificantly less severe
and he's growing and isdoing so much better.
The question then is, in thefuture, can we get to a place
(09:22):
where everyone will have theirpersonalized CRISPR system
or is that just a mode of drug development
that is a bridge too far
and instead we're gonna haveto go back to one system
that could treat one disease?
- That's such a dramatic departure
from how we've historicallymanaged chronic conditions.
(09:43):
- Yeah.- I'm also thinking about
the scalability of this andhow all of that would work.
How close are we to CRISPR based therapies
becoming part of mainstream treatment?
- To the first part of the question,
maybe I'm not idealistic enough
to think that personalizedCRISPR therapies
will become common.
That's really hard to get my head around.
(10:05):
I feel like it might work fora handful or more patients,
but you know what?
I might be proven wrong and in 10 years,
I might have to eat mywords, which is fine.
In terms of sickle cell disease,
we don't really have that issue
because every patienthas the same variant.
So you don't have to designa personalized system.
In December of 2023, twogene therapies were approved
(10:26):
for the treatment of sickle cell disease.
One developed and sponsoredby a biotech company
called bluebird bio wasbased on using a virus
to deliver a copy of the beta globin gene
into hematopoietic stem cells,
the cells that giverise to red blood cells
so that you now create acell that has the S gene
(10:46):
and NA gene.
They treated in the rangeof 40 to 60 patients.
They showed that thosewho got the therapy,
their amount of pain, thefrequency of their pain crisis,
the amount of pain wassignificantly better.
And that led to its approval.
The trade name for that drug is LYFGENIA.
Casgevy is the CRISPR drugthat was approved in the US
(11:07):
by the FDA on the exact same day.
The way Casgevy works,
it is known thatcounteracting the S protein
is something called hemoglobin F,
the fetal hemoglobin that we have
before we're born.
If you have S and F, theF can counteract the S.
What Casgevy does is,so before we're born,
(11:29):
we have lots of F in our red blood cells.
And after we're born, ourgenetics puts a break on F
to allow the adult hemoglobin to turn on,
which in this case is S.
What years of genetic research
and then molecular biology research
and mouse studies showed
is that a protein called BCL11A
is one of the major breaks on F.
(11:51):
If you inhibit thebreak, you can release F.
What Casgevy does is it inhibits BCL11A
from being turned on indeveloping red blood cells.
And so now you get F to counteract the S.
Now you'll notice thatthey're indirect workarounds
to address the SS.
What my lab has done is to useCRISPR-based genome editing
(12:14):
to directly change the S to A.
Now instead of having SS,we will convert the S to A.
You only need to convert one S to A
to create sickle cell trait.
That's what we're trying to do
'cause we think that is the true endpoint
for gene editing for sickle cell disease.
- It sounds like there havebeen some real landmark moments
(12:37):
both in terms of new approvals
and the shift to frontline therapies
and your lab is also contributing
to the next phase of this work.
When I think about what comes next,
especially as these therapiesmove from development
into real world use, two thingsimmediately come to mind.
Access and safety.
(12:58):
Safety in particularbecomes even more critical
when we're talking aboutintroducing genomic changes.
From your perspective,
what are some of the mostsignificant challenges
in translating gene editinginto clinical practice?
- For sickle cell disease
and for other geneticdiseases of the blood,
the processes goes through
what we call an autologousbone marrow transplant.
(13:19):
The patient is hooked up toa machine apheresis device.
We have to get theirhematopoietic stem cells
or blood stem cells out.
You can spin out the nucleated cells,
and then that goes into a bag.
Then the cells get either genome edited
or lentiviral engineered.
Then if that product of cells,
which is several hundredmillion if not a billion cells,
(13:41):
passes all the criteria,hasn't gotten contaminated,
it's then ready to be released.
Patient has to come back in
and get chemotherapy to ablate
all of their endogenoushematopoietic stem cells
to create space for the new stem cells,
and then they get infused.
Now, that chemotherapy treatment
using a drug calledbusulfan causes mucositis,
(14:04):
it can cause long-termissues, infertility,
it causes your blood counts to be low
for several weeks or longer.
So you're at risk of infections,
while the new cells find their homes
and start making blood cells.
The first hard thing wasgetting the efficiency
of the genetic engineering highenough in the cells you need
without killing the cells.
(14:24):
You have to keep the cells healthy
so that they will engraftand make new blood cells.
Then the next part is howdo you incorporate that
into a very complicated process?
In the long term, wewould of course like to
get rid of that chemotherapyfor the conditioning.
We'd like to make themobilization of the stem cells
easier on some of the bigger issues
(14:45):
around genome editing.
I heard a social scientistdescribe a dichotomy
between perfection and perfectability.
We're always shooting for perfectability.
We have a north star to get to perfection,
but we almost never get there,
but we have to have that process
that we can always do better.
These are some of the areas
where we'll do better in the future.
Stanford is leading thecharge in some of those areas,
(15:05):
which is really exciting
to have my colleagues be doing that.
- How much of a concern arethings like off target effects
or insertion deletion errors
when you're thinking aboutclinical applications
of gene editing?
- We are always concerned.
Do they make breaks where we don't want?
And when 10 years ago,
when the CRISPR-Cas9 system was described,
it was like, is this gonna be a problem?
(15:27):
It turns out this systemis remarkably specific.
We didn't know it at the time.
One of the things you have to do
is you have to show to theFDA that you have assessed
how specific your process is.
And often, you can find noevidence of off targets.
It may mean they're not there,
but it also may mean thatyou just can't find them.
(15:48):
When Casgevy was approved,
they had a scientific advisory board
spending the day to advise the FDA.
And most of the day was spenton have they demonstrate
the specificity to a degreewe should have confidence.
And the advisory board was unanimous
in saying that the specificityhad been demonstrated
and the risk benefit entirely favored
(16:11):
that this should be approved.
Now, that's just an advice to the FDA.
They ended up following thatadvice, but that's true.
We, meaning the entire field,
spends a lot of time on making sure
that the process is specific,but we've gotten to a point
where I will even challengemy sequencing colleagues
that if I give them two samples,
I don't think they couldfigure out which one was edited
(16:33):
and which one wasn't basedon off-target effects.
We have to remember two things.
One is that the chemotherapywe give for the conditioning
is far more genotoxicthan any CRISPR editing.
The other thing to rememberis our genomes in our cells
acquire mutations every day of life.
I like bacon.
We know bacon has chemicalsin it that damage our DNA.
(16:54):
We breathe pollution that damage our DNA.
Actually, just cells living
where they create reactiveoxygen species damages the DNA.
So there's no such thing as a cell
that doesn't get damagedDNA and acquire changes.
Again, it's putting this all in context,
how severe the disease is,
what's going on in thebackground, can you detect it,
(17:15):
and putting that equation together.
- That's really helpful context.
I imagine that when we're talking about
applying these therapies to children,
the bar is even higher, bothethically and clinically.
How do you navigate the balance
between therapeutic potentialand the unique ethical
and regulatory complexities
(17:36):
that come with treatingpediatric populations?
- We and others could havehours of conversations,
but the general frameworkis that if a disease
is so lethal that peopledon't even reach adulthood,
then of course, gettingconsent from a parent
to investigate a therapyis ethically justified.
(17:56):
If it's a disease that's severe,
but people reach adulthood,then the clinical trial
has to start in adultsfor ethical reasons.
It's only after you've done a few adults
that then you can move to adolescents.
Actually, both LYFGENIA and Casgevy
are approved for the age of 12 and above.
What both companies are doing now
(18:16):
is running the clinicaltrial in younger people
to expand who can get it, whowould be approved to get it.
Now, I will say for a diseaselike sickle cell disease
and others, but sickle celldisease is a great example,
it's a progressively destructive disease.
Even a healthy 23-year-oldwith sickle cell disease
still has organ damage that afive-year-old wouldn't have.
(18:39):
This is a disease that in the long term,
I think we wanna treat in early childhood
before that inevitable destruction occurs.
- There seems to be a really thoughtful
multidisciplinary approach
to involving childrennot just in treatment,
but in the broader processincluding clinical trials,
(19:00):
and yet even as enthusiasmfor these technologies grows,
especially in areas likesickle cell disease,
broader adoption stillseems to be limited.
What's continuing tohold that adoption back?
Is it the complexityof the therapy itself,
the infrastructure thatis required to deliver it
or something else?
(19:21):
- Treatment centers likeStanford's that have that capacity,
that expertise,
the first delay in getting this rolled out
was getting treatment centers qualified
to be able to administerthis commercial therapy.
And I can tell you, it's very complicated.
Then patients have to be interested.
And to fit the eligibility criteria,
they have to decide with theirphysicians and their family
(19:42):
whether this is thebest approach for them.
Once all that's happened,
then it's a between six to nine months,
maybe even longer processbetween I wanna get this
and actually getting it.
The approval in December of 2023,
it wasn't like there was amillion pills on the shelf
ready to give to patients.
It's not surprising
that it's taken a littlewhile for it to roll out.
(20:04):
We're seeing increasing number of patients
coming into the queue
and getting increasingnumber of treatment centers
up and running.
Now, what the cap will beon that remains to be seen.
We're still very muchin the build out phase.
I'm a believer thatthere are enough people
with severe sickle celldisease that we need
(20:25):
three or four or even fivedifferent products on the market
to meet demand because theseare complicated therapies.
We can argue about, is thatbetter than one or that better?
But they're all falling intothis really transformational
approach to patients.
Third patient treated
is a man named Jimi Olaghere from Georgia.
And listening to him talk about
how it's changed his life is spectacular.
(20:48):
And I'll just highlight a couple points
that I've heard him say.
One is that he used to thinkhe was allergic to snow
because every time hewould go out into the snow,
he'd have a crisis
because that's known in peoplewith sickle cell disease.
After his therapy, it snowed in Atlanta,
which it occasionally does,
and of course, the city shuts down.
He went on and played inthe snow with his kids
(21:09):
and realized he wasn't allergic to snow
because he no longerhad sickle cell disease.
The other great thing is that last summer,
he was part of a fundraisingeducational effort
that resulted in himclimbing Mount Kilimanjaro
and he believes he's the first person
with sickle cell disease everto climb Mount Kilimanjaro
because at 21,000 feet, thelow oxygen's not so good.
(21:32):
Those are the life-changing stories.
Many other patients have been very public
about their stories and howthey had put their life on hold,
they weren't sure where their future was.
They get the therapy,
and now they're back atit a hundred percent,
fully optimistic abouttheir future and onwards.
- These are such powerful stories.
Thank you for sharing them.
(21:52):
They really speak to whatkeeps people like you energized
and committed to this work
and to the hope of expandingaccess to these technologies.
You touched on this earlier,
but one of the major challenges is cost.
These therapies hold incredible promise,
but they come with a high price tag.
The cost of these technologiesare probably upwards
(22:15):
of a million or so.
- It's an interesting debate,
and I'm gonna give a slightlydifferent perspective.
The list price for Casgevyis around $2 million.
List price for LYFGENIA is $3 million.
And you're shaking yourhead and you're going,
"That is way too expensive," and it is.
It is clearly a barrier,
and what that means isthat one of the barriers
to the uptake is finding payers
(22:37):
who are willing to pay that price.
Several of us have arguedthat actually, it's a bargain.
When you think about what the impact
this disease has on people's lives,
and when you hear storieslike Jimi's and others
about how they're now able to hold jobs,
they're now able to pursue their careers,
now I think about childrenwho I've taken care of
(22:58):
where the parents, often the mom,
have to change theirentire career trajectory
because they never know whatday they can't show up for work
'cause they have to take careof their kid who's in pain.
I think the direct and indirect costs
and lifetime benefits, this is a bargain.
Now, that does not mean
that the sticker shock priceis not causing people to pause.
(23:19):
That does not mean thatwe shouldn't find ways
to make it cheaper.
I just don't want it get out there.
This is great, but it's tooexpensive and it's not worth it.
I wanna say, "This is great.
It is expensive, it isworth it even at this price,
but let's figure outhow to make it cheaper."
- I really appreciate theperspective you're offering
and I agree the frameworkmakes a lot of sense,
(23:41):
but I think it's a yes and situation.
The context is compelling,
but how does it actuallytranslate into real world access
for the people who need it most?
Because if access isn't built in,
then even the most promising frameworks
ultimately fall short.
- Exactly.
I don't wanna get intohuge political discussions,
(24:03):
but this is why fundingfor Medicaid and Medicare
are so important because no individual
can pay for this out of their pocket.
This is paid for either through their own
private health insurance,through Medicaid,
or through Medicare.
When there are threats to those systems,
then access to payment for these therapies
is significantly burdened.
(24:24):
In the meantime, that'sour job in academia
and biotech is to figure outhow to bring that cost down
so the upfront burden is lower.
- Absolutely, I couldn't agree more.
That's such a valuable perspective
and one I honestlyhadn't considered before.
It's exactly why I lovehaving these conversations.
They expand how we think.
(24:44):
As we begin to wrap up, I'm curious,
for clinicians who don't workdirectly in gene therapy,
what practical implicationsshould they be aware of
as these treatments start toenter broader clinical use?
- I'm just one personwith a poor crystal ball.
Take it for what it's worth.
There's a couple things that come to mind.
(25:05):
One is that right now, thegene therapy, gene editing,
and the entire biotechdrug development space
is very much in a winter.
There was tremendousenthusiasm in 2019, 2020,
and since COVID,
I don't think it had anythingto do with COVID honestly.
The enthusiasm has swung toofar in the other direction.
(25:25):
My word is that it will come back.
That gene editing, genetherapies, they work.
Just came back from the annual meeting
for the American Societyof Gene and Cell Therapy
and the science is amazing.
It just keeps working.
It keeps getting better.
People are doing cooler and cooler things.
So we'll get there.
That being said, most of these therapies
(25:46):
and even sickle cell diseasefalls into this category,
are directed at rare diseases.
At some point,
the ability to use gene editing,
gene therapy to treat a common disease
is going to happen.
That's when this modalityis going to change medicine.
When instead of havingto take a pill every day
(26:06):
of your life, a one-time therapy
that will treat your diseasefor the rest of your life,
that's our goal.
That's what we're tryingto do at Stanford.
Our Center for Definitiveand Curative Medicine
is rock the boat on howwe think about treating
not just rare genetic diseases,
but more common diseasesthat might affect all of us
with one and done type therapies.
(26:27):
Are we there yet? No.
But are we there in mice?We are there in mice.
Now, how do we get from mice to humans?
And I think for thoseout there listening in,
thank you for listening.
That's what you wannastart listening about.
When do you hear about something
that isn't just for rare diseases?
Now, as a pediatrician, I'm allin on rare genetic diseases.
Those patients, thosefamilies mean everything to us
(26:50):
and many of my colleagues,
but we also need to get tomore common diseases as well.
- Thank you so much for walking us through
both the complexity and the promise
of CRISPR-based therapies.
It's clear that movingfrom bench to bedside
isn't just about innovation.
It's about translatingscience into meaningful
patient-centered change.
As gene editing continuesto shift from novel
(27:13):
to standard practice,
your insights will be incredibly valuable
to both clinicians and patients.
Thanks again for joining us.
- Thank you again, Ruth.
- This episode was broughtto you by Stanford CME.
To claim CME Forlistening to this episode,
click on the claim CME link below
or visit medcast.stanford.edu.
(27:34):
Check back for new episodes
by subscribing to Stanford Medcast
wherever you listen to podcasts.
(ambient music)
(bright music)
- Welcome to "Stanford Medcast,"
the podcast from Stanford CME
that brings you the latest insights
from the world's leadingphysicians and scientists.
If you're joining us for the first time,
be sure to subscribe on Apple Podcast,
(00:20):
Amazon Music, Spotify, or YouTube
to stay updated with our newest episodes.
I am your host, Dr. Ruth Adewuya.
Joining me today is Dr. Matthew Porteus,
who is a physician scientist
and a global leader infield of gene editing
and STEM biology.
He's currently the Sutardja Chuk
professor of definitiveand curative medicine
(00:42):
and professor of pediatrics
at Stanford University School of Medicine.
A pioneer in the field,
Dr. Porteus was the first todemonstrate the feasibility
of precise genome editing in human cells
using engineered nucleuses,
laying the foundation fortherapeutic gene correction.
His research focuses ondeveloping curative therapies
(01:03):
for genetic diseases,particularly sickle cell disease
and other blood disorders byediting hematopoetic stem cells
using CRISPR-based technologies.
He has played a central rolein translating genome editing
from the lab to the clinic,
and his team continues
to lead early phase clinical trials
designed to evaluate the safety, efficacy,
(01:26):
and scalability of thesegroundbreaking approaches.
Dr. Porteus, thank you somuch for chatting with me
on the podcast today.
- Thank you, Ruth.
Really glad to be here.
- For listeners who maynot be deeply familiar
with the science, couldyou walk us through
how CRISPR works, what itis, how it edits genes,
and why is it considered
(01:47):
to be such a breakthroughin molecular science?
- I'm gonna even stepback a bit before CRISPR.
As you're going through medical training,
we recognize that for certain diseases,
if one could just change a nucleotide
in the DNA of a cell or changethe DNA sequence precisely,
(02:08):
that you could address many diseases.
In the early 2000s, aspeople, including myself
started to figure out ways of doing
what we now call gene editing in cells.
The tools we had at the time
were tools called zinc finger nucleases
and TAL effector nucleases.
The way they worked isthat you design a nuclease,
(02:32):
a protein that makes a break in the DNA.
So it recognizes exactlywhere you want in the DNA.
It makes a break,
and then that triggers thecell to repair the break.
By allowing the breakto repair on its own,
you can create new mutationsat the site of the break,
and we'll get into why that's important.
(02:54):
Or if you provide what wecall a donor piece of DNA,
the cell will use, the homologousrecombination machinery
to make a copy of the undamaged donor
and paste it over thebreak to fix the break.
By designing the donorDNA in the right way,
we can now introduce those exactchanges to the DNA we want.
(03:15):
So this was all goingon in the late 1990s,
early 2000s, but thetools were hard to use.
What CRISPR did when it was discovered
that you could reprogramit to make a break
at a sequence very easily,
and then when it was shownthat this bacterial system
worked very well in human cells,
(03:38):
it totally changed the field.
Now, instead of havingto spend several years
to make a specialized protein,
you could spend several daysmaking a CRISPR nuclease.
The way the CRISPR system worksis it has two parts to it.
It has a protein part called Cas9.
That is the scissorsthat's gonna cut the DNA.
(03:59):
And then it has an RNA part
that gets abound by the Cas9 protein,
and it's the sequence of the RNA
that guides the molecular scissors
to the right site in thegenome to cut the DNA.
It's this very elegant two-part system
where the Cas9 is used all the time,
and by just changing 20nucleotides in the RNA,
(04:23):
you now can move the scissors
to different parts of the genome.
- It sounds like whatmakes CRISPR revolutionary
is its precision, flexibility,and accessibility.
And what you've said has set the stage
for everything else thatwe will be discussing
because it's really reshaping our ability
to intervene at the root cost of disease.
(04:45):
- That's right.
Genome editing is a processof changing the DNA of a cell
in a precise manner.
CRISPR is a tool to enable us to do that,
but CRISPR is not genome editing.
And we'll get into maybe a little later
that there are other differentgenome editing tools.
So you have a class and a tool.
(05:05):
- Yes, and we'll certainlytalk more about that later,
but one of the things
that I also wanted tostart our conversation with
is to center the impact of this work
because it becomes clearest
when we move from talkingabout molecules and genes
and all of that, and we move to people.
How has your experience as a clinician
(05:27):
informed your approach
to designing and translatinggene editing therapies
for real world use?
- I'll start with my personal story.
I was an MD PhD student here at Stanford,
and it was on my clinical rotations
in my third and fourthyears of medical school
that I met and took care of a young woman
with sickle cell disease whocame into the emergency room
(05:48):
with pain in her bones,
which is a commonmanifestation of the disease.
For the most part, the treatment of anyone
who has sickle cell disease
who goes into what we call a pain crisis
is depending on the severity of the pain.
In its most severe cases,they're admitted to the hospital,
they're given hydration,
and they're given opiate pain medicine,
(06:08):
and you'd wait for that paincrisis to resolve on its own.
What was striking to me and to many others
is that what we were doing clinically
to treat the pain crisiscaused by the variation
that causes sickle cell disease
compared to what we knew aboutit from a molecular biology
and genetics perspective.
One could argue the disease
(06:30):
that has taught us the mostabout how genetics interface
with human health.
It has always been apioneer in our understanding
of that really complicated
and industry relationship thatpermeates all of medicine.
Yet we had no good therapiesbased on that knowledge.
I came out of medical school idealistic.
(06:51):
We need to bridge the gapbetween the knowledge of genetics
and developing genetic therapies,
highly precise genetic therapies
to address the geneticbasis of the disease.
- It's incredibly powerful to hear
how a patient's experience
can directly shape scientific priorities
and a reminder of how important it is
(07:14):
to ground research in thereal world realities of care
and to stay connected to whatpatients are truly facing.
In what ways is genome editing
enabling a more personalizedapproach to care,
especially for patients with rare
or treatment resistant genetic conditions?
- That is a problem thatwe're still working on.
(07:36):
Sickle cell disease is unique
among serious genetic diseases
in that every patient has the same,
and I use variant not mutation
because if you have onecopy of the sickle cell gene
and one copy of the A gene, so your SA,
you're actually resistant to malaria.
(07:56):
So it's beneficial to have one S and one A
if you get malaria.
It is only detrimentalif you get two S genes.
So I don't like to thinkof it as good or bad.
It's all contextual.
But every person with sickle cell disease
has that same S gene,
which means that if youdesigned an approach
(08:17):
for one patient, you could treat them all.
Most genetic diseasesdon't have that feature.
Instead, there might behotspots that cause the disease,
but there are mutations thatcause the genetic disease
that are scattered throughout the genome.
A CRISPR system
that could treat a onesize fits all mutation
(08:38):
for any given genetic disease.
My lab and other labs have worked on that.
It's a specific genetictherapy for one disease.
What was exciting two weeksago was the announcement
that was designed to correctthat patient's mutation
and only that patient's mutation,
and that was so super personalized.
(08:59):
Six months in multimilliondollars of work,
they only worked for thatone patient and that boy,
who's been publicly described as baby KJ,
had a super severe metabolicdisease of the liver,
and now his disease issignificantly less severe
and he's growing and isdoing so much better.
The question then is, in thefuture, can we get to a place
(09:22):
where everyone will have theirpersonalized CRISPR system
or is that just a mode of drug development
that is a bridge too far
and instead we're gonna haveto go back to one system
that could treat one disease?
- That's such a dramatic departure
from how we've historicallymanaged chronic conditions.
(09:43):
- Yeah.- I'm also thinking about
the scalability of this andhow all of that would work.
How close are we to CRISPR based therapies
becoming part of mainstream treatment?
- To the first part of the question,
maybe I'm not idealistic enough
to think that personalizedCRISPR therapies
will become common.
That's really hard to get my head around.
(10:05):
I feel like it might work fora handful or more patients,
but you know what?
I might be proven wrong and in 10 years,
I might have to eat mywords, which is fine.
In terms of sickle cell disease,
we don't really have that issue
because every patienthas the same variant.
So you don't have to designa personalized system.
In December of 2023, twogene therapies were approved
(10:26):
for the treatment of sickle cell disease.
One developed and sponsoredby a biotech company
called bluebird bio wasbased on using a virus
to deliver a copy of the beta globin gene
into hematopoietic stem cells,
the cells that giverise to red blood cells
so that you now create acell that has the S gene
(10:46):
and NA gene.
They treated in the rangeof 40 to 60 patients.
They showed that thosewho got the therapy,
their amount of pain, thefrequency of their pain crisis,
the amount of pain wassignificantly better.
And that led to its approval.
The trade name for that drug is LYFGENIA.
Casgevy is the CRISPR drugthat was approved in the US
(11:07):
by the FDA on the exact same day.
The way Casgevy works,
it is known thatcounteracting the S protein
is something called hemoglobin F,
the fetal hemoglobin that we have
before we're born.
If you have S and F, theF can counteract the S.
What Casgevy does is,so before we're born,
(11:29):
we have lots of F in our red blood cells.
And after we're born, ourgenetics puts a break on F
to allow the adult hemoglobin to turn on,
which in this case is S.
What years of genetic research
and then molecular biology research
and mouse studies showed
is that a protein called BCL11A
is one of the major breaks on F.
(11:51):
If you inhibit thebreak, you can release F.
What Casgevy does is it inhibits BCL11A
from being turned on indeveloping red blood cells.
And so now you get F to counteract the S.
Now you'll notice thatthey're indirect workarounds
to address the SS.
What my lab has done is to useCRISPR-based genome editing
(12:14):
to directly change the S to A.
Now instead of having SS,we will convert the S to A.
You only need to convert one S to A
to create sickle cell trait.
That's what we're trying to do
'cause we think that is the true endpoint
for gene editing for sickle cell disease.
- It sounds like there havebeen some real landmark moments
(12:37):
both in terms of new approvals
and the shift to frontline therapies
and your lab is also contributing
to the next phase of this work.
When I think about what comes next,
especially as these therapiesmove from development
into real world use, two thingsimmediately come to mind.
Access and safety.
(12:58):
Safety in particularbecomes even more critical
when we're talking aboutintroducing genomic changes.
From your perspective,
what are some of the mostsignificant challenges
in translating gene editinginto clinical practice?
- For sickle cell disease
and for other geneticdiseases of the blood,
the processes goes through
what we call an autologousbone marrow transplant.
(13:19):
The patient is hooked up toa machine apheresis device.
We have to get theirhematopoietic stem cells
or blood stem cells out.
You can spin out the nucleated cells,
and then that goes into a bag.
Then the cells get either genome edited
or lentiviral engineered.
Then if that product of cells,
which is several hundredmillion if not a billion cells,
(13:41):
passes all the criteria,hasn't gotten contaminated,
it's then ready to be released.
Patient has to come back in
and get chemotherapy to ablate
all of their endogenoushematopoietic stem cells
to create space for the new stem cells,
and then they get infused.
Now, that chemotherapy treatment
using a drug calledbusulfan causes mucositis,
(14:04):
it can cause long-termissues, infertility,
it causes your blood counts to be low
for several weeks or longer.
So you're at risk of infections,
while the new cells find their homes
and start making blood cells.
The first hard thing wasgetting the efficiency
of the genetic engineering highenough in the cells you need
without killing the cells.
(14:24):
You have to keep the cells healthy
so that they will engraftand make new blood cells.
Then the next part is howdo you incorporate that
into a very complicated process?
In the long term, wewould of course like to
get rid of that chemotherapyfor the conditioning.
We'd like to make themobilization of the stem cells
easier on some of the bigger issues
(14:45):
around genome editing.
I heard a social scientistdescribe a dichotomy
between perfection and perfectability.
We're always shooting for perfectability.
We have a north star to get to perfection,
but we almost never get there,
but we have to have that process
that we can always do better.
These are some of the areas
where we'll do better in the future.
Stanford is leading thecharge in some of those areas,
(15:05):
which is really exciting
to have my colleagues be doing that.
- How much of a concern arethings like off target effects
or insertion deletion errors
when you're thinking aboutclinical applications
of gene editing?
- We are always concerned.
Do they make breaks where we don't want?
And when 10 years ago,
when the CRISPR-Cas9 system was described,
it was like, is this gonna be a problem?
(15:27):
It turns out this systemis remarkably specific.
We didn't know it at the time.
One of the things you have to do
is you have to show to theFDA that you have assessed
how specific your process is.
And often, you can find noevidence of off targets.
It may mean they're not there,
but it also may mean thatyou just can't find them.
(15:48):
When Casgevy was approved,
they had a scientific advisory board
spending the day to advise the FDA.
And most of the day was spenton have they demonstrate
the specificity to a degreewe should have confidence.
And the advisory board was unanimous
in saying that the specificityhad been demonstrated
and the risk benefit entirely favored
(16:11):
that this should be approved.
Now, that's just an advice to the FDA.
They ended up following thatadvice, but that's true.
We, meaning the entire field,
spends a lot of time on making sure
that the process is specific,but we've gotten to a point
where I will even challengemy sequencing colleagues
that if I give them two samples,
I don't think they couldfigure out which one was edited
(16:33):
and which one wasn't basedon off-target effects.
We have to remember two things.
One is that the chemotherapywe give for the conditioning
is far more genotoxicthan any CRISPR editing.
The other thing to rememberis our genomes in our cells
acquire mutations every day of life.
I like bacon.
We know bacon has chemicalsin it that damage our DNA.
(16:54):
We breathe pollution that damage our DNA.
Actually, just cells living
where they create reactiveoxygen species damages the DNA.
So there's no such thing as a cell
that doesn't get damagedDNA and acquire changes.
Again, it's putting this all in context,
how severe the disease is,
what's going on in thebackground, can you detect it,
(17:15):
and putting that equation together.
- That's really helpful context.
I imagine that when we're talking about
applying these therapies to children,
the bar is even higher, bothethically and clinically.
How do you navigate the balance
between therapeutic potentialand the unique ethical
and regulatory complexities
(17:36):
that come with treatingpediatric populations?
- We and others could havehours of conversations,
but the general frameworkis that if a disease
is so lethal that peopledon't even reach adulthood,
then of course, gettingconsent from a parent
to investigate a therapyis ethically justified.
(17:56):
If it's a disease that's severe,
but people reach adulthood,then the clinical trial
has to start in adultsfor ethical reasons.
It's only after you've done a few adults
that then you can move to adolescents.
Actually, both LYFGENIA and Casgevy
are approved for the age of 12 and above.
What both companies are doing now
(18:16):
is running the clinicaltrial in younger people
to expand who can get it, whowould be approved to get it.
Now, I will say for a diseaselike sickle cell disease
and others, but sickle celldisease is a great example,
it's a progressively destructive disease.
Even a healthy 23-year-oldwith sickle cell disease
still has organ damage that afive-year-old wouldn't have.
(18:39):
This is a disease that in the long term,
I think we wanna treat in early childhood
before that inevitable destruction occurs.
- There seems to be a really thoughtful
multidisciplinary approach
to involving childrennot just in treatment,
but in the broader processincluding clinical trials,
(19:00):
and yet even as enthusiasmfor these technologies grows,
especially in areas likesickle cell disease,
broader adoption stillseems to be limited.
What's continuing tohold that adoption back?
Is it the complexityof the therapy itself,
the infrastructure thatis required to deliver it
or something else?
(19:21):
- Treatment centers likeStanford's that have that capacity,
that expertise,
the first delay in getting this rolled out
was getting treatment centers qualified
to be able to administerthis commercial therapy.
And I can tell you, it's very complicated.
Then patients have to be interested.
And to fit the eligibility criteria,
they have to decide with theirphysicians and their family
(19:42):
whether this is thebest approach for them.
Once all that's happened,
then it's a between six to nine months,
maybe even longer processbetween I wanna get this
and actually getting it.
The approval in December of 2023,
it wasn't like there was amillion pills on the shelf
ready to give to patients.
It's not surprising
that it's taken a littlewhile for it to roll out.
(20:04):
We're seeing increasing number of patients
coming into the queue
and getting increasingnumber of treatment centers
up and running.
Now, what the cap will beon that remains to be seen.
We're still very muchin the build out phase.
I'm a believer thatthere are enough people
with severe sickle celldisease that we need
(20:25):
three or four or even fivedifferent products on the market
to meet demand because theseare complicated therapies.
We can argue about, is thatbetter than one or that better?
But they're all falling intothis really transformational
approach to patients.
Third patient treated
is a man named Jimi Olaghere from Georgia.
And listening to him talk about
how it's changed his life is spectacular.
(20:48):
And I'll just highlight a couple points
that I've heard him say.
One is that he used to thinkhe was allergic to snow
because every time hewould go out into the snow,
he'd have a crisis
because that's known in peoplewith sickle cell disease.
After his therapy, it snowed in Atlanta,
which it occasionally does,
and of course, the city shuts down.
He went on and played inthe snow with his kids
(21:09):
and realized he wasn't allergic to snow
because he no longerhad sickle cell disease.
The other great thing is that last summer,
he was part of a fundraisingeducational effort
that resulted in himclimbing Mount Kilimanjaro
and he believes he's the first person
with sickle cell disease everto climb Mount Kilimanjaro
because at 21,000 feet, thelow oxygen's not so good.
(21:32):
Those are the life-changing stories.
Many other patients have been very public
about their stories and howthey had put their life on hold,
they weren't sure where their future was.
They get the therapy,
and now they're back atit a hundred percent,
fully optimistic abouttheir future and onwards.
- These are such powerful stories.
Thank you for sharing them.
(21:52):
They really speak to whatkeeps people like you energized
and committed to this work
and to the hope of expandingaccess to these technologies.
You touched on this earlier,
but one of the major challenges is cost.
These therapies hold incredible promise,
but they come with a high price tag.
The cost of these technologiesare probably upwards
(22:15):
of a million or so.
- It's an interesting debate,
and I'm gonna give a slightlydifferent perspective.
The list price for Casgevyis around $2 million.
List price for LYFGENIA is $3 million.
And you're shaking yourhead and you're going,
"That is way too expensive," and it is.
It is clearly a barrier,
and what that means isthat one of the barriers
to the uptake is finding payers
(22:37):
who are willing to pay that price.
Several of us have arguedthat actually, it's a bargain.
When you think about what the impact
this disease has on people's lives,
and when you hear storieslike Jimi's and others
about how they're now able to hold jobs,
they're now able to pursue their careers,
now I think about childrenwho I've taken care of
(22:58):
where the parents, often the mom,
have to change theirentire career trajectory
because they never know whatday they can't show up for work
'cause they have to take careof their kid who's in pain.
I think the direct and indirect costs
and lifetime benefits, this is a bargain.
Now, that does not mean
that the sticker shock priceis not causing people to pause.
(23:19):
That does not mean thatwe shouldn't find ways
to make it cheaper.
I just don't want it get out there.
This is great, but it's tooexpensive and it's not worth it.
I wanna say, "This is great.
It is expensive, it isworth it even at this price,
but let's figure outhow to make it cheaper."
- I really appreciate theperspective you're offering
and I agree the frameworkmakes a lot of sense,
(23:41):
but I think it's a yes and situation.
The context is compelling,
but how does it actuallytranslate into real world access
for the people who need it most?
Because if access isn't built in,
then even the most promising frameworks
ultimately fall short.
- Exactly.
I don't wanna get intohuge political discussions,
(24:03):
but this is why fundingfor Medicaid and Medicare
are so important because no individual
can pay for this out of their pocket.
This is paid for either through their own
private health insurance,through Medicaid,
or through Medicare.
When there are threats to those systems,
then access to payment for these therapies
is significantly burdened.
(24:24):
In the meantime, that'sour job in academia
and biotech is to figure outhow to bring that cost down
so the upfront burden is lower.
- Absolutely, I couldn't agree more.
That's such a valuable perspective
and one I honestlyhadn't considered before.
It's exactly why I lovehaving these conversations.
They expand how we think.
(24:44):
As we begin to wrap up, I'm curious,
for clinicians who don't workdirectly in gene therapy,
what practical implicationsshould they be aware of
as these treatments start toenter broader clinical use?
- I'm just one personwith a poor crystal ball.
Take it for what it's worth.
There's a couple things that come to mind.
(25:05):
One is that right now, thegene therapy, gene editing,
and the entire biotechdrug development space
is very much in a winter.
There was tremendousenthusiasm in 2019, 2020,
and since COVID,
I don't think it had anythingto do with COVID honestly.
The enthusiasm has swung toofar in the other direction.
(25:25):
My word is that it will come back.
That gene editing, genetherapies, they work.
Just came back from the annual meeting
for the American Societyof Gene and Cell Therapy
and the science is amazing.
It just keeps working.
It keeps getting better.
People are doing cooler and cooler things.
So we'll get there.
That being said, most of these therapies
(25:46):
and even sickle cell diseasefalls into this category,
are directed at rare diseases.
At some point,
the ability to use gene editing,
gene therapy to treat a common disease
is going to happen.
That's when this modalityis going to change medicine.
When instead of havingto take a pill every day
(26:06):
of your life, a one-time therapy
that will treat your diseasefor the rest of your life,
that's our goal.
That's what we're tryingto do at Stanford.
Our Center for Definitiveand Curative Medicine
is rock the boat on howwe think about treating
not just rare genetic diseases,
but more common diseasesthat might affect all of us
with one and done type therapies.
(26:27):
Are we there yet? No.
But are we there in mice?We are there in mice.
Now, how do we get from mice to humans?
And I think for thoseout there listening in,
thank you for listening.
That's what you wannastart listening about.
When do you hear about something
that isn't just for rare diseases?
Now, as a pediatrician, I'm allin on rare genetic diseases.
Those patients, thosefamilies mean everything to us
(26:50):
and many of my colleagues,
but we also need to get tomore common diseases as well.
- Thank you so much for walking us through
both the complexity and the promise
of CRISPR-based therapies.
It's clear that movingfrom bench to bedside
isn't just about innovation.
It's about translatingscience into meaningful
patient-centered change.
As gene editing continuesto shift from novel
(27:13):
to standard practice,
your insights will be incredibly valuable
to both clinicians and patients.
Thanks again for joining us.
- Thank you again, Ruth.
- This episode was broughtto you by Stanford CME.
To claim CME Forlistening to this episode,
click on the claim CME link below
or visit medcast.stanford.edu.
(27:34):
Check back for new episodes
by subscribing to Stanford Medcast
wherever you listen to podcasts.
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