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- Hi everyone, my name is Tippi Mackenzie,
and I'm a professor of surgery at UCSF.
Today I will speak to you about our clinical trial
of fetal stem cell transplantation in fetuses
with alpha thalassemia major.
So imagine a world where we could treat or even cure
a deadly genetic disease before birth.
We don't think too much about going to the doctor
for various problems we have after birth.
But the concept of the fetus as a patient
is only several decades old and was actually invented
right here at UCSF.
So did you know that doctors can actually operate
on a fetus in the womb and this ability,
which started in the 1980s with fetuses
with various anatomic conditions helps us treat fetuses
with a number of birth defects.
And what we're trying to do is to move this field
to now treat genetic conditions.
Here's a repertoire of what we're able to do
in fetal surgery that involves open fetal surgery,
laparoscopic or fetoscopic surgery
or catheter-based interventions.
But as I said, what we're focused on
is putting in stem cells or other therapeutic agents,
just using a needle into the umbilical vein
to treat various genetic diseases.
And these possibilities exist in this decade because
of the convergence of a number of technologies.
So right now we can do rapid genetic diagnosis
using whole exome or whole genome sequencing.
We have a much better understanding of maternal
and fetal biology and our repertoire of being able
to treat diseases using the cutting-edge methods
of gene therapy or gene editing are really exploding.
So this gives us a number of techniques to be able
to treat fetuses with genetic diseases.
So today I'll talk about our work
on stem cell transplantation,
but there's ongoing work both in our lab and in the labs
of our collaborators for additional techniques,
such as enzyme replacement or gene therapy.
There are a number of single gene disorders
that we can potentially treat with these techniques.
And today I'll talk about the thalassemias, but of course,
other single gene disorders, such as
lysosomal storage disease or spinal muscular atrophy
to name a few, could also be treated.
And the main reason to treat the fetus before birth,
as opposed to waiting until after the child is born,
there are a couple of reasons actually.
The number one reason is that the fetus
has a very unique immune system,
which I'll talk about in a little bit, where they can be
tolerized to new proteins that they see before birth.
You can also of course protect the brain
before the blood-brain barrier forms.
And you can access stem cells during their migration.
For example, for blood stem cells migration
from the fetal liver to the bone marrow.
So here's a proposed pipeline of fetal molecular therapies
that we're working on at UCSF.
Right now, we have a phase one clinical trial
of stem cell transplantation for alpha thalassemia major.
And we're hoping to expand that
to other disease indications
once we have more safety and efficacy data.
We're working on in utero enzyme replacement therapy
for lysosomal storage disorders,
and we're speaking to ethics experts and the FDA about
in-utero gene therapy, of course only in somatic cells,
not in the germline.
So a lot of this is made possible by this beautiful concept
in biology where cells traffic back and forth
between the mother and the fetus,
and the fact that you can find fetal cells or DNA
in the mother forms the basis of the whole field
of prenatal genetic diagnosis.
And this is what enables us to even diagnose
a lot of these genetic diseases before birth.
But the trafficking also happens the other way
in that there are mother cells in the fetuses.
And the very interesting thing is that the fetus actually
learns to tolerate these foreign cells and proteins
it sees during development.
So because it sees maternal cells during development,
it just so happens that it learns to tolerate the mother's
antigens or proteins on those cells before birth.
And a lot of this biology was worked out by Jeff Mold
and Mike McEwan at UCSF about a decade ago.
And what they showed is that the fetus's T cells,
which are the main transplant rejecting
or fighting cells, when they see a new protein,
instead of becoming these effector T cells, the red ones,
which they would in you or me,
they actually are more predisposed to become these green
regulatory T cells that confirm tolerance.
And that the fact that the fetus is seeing and learning
to tolerate these maternal cells forms one of
the backbones of the miracle of pregnancy,
how the mother and the fetus, with their
different genetic backgrounds, can tolerate each other.
And then if you think about applying this to a situation
where the fetus has a birth defect
that requires a bone marrow transplant before birth,
you get the logical conclusion that we should be
transplanting maternal cells.
So these are fetuses with thalassemias,
or sickle cell disease or Fanconi anemia that could be cured
with a bone marrow transplant before birth.
And the concept that you can do a bone marrow transplant
before birth had been tried some decades before,
and it really only works for a small subset of disorders,
but that it hadn't worked for thalassemias before.
But this work shows that we can potentially transplant
maternal cells and that it should work
if we transplant a very high dose of cells using
an intravascular method
and using maternal cells in particular.
So after a number of years of preclinical experiments,
collaborators in Philadelphia, in Dr. Flake's lab
did a seminal study in dogs where they showed
that if you transplant maternal cells into fetal dogs,
you get good levels of engraftment of the maternal cells,
between five to almost 40%.
And that these dogs become tolerant now permanently
to their mothers.
So usually that tolerance to the mother wanes
immediately after birth, but in these dogs,
they show that they can actually do a kidney transplant
from the mother and there's no rejection.
So this is a great proof of concept to show that
transplantation of the mother cells
can result in tolerance.
And in terms of thinking about these blood disorders,
the goal is not necessarily a single-shot cure because
you're not giving any conditioning into the fetus,
which is usually what creates space in the bone marrow
to have securative level of cells after
a bone marrow transplant.
So the idea is that it's a two-step process.
So you have a fetal transplant that induces tolerance,
and then you do a postnatal booster transplant
to really increase the levels of engraftment
of those maternal cells to definitively cure the disease.
And this concept has been shown in mice
by Bill Peranteau's lab, again in Philadelphia,
where they took mice with sickle cell disease
or thalassemia, and you can see here after the initial
in-utero transplants, you could see the cells,
but they weren't really cured of levels of engraftment,
but then after birth, they were able to boost the levels
to curative levels.
So in thinking about applying this to human fetuses,
we thought very long and hard about what might be
the perfect first disease.
And in discussions with international colleagues,
we came up with alpha thalassemia major
and alpha thalassemia's a very interesting disease.
And I'll tell a little bit about fetal hemoglobin biology.
So hemoglobin is the molecule in red blood cells
that of course carries oxygen.
And in adults, there are two chains, the alpha
and beta chains, but in a fetus there's just
alpha and gamma chains and a fetus that has mutations
in all four of the alpha globin genes
doesn't have any alpha chains.
And so it makes these abnormal gamma tetramers.
And these are also called hemoglobin parts.
And those fetuses get very sick because those
red blood cells, they can't release oxygen to the tissues.
So there's low oxygen in the tissues.
And we can see this in ultrasounds where
the fetus develops fluid around the liver
and around the lungs.
This is a condition called hydrops, which is fatal,
unless you give a blood transfusion to the fetus.
It's actually a common disease,
multiple populations around the world, including in China
and Southeast Asia have a very high carrier rate,
but because the fetuses can be treated
with blood transfusions before birth,
we thought it was an ideal disease to do
an in-utero stem cell transplant using maternal cells,
because you already have to do an intervention on the fetus.
So you get rid of any additional technical issues.
Families interestingly, with a pregnancy
with alpha thalassemia major are often counseled
to end the pregnancy because of several concerns.
If the fetus is hydropic and they don't get
any therapy at all, that's a very dire situation.
The mother can get sick as the fetus gets sick,
that's called Muir syndrome.
Because the brain hasn't had oxygen during development,
you can have poor neurologic outcomes in the child
after birth and the alpha thalassemia,
it was felt previously to be a very severe chronic disease
with an untenable medical burden.
So we first set out to understand, are these valid concerns?
Is this a disease where it's ethical
to think about fetal therapy?
Can there be meaningful survival and how can we
improve outcomes for these families?
Well, it turns out that there are multiple reports
of good outcomes in fetuses with alpha thalassemia major
if you do these blood transfusions before birth,
and if you do them very rigorously.
So this is our series that we published in 2014
of around 20 patients.
There was an international registry that was published
around the same time, and then one from Hong Kong.
And the upshot of all these series is that
if you do fetal blood transfusions, the hydrops resolves,
the mom does not get sick.
The babies can be born near term or term, and they have
in many cases, excellent neurological outcomes.
So even if these fetuses were initially sick in utero,
some of them do very, very well.
And some of them can even be cured after getting
a bone marrow transplant after birth.
So to really understand at a larger level
how these patients are doing,
we've started a UCSF international registry to understand
both the neurological outcomes of fetuses who had adequate
transfusions and really understanding patient
and provider attitudes regarding fetal therapy
versus ending the pregnancy.
So what happens to patients with alpha thalassemia major
after birth?
Well, it turns out it's a very similar disease
to beta thalassemia major, where there are basically
two kinds of therapies.
You can either have chronic transfusions once a month
or every three to four weeks, and the complications
there can be iron overload, or now there are medicines
for chelation, but there can be toxicity from that.
Or you can have a bone marrow transplant.
And as I mentioned, this can be a definitive cure.
However, there is about a 10% mortality because
of all the medicines that we need to give
to prepare the bone marrow to accept the transplants.
It can be difficult to find a suitable donor.
The mom is only the perfect donor before birth
and patients can have graft versus host disease, et cetera.
So we think that in-utero stem cell transplantation
may decrease the burden of disease.
And that's the idea behind our fetal
bone marrow transplantation clinical trial.
So in this phase one clinical trial,
we're giving a stem cell transplant
from the mother before birth.
And the way that it works is we do
an initial video consultation.
And if the patient meets the inclusion criteria,
we do the transplant and then evaluate
the chimerism after birth.
So I'll tell you a little bit about our first patients.
They were written up in the New York Times after birth.
They did very well, although they presented with hydrops
at 18 weeks, they improved with in-utero transfusions
and transplanted at 23 weeks.
And we did five total in-utero transfusions,
and the hydrops resolved with careful transfusions.
We saw that the clinical protocol is feasible
and appeared safe, and the fetal transplant
can establish long-lasting tolerance.
So these are some pictures of how we do
the bone marrow transplants.
And here you see the bone marrow harvest.
We select the cells and then infuse them back
into the fetus using ultrasound guidance.
And as I mentioned, we have to do further work
to expand the indications and also to optimize the efficacy.
There are a number of ethical considerations of course,
for non-directive counseling and patient representation
is really critical for planning the therapies.
So the main lessons we're learning is that
the moms can tolerate the bone marrow harvesting well,
the fetuses are doing well so far,
and really that patients with alpha thalassemia can be given
multiple pregnancy options, including fetal therapy.
And as I mentioned,
we are currently recruiting for enrollment.
All of this has made possible at
The Center For Maternal-Fetal Precision Medicine,
which I co-direct with Mary Norton and our clinical arm,
which is the Fetal Treatment Center.
And I'd like to acknowledge both funding from CIRM,
which is funding this phase one clinical trial,
as well as my multiple colleagues
at the Precision Medicine Center, as well as our
thalassemia team, particularly Dr. Byczynski
who's a thalassemia expert.
And thank you for your participation for our patients.
Thank you.
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