LENORA JOHNSON: Good afternoon, and thank
you for joining us.
My name is Lenora Johnson, and I am the director
of the Office of Science Policy, Engagement,
Education, and Communications here at NHLBI.
We welcome you today to launch and move forward
our Sickle Cell Awareness Month.
This is the webinar series.
It's titled Sickle Cell Science, Path to Progress.
In this series, we aim to address some of
the educational and information needs shared
by us with the sickle cell community.
Today's webinar is entitled Genetic Therapies
in Sickle Cell Disease.
We hope to give you an overview of genetic
therapies, what they are, how they work, and
how genetic therapies are being explored to
prevent or treat diseases.
Today's webinar is also highlighting activities
of the Cure Sickle Cell Initiative, an NHLBI-led
collaborative research effort aimed at accelerating
the development of genetic therapies to cure
sickle cell disease, and features a patient
perspective on participating in clinical trials
and the importance of safe and widely available
cures.
Today we have joining us, as presenters, Dr.
Mark Walters, professor of Pediatrics at the
Jordan Family Director BMT Program, interim
director of research at UCSF Benioff Children's
Hospital, which is located in Oakland.
We also have Dr. Traci Mondoro of the Translational
Blood Science Resource branch within our division
of Blood Diseases and Resources here at the
NHLBI.
And then our final perspective will be Lynndrick
Holmes.
Lynndrick is a patient participant and a representative.
With that, I'd like to, first, remind all
of the presenters to please mute yourself
if you're not talking.
For those that are participating as listeners,
if you have questions at any time throughout
the session, please use the chat feature on
the WebEx, and send your questions directly
to the host.
There's a drop-down that enables you to send
your question to everyone or someone.
In this case, we'd ask you to send it to the
host.
You may also forward questions to an email
address here at NHLBI, and that address is
nhlbinews one word @nhlbi.nih.gov.
We'll take some time to answer your questions
once we've gotten through all of the presentations.
A final note, with regard to process and technology:
If you have any experience that's challenging,
or technological difficulties today, I would
encourage you to try to log back in using
Chrome or Firefox.
Those browsers seem to work better on this
platform.
As a reminder, today's webinar is the second
of four webinars that we will host on Wednesdays
from 1:00 to 2:00 p.m. during the month.
You can find more information about other
sessions by searching Sickle Cell Science,
Path to Progress on either Event Bright or
the NHLBI website.
Again, thank you for joining us.
At this time, I'm going to invite Dr. Mark
Walters to begin his presentation.
Dr. Walters?
MARK WALTERS: Yes, can you hear me?
LENORA JOHNSON: Are you there?
We can hear you.
MARK WALTERS: You can hear me?
Thank you.
LENORA JOHNSON: Yes, thanks.
MARK WALTERS: Thanks very much for the kind
invitation to participate in this webinar
series and, in particular, to Dr. Traci Mondoro
at NHLBI who's leading the Cure Sickle Cell
Initiative for the NIH.
Next slide.
I wanted to highlight some of the approaches
to curative therapies for sickle cell disease
today.
Allogeneic hematopoietic cell transplantation
using bone marrow, or the blood that's left
over after the birth of a child, umbilical
cord blood, or a newer method, where we coax
the stem cells out of the bone marrow where
they normally reside into the bloodstream,
called mobilized blood stem cells.
All three have been utilized in sickle cell
disease and, in some ways, are the gold standard
of curative therapy for this disorder.
The exciting future has to do, though, more
with gene addition therapy, where an anti-sickling
beta-globin or the fetal-globin gene is introduced
into that hematopoietic stem cell harvested
from a person's own blood stem cell to elicit
a curative effect.
This is experimental therapy but looks very
promising.
There are also gene editing, where you change
a gene in one stem cell directly to increase
the fetal hemoglobin for the beneficial effects
this might cause.
And then there are gene editing approaches
to correct the sickle mutation itself which,
obviously, should be a cure if that's converted
from sickle to healthy.
What I'm not going to talk about today are
in-vivo gene editing techniques to correct
the sickle mutation, which are, in some ways,
the most exciting but not yet under clinical
development.
Next slide, please.
I thought I would begin even though next week,
I see you're going to have a session about
bone marrow transplantation just a quick schematic
about how a bone marrow transplant is performed.
The panel on the left is a cut-out from a
cartoon of a blood vessel.
And, in each blood vessel in our circulation
are red blood cells that carry oxygen to the
body, white blood cells that help fight infections,
and then a smaller type of white blood cell,
called platelets, that control bleeding stop
bleeding after you'd have a cut.
So the way a bone marrow transplant works
is that the mother, or seed, cells the hematopoietic
stem cells that give rise to those red blood
cells, white blood cells, and platelets in
the circulation actually grow and divide in
the bone marrow, which is the hollow liquid
part of the blood system in the middle of
a bone, like the one that's shown on the slide.
Those are extracted in liquid form and then
transferred to a transfusion bag where they're
administered to the transplant recipient in
the same way as a blood transfusion.
So those bone marrow stem cells know where
to circulate in the body, land in the bones
of the recipient, and begin to grow and replace
to make healthy red blood cells and correct
the sickle cell anemia.
Now, in order to do this successfully, one
has to administer very high-dose chemotherapy,
both to destroy the sickle cell-producing
cells in the body before the transplant, and
also, to paralyze the immune system to accept
the cells from the healthy donor.
And, ideally, the healthy donor will have
the same transplant plate that is, will be
immunologically that is, the immune systems
will be compatible, identical, or as close
as they can be.
Otherwise, there can be complications.
And one of the important complications that's
highlighted in that little figure on the right
are skin rashes and infection, which are complications
of a condition called Graft-versus-host disease,
where the immune system of the donor attacks
the recipient, and its the leading cause of
transplant-related problems, including dying
of the transplant itself.
It's a complicated and intensive therapy,
but it's the same principle that will be applied
to gene therapy, in which case, instead of
using a healthy donor's bone marrow, a patient's
own bone marrow will be used as the source
of the donor cells.
Next slide.
So, why isn't bone marrow transplant the universal
cure for sickle cell disease?
Well, as it turns out, only 18% of families
will have that fully matched, ideally matched,
bone marrow donor.
And, when we look for an unrelated donor who,
by chance, has inherited the same transplant
type as our sickle cell patient, only another
19% will have a well-matched, unrelated donor.
So, even if we wanted to treat every patient
by a bone marrow transplant, only about a
third will have a donor.
In addition, because of this problem that
I've just described of Graph-versus-host disease,
and this small risk of dying of the transplant
itself, some clinicians are reluctant and
patients, as well to proceed to a transplant.
And so, for this reason until lately, transplant
is largely restricted to children and applied
very sparingly, so not really at all a universal
cure.
Next slide.
What are the approaches that might elicit
a universal cure?
There are two approaches, primarily gene addition,
where we add a gene to that hematopoietic
stem cell, that mother, or seed cell, that
gives rise to all the blood cells in the circulation,
including the red blood cells, or gene editing,
where we make a change in an existing gene
in the hematopoietic stem cell to elicit a
curative effect.
In the gene addition category, it's possible
to add a healthy beta-globin gene to equal
the beta-s, the sickle-globin level, or inhibit
the effects of the sickle-globin to add a
fetal-globin because it's anti-sickling.
It interferes with the formation of those
long strands of hemoglobin the sickle hemoglobin
that form in the red cell after the oxygen
is delivered to the tissues, which deform
the red cell, make it stiff, damage it, so
it doesn't last as long in the circulation,
and cause all the hallmarks of sickle cell
disease, which are anemia and pain.
Express a fetal-like beta-globin gene because
it will have anti-sickling activity, adding
that.
Or reawaken the fetal-globin gene with gene
therapy.
There is a way to add an anti-gene, if you
will, an anti-effect to activate, reawaken
the fetal-globin gene.
The gene editing approach, changing an existing
gene in the hematopoietic stem cell, targets
a gene that allows reawakening of the fetal-globin
gene.
Or using CRISPR or other techniques to correct
the sickle gene directly.
Next slide.
I think you've already heard about fetal hemoglobin,
or hemoglobin F, and how when its level is
increased in a person with sickle cell disease,
it helps prevent sickling, making the sickle
cell disease milder.
It's one of the targets in how hydroxyurea
has a benefit when it's given to a sickle
cell disease patient.
And raising it has become a therapeutic target.
Raising the level of fetal hemoglobin, awakening
it after it's been silenced, has been the
basis of several new investigational studies
for sickle cell disease.
So, how does this work exactly?
Next slide.
So, this is a picture, or cartoon, of the
type of globins that are made before birth
and after birth.
So, follow the orange curve, which has the
Greek symbol, gamma.
That's the fetal hemoglobin.
And that's the only type of beta-like globin
gene that pairs with the alpha to make hemoglobin
before a baby is born.
So, the gamma-globin gene is perfectly healthy
in a fetus with sickle cell disease.
And so, there are no problems before the baby
is born.
This is why we have to rely on newborn screening
to make the diagnosis of sickle cell disease
at birth, because the examination of the blood
and of the baby would show no signs of sickle
cell disease, whatsoever.
But look what happens right after birth.
The green beta-globin gene shoots up.
It's turned on.
And this is the one that carries the sickle
cell gene.
And the gamma-globin gene is turned off.
So, by six months of age, there's very little
of that gamma-globin gene available.
So, the gamma-globin gene, which elicits an
anti-sickling effect, that effect is lost.
And that's when the symptoms and signs of
sickle cell disease emerge in the first year
of life.
Now, by chance, some individuals have an inherited
condition, whereby the gamma-globin gene isn't
turned off at birth.
It persists after birth.
And, in those individuals, if they inherit
the sickle gene with that, they have a much
milder disease.
We've learned from nature that these natural
causes that raise the fetal hemoglobin will
have a beneficial effect.
Next slide.
So how does this work?
And this is a pretty wonkish slide, so bear
with me.
I'm going to walk you through it.
There are three types of oxygen-carrying molecules
depicted.
The purple is the regular adult hemoglobin.
That dashed yellow line is the fetal-globin.
And then the blue is an oxygen-carrying protein,
called myoglobin, in the muscle where the
oxygen is needed for energy and for development.
So in the lungs, in that pink-shaded area,
all three types of oxygen-carrying proteins
are fully saturated, 100%.
They're fully loaded with oxygen.
But as the blood circulates and reaches the
tissues, there's this natural decline in that
purple loading down to 50% in the tissues,
so that the oxygen can be, if you will, transported
up to the yellow and blue curves where the
oxygen is needed for growth and development.
So before a baby is born, since they can't
breathe the air they don't have lungs all
of the oxygen transfers from that purple adult
hemoglobin to the yellow dash fetal hemoglobin
in the baby's circulation and then, from there,
to the muscles in the fetus, so that the organs
in other tissues can grow and utilize energy.
So, you can imagine that, even if that fetal
hemoglobin persists, there's still room throughout
the travels of the red blood cells, from the
lungs to the peripheral tissues, to deliver
oxygen to that blue line, the higher one,
for growth and development.
That's why persistent, or elevated, fetal
hemoglobin isn't damaging and, in fact, can
be quite helpful in counteracting the negative
effects of the sickle hemoglobin.
Next slide.
So, how would this work in a gene therapy?
It begins at the very top with a virus depicted
in red that has all of the genes the virus
needs to cause an infection, destroy the cell
it attacks, and then reemerge from that cell
that's been destroyed, to infect another cell.
So, beginning with that harmful virus, a disabled
virus is created in green, so that's no longer
harmful because all of the pieces in the middle
of that squiggly strand in the middle, those
represent genes that have been removed that
are necessary for infection and causing harm.
And all that's left is that dark green dash
at the very end that will enable that virus's
DNA, the genetic material, to be inserted
into the DNA of the target stem cell.
Into that disabled virus, the rescue gene
is packaged.
So, it could be a fetal-globin gene.
It could be a healthy beta-globin gene.
And then that's incubated with the stem cells
from patients.
The stem cells are collected those are the
purple cells and then co-incubated, thrown
in a tissue culture flask together, so that
the packaged, altered, disabled virus can
now insert that DNA into the stem cell.
The stem cell takes up the DNA.
It doesn't land in the sickle gene, but it
lands someplace in the DNA, which is the genetic
material of that stem cell.
And then those stem cells that have been altered,
now with a rescue gene inserted, those cells
are injected into the recipient, so that they
can begin to grow and have this positive,
curative effect.
Next slide.
So, how well does this work?
This is an ongoing clinical trial sponsored
by an industry partner, bluebird bio, Incorporated,
with several different transplant sickle cell
centers in the U.S. and Europe.
And this shows the results to-date.
These are patients who have undergone the
procedure and then had their hemoglobin type
monitored in the blood from three months through
15 months after the infusion of those modified
stem cells, after the gene addition therapy.
This is an anti-sickling hemoglobin, and it's
depicted in red.
The green is the sickle hemoglobin.
And the blue is transfusion hemoglobin.
And, if you follow the path of that pink line
the rectangle with the pink it increases from
33% all the way to 59% in that one patient
who's been followed now 15 months post-infusion.
And what it looks like to us is that this
is more like sickle cell trait than sickle
cell disease.
The green is, effectively, diluted.
And, in fact, since this hemoglobin has anti-sickling
activity, it's even better than that.
These patients who have this experience, as
far as we can tell, no longer have any signs
or symptoms of sickle cell disease.
They don't have anemia.
They're not having painful events.
And, while it's too early to call this a cure,
if it were extended for five, or 10, or 15
years, I think everyone would agree that this
would be a cure.
So, this is a very interesting and exciting
result.
And, again, it could be universally available
because we're using, as the donor, a person's
own stem cells.
So, the sickle cell patient is the donor for
the gene therapy modified stem cells.
So, can't get Graph-versus-host disease.
There won't be any problems with immune reactions
in either direction.
This is just re-growing cells that now carry
a healthy copy of that globin gene to outcompete
the sickle gene.
Next slide.
Now, this is really wonkish, so bear with
me.
We did a clinical trial, some time ago, where
we attempted to do a bone marrow transplant
in a safer way, as an outpatient just using
a little bit of chemotherapy, with the idea
that we could get a mixture of both the donor
and the recipient cells in the bloodstream.
This has been perfected more recently by a
team at the NIH.
But when we first tried it, we ran into problems.
And it's shown by that graph on the left.
So, by several months after the transplant,
we could detect only 2% to 5% donor cells
in the bloodstream.
But, despite that, if you look at that curve
with the open, round circles, that's the level
of the sickle hemoglobin.
And it settled out at around 50%.
So during that period of time when we were
limping along with just 2% to 5% donor cells
growing in the bone marrow, because those
healthy red cells that were derived from the
donor stem cells had a long lifespan, they
outcompeted the sickle red blood cells and,
effectively, for a period of time, eliminated
all of the symptoms of sickle cell disease.
Eventually, those few stem cells are rejected.
But the principle was that we didn't have
to correct all the stem cells in the bone
marrow.
We only have to correct, as it turns out,
about 20% of them.
And that's shown by the panel on the right,
where the blue which is the percent sickle
hemoglobin you can see it's right at 50%.
When, there in red, are 20% donor cells.
So, 20% donor cells if you can correct 20%
of the stem cells and eliminate the sickle
gene in those cells, you should have a very
strong effect, if not cure.
So that's the principle underlying gene editing,
because it's going to be very difficult to
correct all of the sickle genes and all of
the stem cells.
But, if we can correct 20% of the gene and
20% of the at least, one of the genes and
20% of the stem cells then that should be
enough.
Next slide.
So, this is the approach with CRISPR.
I know that many of you have heard of this.
The schematic shows an aqua-colored elongated
protein that's anchored in place by a yellow
sequence, called the PAM sequence, that adds
to the specificity of this reaction.
And then the proofreading activity, the way
this is so specific for one particular DNA
sequence in the target cell, is through an
RNA molecule, what we call a guide RNA.
In this case, once everything's lined up,
the aqua protein makes cut, a double-stranded
break, in the DNA.
And, if you supply the donor DNA, after the
sickle allele is cut out, and the same machinery
will add the right sequence and correct the
mutation.
So that's the last piece of DNA at the very
bottom with the green, healthy sequence inserted.
So, this has been successfully accomplished
in all kinds of organisms.
It's quite a fast reaction.
It's very efficient, simple, and, potentially,
inexpensive.
Next slide.
This is my last wonkish slide.
But, again, I think I can walk you through
the principle.
So, there is a team of us supported, actually,
by the Cure Sickle Cell Initiative, who have
attacked this problem.
So, it's a disease team.
It's a project.
And this is an experiment done by my colleagues,
Wendy Magis and David Martin, at the Research
Institute in Oakland, at UCSF Benioff Children's
Hospital.
So, what they did was make the correction
in blood stem cells that we had donated to
us from a person with sickle cell disease
and asked the question: After you made the
correction, injected those stem cells into
a mouse that accepts human cells, and then,
after 20 weeks long enough to get these bone
marrow cells from those human cells that derived
from a true stem cell, so you have to wait
five months or so, to be able to say that
and ask, what type of blood cell was enriched
after the correction?
So, the panel on the right are some stem cells
that went through attempting to insert the
healthy copy of the DNA.
Did insert part of it, but not enough of it
to correct the sickle allele.
So, these still have sickle cell disease.
And what's shown is that, luckily, that only
happens about 2% or 3% of the time.
And the bone marrow on the left is not really
different from the red cells.
Those are depicted by the label CD235A.
So, no changes there, but look what happens
where the sickle allele has been corrected.
So, now, this is healthy globin gene.
So, it's much higher.
We're getting 20% to 25% of the marrow, or
stem cells, corrected, exactly what we need
to target for a curative effect.
And look at the red cells, the CD235A positive
cells.
Fifty percent of those have the corrected
gene.
So, just as we predicted based on our experience
in bone marrow transplant, there's this natural
enrichment of the healthy, corrected red blood
cells in the circulation.
And it looks a lot like sickle cell trait
to me.
So, we're quite excited about this result.
And we're going through all of the steps needed
to ensure safety and potency.
But we think we'll be in a position to begin
to enroll patients in a clinical trial in
the next year or two.
So, that's where that project is.
Next slide.
And how would it work?
Well, we would collect stem cells with that
instrument at the top left by a process called
apheresis.
We would then remove the red cells and the
platelets from that stem cell collection and
then enrich the stem cells.
That instrument on the right does that.
So we put all the blood stem cells in a culture
bag and then apply an electrical current that's
the day two package with the gene editing
components so the CRISPR-Cas9 and the rescue
target DNA and then, after putting them back
into culture for a day or two, infuse those
into a patient who's received a high-dose
chemotherapy drug to make room for the gene-edited
stem cells to grow.
So, this is how the clinical trial would be
conducted.
Next slide.
Now, gene therapy is also being developed
for other disorders.
This is a product called Zolgensma, for a
uniformly fatal disorder in childhood called
spinal muscle atrophy.
But look at the price tag.
$2.125 million per dose.
So, that would be quite challenging if that
were the price of gene therapy in sickle cell
disease, because it's much less rare than
spinal muscle atrophy.
And it's a concern that all of us should have.
Next slide.
So, in conclusion, I think the gene therapy
is going to work.
I think the early results are very exciting.
But I worry that the availability and affordability
of the treatment will be a limiting factor.
So, I urge all of the health policy interested
folks, the sickle cell disease advocates,
family members: Work with us right now.
Let's get working on this right away to ensure
that once we have that universal cure in hand,
that we can begin to give it to the persons
who we think would benefit from it.
Thanks very much.
TRACI MONDORO: So, thank you, Dr. Walters,
for that great talk.
My name is Traci Mondoro, and I am the chief
of the Translational Blood Science Branch
in the Blood Division here at NHLBI.
And I'm here to talk about the Cure Sickle
Cell Initiative.
So NHLBI has funded oh, next slide, please.
That one.
NHLBI has funded much of the breakthrough
research that has led to improvements in treating
sickle cell, as well as the transplant biology
that led to one curative strategy.
The Cure Sickle Cell Initiative has been established
to build upon all of these successes, and
our efforts are guided by our desire to build
upon, as I said, decades of research, but
we want to further explore novel genetic therapies
as a potential option for people living with
sickle cell disease.
And we know that genetic therapies may not
be for everyone, and that focusing on cures
and using the word "cure" may seem overly
ambitious, but it's our hope that we can come
together as a community to accelerate the
development of safe and effective new approaches
that will allow people to live free of sickle
cell disease.
Next slide, please.
The Cure Sickle Cell Initiative is working
to bridge the gap between the research and
those that are impacted by sickle cell disease,
so NHLBI is involving patients at every level
of this initiative.
In essence, our goal is to bring individual
components of the sickle cell disease community
together, including patients, families, providers,
and advocates, to help design and to participate
in genetic-based studies to advance cures.
Next slide, please.
These are the folks who are leading the Initiative.
We have Dr. Gary Gibbons, the head of the
NHLBI.
We have Dr. Ed Benz, who is the President
Emeritus of Dana-Farber; Dr. Leslie Silberstein
at Boston Children's; Dr. Keith Hoots, who's
the director of the Blood Division at NHLBI;
and there you see my picture at the bottom,
the chief of the Translational Branch.
Next slide, please.
Obviously, we're not doing this alone.
In addition to our other partners in the federal
government and all of the investigators and
patients, we do have some formal relationships
with the California Institute of Regenerative
Medicine, or CIRM, and the American Society
of Hematology, or ASH, to collaborate in areas
of common interest, such as co-funding projects
and working with patients, providers, and
laboratory scientists.
Both of these organizations have dedicated
substantial portions of their budget to work
in sickle cell disease.
We are pleased to report that CIRM and NHLBI
are co-funding work that Dr. Walters is performing
and just spoke about.
Next slide, please.
The Initiative was launched in September 2018.
And just a note about the other work that
NHLBI does.
The Initiative will not replace any ongoing
efforts of NHLBI.
Instead, it will complement the Institute's
broader sickle cell disease research investments
in basic clinical, translational, and implementation
science.
NHLBI will continue to fund research being
conducted by investigators focused on sickle,
and this initiative will help fill the gaps
that cannot be covered by traditional funding
methods.
So, after some stakeholder meetings, the following
goals were established.
Next slide, please.
So, I'll get back to the goals in a moment.
I just wanted to note that we're not looking
for one curative strategy.
As Dr. Walters stated, transplant is a cure
when a donor is available, but there are multiple
approaches, through gene therapy and gene
editing, that Dr. Walters alluded to, and
the Cure Sickle Cell Initiative wants to bring
as many of these forward as possible and not
pick a winner, because we think that different
patients will require different strategies.
And ideally, what we would like to do is assemble
a large body of data on different approaches,
or variations of some of the approaches, because
we want to be able to give these therapies
to adults, but we also want the FDA to allow
us, once they're very safe, to scale down
to children.
Because if children could be cured when they're
young, then some of this irreversible organ
damage, such as kidney or vision or cardiovascular,
would not occur, and then the cure would be
complete, with no side effects, as we see
in some adults.
Next slide, please.
So, we are currently exploring, as I mentioned,
different things that can't be funded through
regular NIH grants.
And so, we want to focus on defining safety
and risks of these different therapies.
We want to look at potential off-target effects.
In other words, how can we make sure that
the sickle cell gene is corrected, and no
other genes are harmed?
We want to identify any hurdles in the technology
that's used to give these therapies.
And we want to look at best practices and
methods to do things such as develop laboratory
tests or assays so we can confirm that the
therapies work; create standard operating
procedures to isolate and modify cells so
every product is made exactly the same way,
just like the aspirin you buy at the drugstore.
We want to produce common data elements, and
this is so data from different trials can
be compared to each other to decide which
therapeutic strategy would be best for a specific
patient.
And we want to design patient-centric clinical
trials with meaningful endpoints.
So, some of the endpoints in trials that you
may have read about are laboratory measurements
that can indicate that your cells are no longer
sickling.
But we want endpoints that are evident to
a patient.
For example, if shortness of breath were reduced
after you received a therapy, then that's
something that would positively affect a patient's
life.
And, as Dr. Walters just mentioned, we want
to assess the clinical and economic impact
of genetic therapies on patients.
So, what are we funding?
We're funding animal studies to show safety
and dosing limits with different kinds of
therapies.
We're going to be funding manufacturing studies
again, ways to make the best and most consistent
products in large quantities.
We want to find safer conditioning regimens.
So, the preparation for transplant or gene
therapy can have adverse side effects, so
we want to find ways to reduce the toxicity
of these procedures.
And diagnostic tools, such as an MRI scale,
so parents could be assured that there have
been no further changes in their child's brain
or sort of quantify a stroke risk after a
curative therapy.
This would apply to transplant or gene therapy.
And we're also supplementing ongoing trials
to make sure they have adequate funding to
complete planned enrollment and to be able
to follow up with patients to record how they're
doing after receiving these therapies.
Next slide.
This is a graphic showing some of the things
that we're doing in the initiative.
We are reaching out to patients.
I mentioned common data elements, manufacturing.
Also, the way we're funding this initiative
allows us to work with the companies and to
help them where they might be stuck, either
in things they need for the FDA or assisting
them with economic data, which we mentioned,
to figure out how to compare the cost of living
with sickle cell to the cost of curing sickle
cell.
And also, working with patient and advocacy
groups.
Next slide, please.
So, we do want to engage the patient in the
advocacy community.
And to do this, we are engaging patients to
participate at all levels of the Initiative.
We have patient representatives on our executive
committee, on our steering committee, on our
subcommittees.
We are also we've had some listening sessions.
And we also want to form some advisory groups
for the Initiative, including patients, scientists,
including young adults.
We think that's a group that we really need
to hear from, because these are some of the
folks who may just be coming of an age where
they can qualify for these trials to give
us advice on how to reach out to other patients.
And then a survey was published, and the citation
is at the bottom, but there have been surveys
and other methods to reach out to patients
to find out how they feel about genetic therapies.
And investigators from the Genome Research
published a survey on patient attitudes and
beliefs towards genome editing.
And so, the responses confirmed that the patient
community is skeptical regarding new curative
strategies.
And after seeing some of Dr. Walters graphs,
one can certainly see why.
I mean, this is new.
Gene editing and gene therapy, it sounds a
little bit like science fiction.
Plus, we know that there have been past disparities
in access to medical care in clinical trials
and in treatment of people with sickle cell
disease.
And so, the conclusion of this paper was that
"The advent of genome editing has renewed
hope for the sickle cell community, but cautioned
tempers this optimism."
And so it's the intent of the Cure Sickle
Cell Initiative, moving forward, to maintain
and invigorate this optimism, but we want
to demonstrate that we're listening and acting
on the promising science as well as remembering
what we're hearing from the patients and keeping
the patients continually engaged as the science
moves forward.
Next slide, please.
And now I'm pleased to introduce Lynndrick
Holmes, a patient representative who has kindly
agreed to speak at this webinar.
LYNNDRICK HOLMES: Hey.
How everybody doing?
Thank you for having me.
I'd like to start off by talking about what
options we have, other than the curative therapies
that are available now.
The first thing I'd like to state is: understand
that the sickle cell community of patients
are not a monolith.
Not all our stories are the same.
So, I'm going to try to talk about my perspective
alone.
But I see a lot of similarities that we all
suffer from.
As far as the treatment options that were
available to me, there was hydroxyurea, which
I had some side effects taking.
I was on it since like, the fifth grade.
There were blood transfusions, which can give
you iron overload and stuff like that.
And then as an adult, they kind of just drop
you and you have to figure out everything
on your own.
And that is a trial in its own, having to
give reason why you should be treated.
That's how it feels.
It feels like you have to give a reason why
you should be treated, why are you struggling
with this.
And it's very hard to deal with.
When I first heard of gene therapy, I was
a little bit skeptical too.
But I had a realization that, over time, if
I wait and try to see how many people go up
and get them to perfect this and get that
stuff together before I give it a try, by
that time, I need a hip replacement, or a
stent for my aneurysm in my brain, or I lose
some organs, I'll be on dialysis, and I wouldn't
have no quality of life at all.
So, for me, it was it was do or die.
And you know, I think one of the main things
that I hear a lot of people talk about, one
of the things that they're skeptical about,
is the vector that they use to try to correct
our gene, or part of the trial that I've been
a part of.
And I mean, it's not really too much to be
afraid of, because they just they take apart
that virus and they just use it as a vehicle
to try to get the corrected gene to burrow
itself and implant itself into your bone marrow
so you can not have sickle cell.
Since I've been I know that curing is a term
that I hear some professionals leery to use,
but I feel cured.
And honestly, I didn't even understand the
level of how bad sickle cell actually was
until I got on this side and I actually had
the ability to be cured.
Being fatigued all the time, being in pain
all the time.
I didn't realize how often that was until
I got the chance to be on the outside looking
in, like I have now.
I feel like it is very important that we have
participants come be a part of the trial so
that we can move forward and have this widely
available.
There's no way that this can be widely developed
if we don't have people partaking in what's
going on here.
If everyone's apprehensive about it, then
I mean, what other options do we have?
The closest thing that I believe, that I found
through the trial, to be a treatment is blood
exchanges.
Blood exchanges I never even heard of them
until I got up on this trial, because they
don't have anything like that available here,
where I'm from, in Mobile, Alabama.
So, I think that's the closest thing that
we can get to some sort of stability.
Hydroxyurea works for some.
It didn't work for me.
Blood transfusions are dangerous.
But blood exchanges is where they take out
a percentage of your blood and they put back
in some healthy blood cells, and for a time
or two you feel kind of normal.
But it's an entirely different feeling when
you're actually cured.
I actually have way more energy than I've
ever had in my life, even when I was going
through the trial and I was getting blood
exchanges.
But to my knowledge, I think that is what
is best.
But without participants, without people becoming
brave enough and I hope not desperate enough
to join or be a part of this, we'll never
get to the point to where we're actually free
of sickle cell.
And I don't know, I'm just [SIGHS] I'm just
tired.
I'm just tired of having to go back and forth.
I was tired of going and having to go back
and forth with doctors and hospitals, and
in and out of pain, starting all over again,
getting an apartment, getting a car, and then
having a sickle cell crisis and then having
to start all over again, and having organ
damage and having AVN.
And a lot of that stuff is just you know,
it sticks with you regardless if you have
the cure or not.
You know?
So, I feel that it's just it's in the best
interest of the community for us to push this
forward, to just put this forward and to just
keep hope alive.
This is the only hope that I had.
I didn't have anything like a clinic where
I can just go to, to get fluids or blood here
in Mobile.
They don't have clinics like that for adults.
They do for kids.
But once you get to a certain age, they don't
have that available for you.
So, I was just kind of left out here for the
wolves.
But that's pretty much just my testimony.
I'm pro gene therapy, and I feel like everyone
needs to at least have an ear out for it because
we don't really have much else besides this.
LENORA JOHNSON: Lynndrick, this is Lenora.
Thank you so much for your comments and your
testimony.
We appreciate it, and I think it speaks volumes
to what we do.
At this time, I'd also like to thank Dr. Mondoro,
Dr. Walters as well.
And we're now able to take some questions
from our listeners.
So again, you may use the chat function on
the WebEx platform, or you can send your questions
directly to nhlbinews one word @nhlbi.nih.gov.
So, we do have a couple of questions.
The first one is for Dr. Walters.
Can you briefly explain the difference between
gamma and beta and why gamma turns off?
MARK WALTERS: Sure.
So, the gamma, that's just a Greek letter,
is the nomenclature for fetal hemoglobin.
So, the fetal hemoglobin is on for birth because
the baby doesn't have lungs that breathe air.
It gets all its oxygen from the mom's circulation.
So, it needs to bind that oxygen tighter than
the mom's hemoglobin.
So, that's why it's on before birth.
And then after birth, when the lungs start
working, the fetal hemoglobin isn't made anymore
and then there's this shift to making the
adult-type beta-globin.
So that, I hope, answers the question.
LENORA JOHNSON: Thank you.
And then another question for you had to do
with, do you know how much gene therapy approaches
cost?
MARK WALTERS: Yeah, the price of these therapies
hasn't been established yet because they're
not yet approved by the FDA.
They haven't been licensed.
But we do get a snapshot of what it might
look like, but what we just don't know.
So, there's another hemoglobin disorder called
thalassemia, and gene therapy is also pretty
far along towards approval for that.
And the price tag we've seen in Europe it's
not approved yet in the U.S., but it's nearing
approval in Europe the price tag we've seen
is close to a million dollars.
So, it's daunting, and these are going to
be expensive.
The price is based on what it costs to care
for a person with the underlying disorder,
lifelong and to save a life, if there's a
risk of dying early of the disease.
So, those are always difficult price tags
to work out.
And then how to get insurance to be able to
cover the high cost of care in a single bundle
that's also being attacked in a way that,
there may be ways to spread out the cost of
the treatment over a longer period of time
to make it a bit more affordable for the insurers.
So, that's kind of the long answer, but to
a short answer, which would be, I just don't
really know the cost of what it's going to
be.
LENORA JOHNSON: OK.
Thank you, Dr. Walters.
A question for Dr. Mondoro.
How can people with sickle cell disease find
out about clinical trials that they might
be eligible for?
TRACI MONDORO: Well, that's a very timely
question.
So, you may have heard, there is a website
called ClinicalTrials.gov.
And, we understand I've been on that site,
I find that site confusing, and I've been
on it probably 50 times in the last year.
So, it is a good resource, but it's hard to
navigate, so the Initiative is working on
trying to find out how, for instance, people
in Oakland because there's good publicity
around Dr. Walters' trials so we're trying
to find out of how people in cities where
there's more than one trial, how they're finding
out about it, how they're interacting with
the trial physician, and then we want to make
that available on our website, probably, for
everyone to see.
So, right now, talk to your doctor, or your
medical provider, or your friends, or your
support group.
And right now, ClinicalTrials.gov unfortunately
is the best that we have, but we are looking
for ways to improve that.
LENORA JOHNSON: Thank you.
Lynndrick, a question for you Lynndrick Holmes.
How long was the process for you in the trial
participation?
LYNNDRICK HOLMES: It took about two years.
It took about two years total.
There was a lot of changes that happened along
the way.
They were still learning as they was going,
so any time they thought that there was something
they could have did better, they'll reschedule,
and they'll come back and do it better.
So yeah, it took about two years for me to
go through it.
LENORA JOHNSON: And then another question
was, do you experience any pain following
the clinical trial in which you participated?
So post-therapy pain.
LYNNDRICK HOLMES: The only pain, I guess,
you feel is like and it's not really nothing
to be afraid of kind of pain it's the engrafting
pain of the stem cells engrafting into your
bone marrow I mean to your bones.
But to me, that was a good pain.
That wasn't a bad pain.
[CHUCKLES] I was like, yeah, it's working.
I knew it was working once I started feeling
that.
And everything after that, no pain.
No sickle cell-related pain whatsoever.
I mean, I stub my toe on something, I feel
it, but that's it.
No sickle cell.
LENORA JOHNSON: Thank you.
I also want to follow up on Dr. Mondoro's
answer about participating in clinical trials.
The NHLBI has a Center for Health Information.
We call it the NHLBI CHI.
They will also answer any questions that you
might have, as well as help you navigate and
find appropriate trials near you.
They also are able to refer you to our Office
of Patient Recruitment within the NIH for
assistance in finding whether or not there
are applicable trials here at the NIH.
And that number is 301-592-8573.
Or you can send an email directly to NHLBI
info I-N-F-O, one word @nhlbi.nih.gov.
Our next question.
Dr. Walters, has there been any progress on
the use of gene therapy in Africa?
MARK WALTERS: Yeah, that's an area where we
need to be more proactive.
I'm not aware of any gene therapy trials active
in Africa.
And that's because there are some significant
challenges to exporting it and getting it
active there.
But we need to put more energy into finding
out how to accomplish that.
LENORA JOHNSON: And then either you or Dr.
Mondoro, what do you think doctors might need
to know about upcoming treatments, and when
might they be available?
TRACI MONDORO: Mark, I'll let you handle that.
[LAUGHS]
MARK WALTERS: Oh, thanks.
Thanks so much.
[LAUGHTER]
Well, I hope the audience gets the sense within
the constraints of a webinar how excited we
are about these developments.
I mean, there is significant movement, in
part because of really good support from both
the NIH and organizations like CIRM, California
Institute for Regenerative Medicine, and other
foundations, to accelerate these curative
therapies.
So, the best way to stay abreast of them is
to go to the national meetings the hematology
and the sickle cell disease meetings.
And in addition, it's possible for individual
sickle cell centers to request one of us to
make a visit and give a talk and update about
the results.
But honestly, none of these therapies is quite
ready for launch in the community and making
them widely available.
That's going to take a longer period of time.
So, it's going to be a concerted effort, I
think, both from the regulatory agencies and
the industry sponsors, and from the hospitals
and doctors who are going to deliver the therapy,
to coordinate running out these therapies
as they become available and getting the patients
treated.
TRACI MONDORO: And I can add to that.
In our conversations with the Food and Drug
Administration, they understand that we want
to move this forward as quickly as possible,
while keeping rigor on safety studies.
But they are very willing to work with investigators
to figure out how to check off all the safety
boxes and not let things linger, and get them
approved as quickly as possible, and to tell
us what needs to be done so that we can do
it.
So, they are very excited as well, to work
with us.
LENORA JOHNSON: And then I did want to follow
up a question on gene editing and gene transfer.
Dr. Walters, are there any side effects to
gene editing or gene addition?
MARK WALTERS: Yes, there are several potential
side effects.
So, this is a population of blood stem cells.
So, this is the source the lifelong source
of all the blood one has in circulation.
And so, you can imagine if you're altering
the DNA code in the blood stem cell, if there
was what we call an off-target change, that
could have dire consequences.
So, for example, what if you damaged a gene
that you need for that stem cell to continue
to divide and give rise to other blood cells,
and if you lost that stem cell?
So that's a problem.
Or what if you caused a DNA change, either
from a gene addition or gene editing, that
awakened cancer-causing gene?
And what if that took a long time to have
that effect because it was a rare event?
Well, we're just not going to have information
about that level of safety for a period of
time.
So, there are some theoretical concerns about
the long-term safety of these kinds of treatments.
So, we build into our plans, as best as we
can, rigorous tests of minimizing the off-targets,
doing a really careful job of screening and
monitoring for the off-targets after we've
delivered the therapy, and so forth.
And the good news is that, so far, we haven't
seen a problem.
But that's something we're always worried
about.
Then, there's the side effects of the preparation
before you infuse the gene therapy or gene-edited
the modified stem cells.
And right now, we're relying on very high-dose
chemotherapy to wipe out destroy the sickle-producing
cells in the bone marrow.
Well, that has side effects too.
You can imagine that I mean, that's the source
of your immune system, so for a period of
time a person would have limited protection
against infection, so you have to accommodate
that.
It causes thinning of the lining the mouth.
That causes mouth sores.
Again, temporary, but still a problem.
And then we have observed, so far, at least
one case where the chemotherapy itself caused
a leukemia, which is a blood cancer.
So, we know that the very high-dose chemotherapy
will cause infertility in adults who were
exposed to the high-dose chemotherapy.
So lots of side effects, actually, that I
just have to gloss over in a short talk, but
something that we go through very carefully
and extensively whenever I meet with a family
or a patient before we make a decision about
whether or not to pursue the treatment.
LENORA JOHNSON: OK.
Thank you for that, Dr. Walters.
There was a point of clarification that just
came in.
And the question is if I understand correctly:
Hemoglobin 206-treated patients do not experience
pain?
And what age group are these patients?
MARK WALTERS: Yeah, that's the bluebird bio-sponsored
trial.
And a small cohort of patients have been evaluated
for pain.
That's right.
The ones in this last cohort of patients using
all the optimized conditions and preparation
don't appear to be having painful episodes
after the infusions.
LENORA JOHNSON: Thank you.
I do want to let people know that we'll put
physician information or a link to ClinicalTrials.gov
on the page where you'll also find the other
information about the upcoming webinars.
And just to let the community know that the
NHLBI and working closely with the Cure Sickle
Cell Initiative will be continuously developing
educational and information that's pertinent
to this area.
And so, stay tuned.
As that information comes out, we'll definitely
take the opportunity to share it with you.
IT IS 2: 00, and I would like to end on one
final question, and that's to Lynndrick.
Post treatment, what's the thing that you
least expected, and what's the thing that
you are most happy about?
LYNNDRICK HOLMES: The thing that I'm most
happy about I don't think it's appropriate
for me to answer.
But
[LAUGHTER]
LENORA JOHNSON: Fair enough.
LYNNDRICK HOLMES: I think I'll just gloss
over it by saying me and my wife are happy,
and that's things that I'm really, really
happy about.
I didn't really have much to expect post I
mean, they had everything that they warned
me about that probably could have happened.
But to be honest with you, I was just grateful
that one of those things wouldn't be sickle
cell.
[CHUCKLES] Whatever it was, it wouldn't be
sickle cell.
So, I had no sickle cell problems.
And I guess it's a surprise to everybody else,
I'm relatively normal, aside from, like I
said, the organ damage.
Like, I've got AVN and I still have an aneurysm
and stuff, but that's it.
Nothing.
Just a pretty normal guy.
LENORA JOHNSON: Thank you.
[LAUGHS] Thank you for that.
And also, for those that want to see more,
hear more about Lynndrick's profile, it will
be posted on NHLBI.gov.
And if you go to the search and search Faces
of Sickle Cell Disease, you'll find Lynndrick's
story there to share.
And thank you for sharing that, Lynndrick.
With that, I'd like to bring to an end our
webinar session today.
Again, thanks to all for joining us.
We hope that you enjoyed learning about how
NHLBI is exploring genetic therapies to prevent
sickle cell disease.
Again, if you still have questions or any
lingering questions, please feel free to email
nhlbinews@nhlbi.nih.gov.
Also, don't forget to join us next Wednesday
for the next webinar in the series, which
will discuss bone marrow transplants, other
therapies, and sickle cell disease.
Join the conversation between webinars on
Twitter using #ScienceofSCD.
Thanks again for joining us.
Good afternoon.
