Today, we're talking about gene therapy
for neurologic disease.
I'll tell you a little bit about our work
in a specific model of neurologic disease.
I think all of us know
someone or several people
with a severe neurodegenerative
disease of some sort.
My own father-in-law died
of Alzheimer's disease,
which was a despicable experience for him
and the entire family.
Of course, President Reagan had
Alzheimer's disease as well.
Michael J. Fox, still
battling Parkinson disease.
And this fella, is named
Lou Gehrig, who died of ALS.
I learned recently that he still holds
the Major League record
for the most number of
grand slam home runs.
One of the greatest baseball
players ever to live,
and died of this severe
neurodegenerative disease,
called now, Lou Gehrig's disease.
In the US, some of the most prevalent
neurologic diseases are listed here.
Globally, roughly one out
of every ten lost years
of health are due to neurologic diseases.
To treat dementia alone, across the world,
we're spending about 604
billion dollars a year.
Which is estimated to
be about one percent of
the gross domestic product of the world.
Economic output losses,
meaning lost productivity
due to neurologic diseases
are estimated to be
about 8.5 trillion dollars annually.
And that should double by the year 2030,
if we continue on the same trajectory.
All of these diseases, or
most of these diseases anyway,
are multifactorial, meaning that one
or several genes can be involved.
Or an interaction between genes
and the environment can be involved.
So they're a little bit tricky to treat
by gene therapy with the idea of replacing
a single gene to make an effect
on the disease progression.
We study a group of disorders
called storage diseases,
which are monogenic diseases,
single gene disorders.
We know the specific gene
in almost all of these
50 disorders that are defective,
and if we can replace that
gene with a functional gene,
we think that we'll be able to
do some good for these diseases.
On the whole, this group of 50 diseases
is about as common as cystic
fibrosis and hemophilia.
Diseases that are more common
than most of us probably have heard of.
Two thirds of the storage
diseases affect the brain,
making them the most common
neurodegenerative disorders of childhood.
So, while you may not have heard
of many of the individual diseases,
such as, Tay-Sachs
disease, Sandhoff disease,
GM-1 gangliosidosis.
The entire class of
disorders is quite common.
And quite a burden for those
who have been affected by them.
Now, this subset of disease
that we study, gangliosidoses,
can be found in animals, cats and sheep.
Unfortunately, they're
also found in children.
This little fella is Porter Heatherly.
Lives in Opelika with his
parents, Sara and Michael.
He was diagnosed with GM-1 gangliosidosis.
This picture was taken not long
after Porter was diagnosed.
This is Porter today.
Actually, a few months ago when he came
to visit us at the vet school.
This is how these kids spend
the majority of their lives,
in a reclining stroller like this.
Barely interactive with
the world around them.
Their parents think that they can pick up
on some responsiveness, but really,
to you and me, they
would be non-responsive.
These are Porter's parents,
this is Henry Baker.
All three of these
actually, his wife Trudy,
all four of those people
are Auburn graduates.
And we hope that we'll
be able to do something
to make an impact on
these diseases very soon.
Henry and Trudy actually
discovered the cat models
in the late 1960s, early 1970s.
And soldiered on and on for many years,
characterizing the
diseases so that we could
get to the point of actually
treating them, some day.
I think we're there right now.
This is the Tay-Sachs disease timeline.
Tay-Sachs disease was
first described in 1881
by Warren Tay and Bernard Sachs.
Hence the name Tay-Sachs disease.
The first animal model
of a storage disease
was described by Dr. Baker in 1971.
The reason I put the
timeline up is to say that
in the 135 years since these
diseases were first reported,
the most effective medical
intervention for these kids
has been insertion of a stomach tube.
So that they can be fed a liquid diet
directly into their stomach and
they don't choke on food taken orally.
The cause of death primarily for kids,
until stomach tubes were
beginning to be inserted,
was aspiration pneumonia.
Now their lives have been expanded,
or extended one to two years.
With the insertion of a stomach tube,
average lifespan is two to five years.
Terrible, awful, miserable, diseases,
that need to be eradicated
from the face of the earth.
You can think of them a little bit like
early onset forms of Alzheimer's disease,
or early onset forms of diseases
that occur later in life.
Because the same
degenerative process occurs.
All right, so what are we going to do?
We don't, have a treatment
today, what are we going to do?
Gene therapy is on the horizon,
I think we're almost there.
This is an image of a
typical gene therapy vector.
The reason that I put it up
there is to show you that
the only part of the native genome,
the only part of the
native genetic material
of this naturally occurring virus,
are these two black rectangles
on either end of the vector.
The vast majority of
the native complement of
genetic material has
been removed and replaced
with beneficial genes to
help treat the disease.
We can treat the cats by one of two ways,
by far the most experience that we've had
is by direct intracranial
injection of the brain.
It's a 90 minute surgery, one-time,
the cats wake up two
hours, they're fully alert
two hours after surgery and are returned
to their mamas by the end of the day.
98% of the cats that have
been treated this way
never looked back, we had
very few complications.
It's an amazingly safe
procedure in the cats.
And actually, humans have this
type of procedure as well.
This is an image of a cat
brain and for the sake of time,
I'm not going to go through
all the details but basically,
what we're looking at here
is a cat brain that's been
divided from front, the
frontal pole right here,
all the way to the back,
the cerebellum right here.
Spinal cord as well.
Anywhere that you see blue staining,
is evidence of the
therapeutic enzyme that we're
trying to replace in these cats.
This is normal level of
that therapeutic enzyme,
in an untreated cat there's
a little residual staining
but not very much, same
thing for the spinal cord.
From the front of the brain,
all the way through the
cerebellum, and throughout
most of the spinal cord,
we see dramatic restoration
of enzymatic activity
after a single surgery,
again that lasts 90 minutes.
All right, for the sake
of time I'm not going to
go over the survival curves
and the clinical rating scores.
We'll just talk about
the effect on ambulation.
This is an untreated cat
at six and a half months,
approaching seven months.
You can see that he has
balance difficulties.
Has trouble standing up, has fine tremors.
And this will progress to
the inability to stand up.
Which is our humane endpoint,
the point at which the
animals are euthanized.
It's important for me to
say, because I'm a cat lover
and I know there are many here,
we don't find any evidence
of pain in this neurodegenerative process.
They don't vocalize a lot,
they don't rub their heads
against the cage, they don't
pant when they breathe.
They're just frustrated because they can't
do the things normal cats can do.
Compare that to a treated cat.
At almost five years of age,
and I think if I put
that cat in a group of
ten normal cats, it would
be hard to pick him out.
This fella is named Amari,
he's now over seven years old.
He looks no different from this video,
taken at five years of age.
He shows, well, knock on wood,
he shows no signs of slowing down.
The average survival of
these cats that have been
treated by intracranial
gene therapy is six times
above the untreated lifespan.
Most of them live a much
better quality of life,
like you're seeing here.
All right, in my last minute,
I just want to tell you
about what's on the horizon.
We are partnering this
intracranial approach
with a French biotechnology
company, called Lysogene.
That has done this for another
lysosomal storage disease,
called Sanfilippo syndrome,
their second indication
is going to be GM-1 gangliosidosis.
I met with them in Boston yesterday.
And the firm target date
for the human clinical trial
is fourth quarter of next year.
So we're getting very close to
getting all that taken care of.
As I finish up, we also are exploring
an intravenous approach.
Up until the last four or five years,
there was no way to get
gene therapy into the brain,
across the blood-brain barrier,
without direct injection.
Recently, it's been
shown that these vectors
can get into the brain if
they're a specific sub-type
after an intravenous injection.
So, we actually treated some cats
by an intravenous injection,
actually just a couple.
The MRIs look fantastic,
this is a normal MRI,
look at the dark area of the
white matter here in the brain.
In the untreated cat, that dark area
of white matter is almost gone.
In the treated cat, at two years of age,
that white matter is preserved.
Same thing in the cerebellum.
This is a video of that treated cat,
let me set this up just a little bit.
When we pull them out of the
kennels in the afternoons,
they're usually sleeping
and they don't want to
get up and be videotaped,
so sometimes we have to
stimulate them with a laser pointer.
All right.
So let's see if Christine is going to
pay attention to the laser pointer.
Yeah, you'll see it come
in, and there she goes.
Off to the races.
I know from this video,
you can't really see
whether she walks normally or not.
I can promise you that gene therapy
does not induce hatred of
laser pointers in cats.
But here's a little clip
showing her walking normally
just to let you know
that this IV gene therapy
may be the real deal as well.
Anyway, that's our hope for the future.
Much less invasive procedure,
and that's where we're going next.
Thank you very much for your attention.
