Perry Wilson, MD: The day when genetic diseases
can be cured in utero is closer than you may
think, with a recent study in Nature Communications
demonstrating for the first time the successful
cure of beta thalassemia in a mouse model.
But humans aren't mice and the biological
and ethical challenges surrounding gene editing
of human embryos are significant.
To discuss these issues with me today is Dr.
David Stitelman.
Dr. Stitelman is a pediatric surgeon and researcher
here at the Yale School of Medicine and the
Surgical Director of the Yale Fetal Care Center,
which specializes in treating children before
birth.
He's the co-author of that Nature Communications
paper and is really on the cutting edge of
research in this area.
Dr. Stitelman, thanks for joining me on Doc-to-Doc.
David Stitelman, MD: Great, thanks for having
me.
Wilson: Congratulations on this paper.
This really struck me as a milestone achievement,
a landmark achievement.
Am I correct in saying that this is the first
time that a genetic disease has been cured
in utero in a mammal, which was brought to
term, which resulted in a live birth?
Stitelman: Yes, this is the first time that
a fetal mammal has been edited and a disease
phenotype has been reversed by that editing.
Wilson: Congratulations.
That's amazing.
This is a mouse model of beta thalassemia,
so this is a single-gene type of mutation,
I assume.
Stitelman: Yes.
Wilson: Is it the same mutation that humans
have?
Stitelman: It is.
Yes, there are a handful of mutations that
cause the disease in humans.
This is a pretty common mutation that causes
the human disease.
Wilson: How do the mice do?
Are they totally normal when they're born,
and what percentage of them actually make
it?
Is this 100% successful?
Stitelman: The mice that are edited, we see
about 6% to 8% editing in their bone marrow.
Their anemia goes away.
Their CBCs look like a normal wild-type mouse
of CBCs.
The mice with beta thalassemia make blood
in their spleens, and so their spleens are
gigantic, and these corrected animals, their
spleen is still a little bit large, but it
goes down to a more normal size.
Wilson: That brings up sort of an interesting
issue, where thalassemia -- and presumably
maybe sickle cell is another human model disease
-- is a disease where you don't have to fix
every gene, right, in every cell?
You just need kind of some population of cells
acting normally.
Stitelman: Right.
Wilson: Is this the sweet spot for in utero
editing right now?
Stitelman: The two things you need are you
need to target the right tissue, meaning that
to get blood diseases, you need to get those
blood progenitors.
Then the level of editing, meaning the percentage
of cells that are corrected, will correct
certain diseases.
Things like hemophilia, if you get 1% of normal,
you'll actually go from severe disease to
mild disease.
For these hemoglobinopathies, usually people
say ... our paper is 6% to 8%, but typically
people say about 10% and you're able to reverse
the disease phenotype.
Things like cystic fibrosis -- 10% or 15%
editing turns cystic fibrosis to chronic bronchitis,
where 25% gets you probably a cure.
Then there are other diseases where you may
need higher levels of editing.
But a lot of these diseases, to get that level
of about 10%, you can probably do quite a
bit of good.
Wilson: That's really amazing.
Let's turn towards humans.
I think a lot of people are kind of really
interested in this technology for humans,
but also, perhaps, reasonably nervous about
it and the applications.
What's the current regulatory environment
like in terms of testing these things on human
fetuses?
Stitelman: As far as I know, to maintain your
national NIH funding you're not allowed to
edit human cells or human embryos.
All of our work is currently in mice and in
rodents.
Wilson: But there have been some papers I've
seen where there's been sort of editing of
fetuses or maybe even blastocysts, like a
few cells of humans which are not then implanted.
They never go to term.
They never turn into a newborn baby.
Is that done extra-governmentally?
Stitelman: The reports that I've seen are
groups in China that are regulated in a different
way than we are.
I think that they're using agents that are
different than the agents that we're using,
so they're using different gene-editing technologies,
things like CRISPRs and TALENs that are a
little bit different than what we're using.
The concern with those agents is that if they
edit your disease-causing mutation, that's
great, but if they alter some other site in
the chromosome while those cells are developing
and becoming a human, then maybe...
Wilson: It could cause more problems than...
Stitelman: Then that wouldn't be safe.
The safety is a major...
Wilson: Obviously.
Stitelman: In terms of the ethics of all this,
you need to make sure that your therapy is
safe before you proceed with any type of clinical
application.
Wilson: Of course.
Is that the Achilles heel of a gene-editing
technology, in general, or CRISPR specific,
is it the off-target effects that we all need
to really worry about?
Stitelman: In terms of safety, I think so,
yes.
I think in terms of efficacy, of it actually
working, you need a certain level of cells
or chromosomes edited.
But in terms of safety, you would worry about
changing the regulation of some other gene.
Wilson: What happened in your mice?
How did they...?
Stitelman: They did very well.
The editing reagents that the Glazer Lab designed
are called peptide-nucleic acids or PNAs.
They work in a little bit of a different way
than CRISPR/Cas9 or these other things.
You can design them so that they can bind
near mutations and edit mutations specifically,
but they use the cells' own editing enzymes
and editing equipment.
They're probably about a thousand-fold higher
fidelity than other reagents.
In our paper, we saw 6% to 8% on-target editing,
meaning that the beta thalassemia gene was
corrected.
We saw no off-target effects...
Wilson: None whatsoever.
Stitelman: ... in the homologous sequences
that we looked at.
Wilson: Wow!
Stitelman: We saw no off-target editing.
Wilson: That's another real feather in the
cap of the lab, that they're able to do this
so precisely.
I'm going to put you on the spot here.
If the U.S. government is not allowing this
research to proceed, are we going to lag behind
other places in the world, places like China?
Obviously, we want to do this carefully and
deliberately, but should we start opening
that door slightly to more robust research
in human embryos?
Stitelman: I think that the next step is working
out safety and efficacy in larger animals,
and then once you've demonstrated that safety,
then you can move on to the next step.
I think, in my mind, the priority is doing
no harm and not racing to do this before somebody
else.
Wilson: You're a pediatric surgeon.
You are taking care of human babies all the
time, many with genetic conditions.
Do families ask you about this?
Have they looked you up?
Do they know the kind of thing that you do
and say, "Stitelman, when can I...?"
Stitelman: No.
No, they haven't.
There have been some.
The Glazer Lab and the Saltzman Lab have been
working on these agents for a very long time,
and there have been families who have approached
them to ask about trials or off-label use,
but no family has approached me to ask.
Wilson: Larger animals are next, so non-human
primates?
Are we at that sort of stage?
Stitelman: I think so.
We're having some conversations to figure
out how to do that.
Wilson: Very exciting.
On the opposite side of families coming and
asking you, do you or does anyone in the lab
get people telling you you're doing the wrong
thing, that you're playing God here?
Stitelman: It's something that we think about
quite a bit.
The focus of what we're doing right now is
curing genetic diseases, meaning to take it
a step back, as an example, sickle cell anemia.
I learned about sickle cell anemia in high
school in the '90s.
They'd worked out the mutation.
It makes the protein fold funny.
It makes the cells funny.
The cells get clogged up in vessels.
As a pediatric surgeon, I take care of these
patients.
I take out gallbladders when they get stones.
I see them in the emergency room with these
abdominal pain crises.
I place lines for blood transfusions.
I unfortunately place feeding tubes in cases
where these children have had strokes and
can't swallow.
Seeing it on that level and knowing that the
mutation is known and you could rationally,
fundamentally cure the problem of the disease
is what drives the lab and what drives our
work.
But we are thoughtful about are we, again,
really focusing on safety, are we causing
any harm in what we're doing?
Wilson: Let's imagine a hypothetical world
where safety is addressed, the technology
is highly specific, there's no off-target
effects.
We've gone through the regulatory process.
We can potentially cure some of these monogenic
diseases in utero.
There, I can imagine, will come a time when
the question is asked, "Can we edit other
genes?"
Genes that, perhaps, aren't disease genes
with a phenotype that is so dramatic, but
perhaps, genes that are associated with a
risk of alcoholism or genes that might affect
your IQ or something like that.
Will there be a demand for these things, and
where do you draw the line?
Is there a clear, ethical place where you
say, "Yes, we will edit this gene, but no,
we will not edit this gene?"
Stitelman: I see where you're going, in that
if you're willing to cure muscular dystrophy,
are you willing to improve the muscles more
to make someone stronger or something like
that?
If you're willing to reverse some genetic
disease that results in developmental delay
and you're willing to make that person brighter,
are you willing to change anything to make
... as people understand how these things
work, are you willing to change those?
I don't have a perfect line in the sand of
what you would correct and what you would
not, although just if it is a disease, we
would want to cure it, whereas if it's augmentation
of...
Wilson: Normal...
Stitelman: ... augmentation of normal...
Wilson: I'm going to make it harder for you
because I agree.
I think the public, in general, would say,
"Oh, no.
You can't make someone smarter."
But let's say that there is a gene, maybe
not associated with a childhood disease, but
a gene like ApoE4 that's associated with Alzheimer's
disease late in life and maybe some other
cardiovascular risk factors.
Is that a gene that we should say, "Yeah,
maybe we should change it?"
If I were a parent, I might want to edit that
in my child.
Stitelman: Yeah, I think so.
I think if you have familial Alzheimer's,
the idea of correcting that in the fetus is
a little bit ... it seems like a treatment
that's a couple decades too early.
But if that's your window to treat it, that
seems reasonable.
If there's some developmental component to
the disease that you don't notice, then perhaps
you'd have even better neurologic outcomes
than if you tried to edit that in a person
who is already showing signs of dementia.
Wilson: Sure.
It's a fascinating area.
There's, obviously, a lot of questions still
out there, but congratulations on your achievement.
The first successful cure of a genetic disease
in a mammal in utero is pretty remarkable.
It does feel a bit like a brave new world.
[LAUGHTER]
Stitelman: It's very exciting times.
Wilson: It is.
We'll be watching closely moving forward and
best of luck as you advance the science.
Stitelman: Great.
Thank you so much.
