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>> We're at the dawn of an age of
potential therapies for a really severe diseases
that is exceptionally exciting.
I've been really lucky in that I started caring for kids with
this disease called spinal muscular atrophy
when I came to Hopkins in '87.
It turned out that this particular disease had all the features,
all the characteristics that made it ideal for
the earliest applications of these new technologies.
I can't emphasize enough how many things
had to happen that were right,
that had to work in the right way so that this was possible.
The first gene transfer experiment was actually
done on a different tissue, the retina.
The treatment was effective in treating
this disease called leber optic neuropathy.
The next one was this disease, spinal muscular atrophy,
which is much like a genetic form of polio.
It affects the motor neurons and the motor neurons wither away.
As a consequence, the muscles that they're
connected to become weaker and weaker.
Typically about 60, 70 percent of the kids who inherit
this disease will die
in the absence of therapy in the first year or two of life.
There are some milder forms in which people are able to
survive for longer intervals afterwards.
The things that had to go right,
is that this has to be a disease in which it is common enough for
a farmer to be able to invest the money because it's
a substantial amount of money that has to be done.
It has to be disease in which we can measure the outcome so that
the abnormality is one in which they progression or
the expression of it is capable of being measured.
Have we done well or have we not done
well with application of therapy.
It has to be a disorder of which we can get
the gene to the tissue of interest.
It has to be one in which
the group of patients that are affected,
the folks who are in
the patient's service organizations
are organized enough so that we
can take advantage of all the research
that's been done previously for characterizing the disease.
There's a whole bunch of things that had to go exactly right.
We've been really fortunate in the development of therapies for
spinal muscular atrophy that
another technology came along antisense oligonucleotide therapy.
That's actually a small stretch of DNA
like molecule that is specifically designed to
bind to DNA or RNA in
exactly the right place and either cleave it or add
it or cover it or otherwise modify
its biology in a way that has benefit to the patients.
In the case of spinal muscular atrophy,
the ability to modify splicing of the aberrant molecule led
to the production of a normal protein amount from
a gene that was otherwise broken that
wouldn't produce much protein at all.
The protein is called SMN and the therapy that was
licensed in late 2016 and now is being used around the world,
the name of it is called nusinersen.
It's a generic term and it's
been exceptionally safe and very successful.
That led to our understanding of the fact that you can measure
this disease and treat it with the new gene transfer experiments.
That led to a series of experiments that we've been
doing about the same period of time since 2016,
2017 and to the licensing of a gene therapy or
gene transfer experiment called onasemnogene
abeparvovec and that was licensed about a year ago now.
We were advantaged to be able to be part of
the multicenter research consortium and also
since its licensing we have been able
to administer it to quite a number of newborn infants.
Another advantage we have for the gene transfer experiment is
that the babies have to be found very soon,
because right after birth,
babies will start manifesting weakness.
If we can treat them very quickly,
we can make a difference in their life.
In parallel with this,
because there was enthusiasm about it,
the various patient service organizations
and pharma and universities developed a newborn screening test,
and we now have it applied in over half the states.
We're finding about 60-70 percent
of the babies that are born with SMA at the time of birth
which enables us to do the gene transfer experiment within
a matter of a couple of weeks and hence
save as many motor neurons as possible.
[MUSIC]
>> The near term experiments are going to be targeted to
those conditions in which
gene transfer will not dilute
as the tissues that we're interested in divide.
The nearest term one I'm aware of is
actually in Duchenne muscular dystrophy,
where research has been successful at making
a smaller and smaller dystrophin gene that can actually
fit into this tiny little AV package.
We're looking forward to having
a research protocol here
to see if we can treat Duchenne muscular dystrophy successfully.
Early evidence which suggest that
the first four kids that were
treated in this manner and a follow-up
were much better off and the next 40 kids that had been
treated at other institutions have been
successfully treated without any untoward effects.
This is the dawn of potentially new age for these two tissues.
Obviously, we were hoping that they're going to be
advances that allow us to move it
into other tissues and other conditions.
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>> As exciting as these new technologies are,
and the antisense oligonucleotide and the gene
transfer and the potential for
other sorts of gene therapies coming along,
it also raises some really important big questions that I
don't think academics like myself have been comfortable with.
That's the issue of cost.
These technologies are personalized.
They are directed to very rare diseases.
With that, it's been possible to
leverage costs of millions of dollars
per patient to be able to deliver this
because the insurance industry and society thinks it's worthwhile.
But as we start talking about giving these to more individuals,
more diseases, I'm seeing
that there's going to be barriers of whether it's right.
Also we're going to have a problem of the effect size.
It's hard to argue with treating spinal muscular atrophy.
The baby is going to die in eight months, 10 months,
15 months, lest we give this therapy.
Of course we're going to treat that
even if it cost a million dollars or two million dollars.
But if the effect size is smaller,
suppose we're only going to slow the rate of degeneration down.
Suppose we're only going to make a relatively minor difference,
but it's enough to get licensing from the agencies.
How are we going to pay for this?
How are we going to afford and
assess whether or not these extraordinary costs are worth it,
especially as they become more and more of an issue.
I think there's a role for academics to help
in determining whether or not
the effect size and the cost are balance in a way.
I can't think of any other agencies.
Certainly the pharmaceutical companies are going to say buy it,
and the people who have the disorders are going to say,
we want to have it and they are absolutely right to say so.
I don't know of anybody who
is in a better position to be able to say,
where are the costs going to be balanced,
mindful of the fact that we're
talking about some extremely
difficult areas and I obviously don't want
to be in that position of talking about restricting access.
But on the other hand, we have
big questions that we're going to have to be
addressing in the next few years or a couple of decades.
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