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Hi everyone. I am very pleased
to be here today.
To have the possibility
to tell you about our project,
towards a cure for IPEX Syndrome.
With two different approaches,
engineered T-reg replacement
or stem cell gene editing.
So, monogenic diseases of the immune system
are represent about 400 of,
among the 7000 monogenic diseases
and manifests not only with immuno deficiencies.
Meaning increases susceptibility to infections,
but also without immunity
depending on the different genes
that are involved,
by the genetic impairment.
And importantly so the one category of this disease,
are the T-reg tregopathies.
So they in which
really the genes that are impaired,
are impairing the functions
ofT-reg cells.
Very important cells
to regulated the immune system.
And in particular FOXP3
is the gene that is mutated in IPEX Syndrome,
of which we are gonna talk today.
In IPEX patients,
what happens is that
the T regulatory cells
normally develop within the times
during the fetal life
and as in after birth.
They are impaired because of this transcription factor
which is essential for their function
is not working.
And therefore this causes their inability
of these dysfunctional T-reg cells
to control T effector cells.
Which by consequence,
they attack the different organs,
not recognizing the self anymore.
And in particular
they attack the pancreas,
skin, gut and kidney,
generating severe enteropathy,
eczema, type 1 diabetes
and nephropathy and autoimmune hepatitis,
and so on.
This disease importantly is as a fatal outcome
if it is not rapidly diagnosed and treated.
And actually this is probably what happened in the past.
The disease has an age onset
very early in life.
As you can see, most of the patients
basically have the onset of the disease,
within one year.
And half of them within the first month.
And definitely the awareness of the disease
has also increased
as also being reflected in the
increased incidences of the disease.
Besides the main triad of symptoms which is,
Diarrhea type 1,
diabetes and eczema.
In the progression of the disease,
many other organs can be affected.
And of course, there is a very severe
failure to thrive.
And interestingly, IPEX is the disease
among all the immune regulatory disorders
in which type 1 diabetes is more frequent.
So what happened to these patients,
what do we have right now for their treatment?
The approaches are essentially
2,1 is immunosuppression,
by pharmacological intervention.
And the other one is,
hematopoietic stem cells transplantation.
Now these both,
these approaches are insufficient and satisfactory
because...so the transplant
really has limited survival.
And the pharmacological treatment,
if we look at the
disease free survival,
is really insufficient.
in guaranteeing a long life,
control of the disease.
And therefore its really for the patient,
is really insufficient to reach the wellness.
So we have, of course the spore
as a gene therapy approaches.
Which are for the FOXP3 as extremely demanding,
because FOXP3 is a transcription factor
with differential expression
in different cell subset of the body.
So it is very highly expressed
and always expressed in FOXP3
positive T regulatory cells
which are a tiny bit
cell subset in the blood.
And whereas they
it is transiently expressed,
but also very important in controlling
immunol responses during you know,
in any T cells that becomes activated
and fight against pathogens.
So, but because of the T-reg
are the main subset affected.
We ask whether T-reg replacement therapy
would be curative
or even also every, any patient
would need a bone marrow transplantation,
or can be cured
by this T-reg cell approach.
So the T-reg cells,
the gene therapy approaches that are nowadays
pursued by different groups,
are basically two.
One is the functional replacement of T-reg
and the other one is the
physiologically regulated expression
of the gene in enotobreic stem cells.
And at Stanford,
we are developing both the T-reg replacement therapy
and the in gene editing approach.
With the T-reg replacement therapy all ready
several years ago.
We have observed that by transducing T cells.
So normal CD4 effector T cells with wtFOXP3,
under a constitutive promoter.
We can generate a subset of cells
which express FOXP3 at very high levels,
exactly like T-reg,
physiological T-reg would do.
And we can do that in the autologous patient cells,
and then purify them
and reinfuse them,
with very limited toxicity.
These cells really become
like the T regulatory cells,
as they you know
from the phenotypic point of view
but also in their suppressive activity.
And they are very stable also when
they are exposed to inflammatory condition.
We are now towards the phase one cell therapy development
with this cell product,
and we have already validated
this cell product in several humanized mice
and also we are also doing
the GMP process development.
With the idea of filling the IND to the FDA
in the next year, in 2021.
And the CIRM funding for this is really essential.
Basically the other important aspect of this cell product
is that once we use IPEX
you know can be used also
in many other different diseases such as,
inflammatory bowel diseases,
graft versus host
and the other autoimmune diseases
in which T-reg deficiency is a problem
to be overcome,
and is responsible of the pathology.
And this cell product represents several advantages
as compared toT-reg cell therapy product,
that are already in the clinic.
One of this is the guarantee of stability.
The other one for example,
is the easy to be manufactured
because we start,
the starting subset is the CD4 positive T cells
and not the T regulatory cells.
But of course the real question is
treatment verses cure.
Would HSC based gene editing for IPEX syndrome
be really the ultimate goal to cure IPEX?
And to provide long lasting
wild type FOXP3 gene expression,
under physiological regulation?
With this question in mind
we are also working on pre clinical studies,
using CRISPR Cas9 for FOXP3 gene correction,
in the enotobreic stem cells of the patient.
And we have already produced very nice data
on feasibility of this approach.
What we do in particular is we transfer the FOXP3 gene,
the all coding sequence,
so that we can
with one gene therapy approach,
cover all the different mutated genes
that the patients may have.
And we insert this coding sequence
after the regulatory sequence
together with NGFR gene,
which allows us to follow the cells
that are genetically modified.
By doing so,
we know that we can replace at least 50%
of the normal physiological expression of FOXP3
and also of its function.
And we can generate as we tested in
vivo in humanized mice,
we can generate functional T regulatory cells,
although in a little bit decreased amount
as compared to normal donor styles.
So we are still working at the pre clinical level
on this cell product.
So, as the conclusion towards the cure of IPEX syndrome,
of course working here on that has being really
increasing the awareness of IPEX disease,
the unmet need
and the possibility of a better treatment.
The support of CIRM on the
CD4 LVFOXP3 project,
allowing the IND filling,
is absolutely important
and critical for the success of this project.
And the pioneering gene editing is also
another promising innovative approach.
And if you want to learn more on what is life with IPEX,
please go to the blog of CIRM
and listen to the story of a dear patient of ours
which is, you know it was really so kind
to advocate for a cure, its touching.
Thank you very much.
Thank you CIRM
and also thank you to all my
FOXP3 team in the lab
and Roncarolo lab
in which with whom I always work
since many, many years
and thank you all for your attention.
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