>> Dr.Berger: Okay, so our next presenter
is Charlotte Sumner.
She is the professor of neurology and neuroscience.
She will discuss genes specific treatments
for people's spinal muscular atrophy.
>> Dr.Charlotte: Thank you so much, Dr. Berger,
I'm just tryna share my screen here.
(keyboard clicking)
Great.
Can everybody hear me?
>> Dr. Berger: Yes, everybody can see your screen.
>> Dr.Charlotte: Great, Good afternoon,
thank you everybody for listening.
Monogenetic neurologic diseases,
together as a group affect, probably one in 1100 people.
And generally these can be very devastating disorders
resulting in significant disability
and often early mortality.
The last several decades has seen really remarkable progress
in identifying the disease genes
that underline many of these disorders.
We now know the genetic basis of Huntington's disease,
multiple spinocerebellar ataxias, muscular dystrophies,
Charcot Marie tooth disease,
and familial forms of ALS, Parkinson's disease
and Alzheimer's disease.
And there's always been the hope
that in identifying these disease genes,
we would also be able to identify
highly efficacious treatment,
that would address the most proximal cause of disease,
and therefore potentially even represent a cure.
But unfortunately, up until very recently,
these treatments have really lagged.
Part of the difficulty is that accessing the nervous system
is difficult and it has very complex anatomy.
But in parallel with identifying the genetic basis
of multiple neurogenetic disorders,
there's been also remarkable progress
in developing gene targeting therapeutics.
Most traditional drugs, of course, target proteins.
But gene targeting therapeutics are really trying
to develop drugs that can target at the level of DNA
or the level of RNA.
And in recent years, there's been really incredible progress
in viral vector technology,
using viruses such as adeno associated viruses,
as a way to package genes and deliver genes
to the nervous system, including to neurons specifically.
And some of these viruses have the remarkable ability
when delivered either intravenously
or intrasequally to be taken up by neurons
and potentially express their gene indefinitely
in a non replicating neuron.
There's also been enormous progress in targeting RNA.
One way that this has been achieved as with what are called
antisense oligonucleotides.
These are chemically modified single stranded
oligonucleotides, you can sort of think of them
as single stranded DNA,
that recognize and bind specific RNA, you know,
Watson-Crick base pairing.
And when they bind that RNA,
they can then modulate that RNA.
They can target that RNA for degradation,
or they can alter its behavior,
including altering its placing.
And though ASOs don't cross the blood brain barrier.
We've learned that we can inject them
into the intrathecal space and there they,
from the CSF can distribute into the parenchyma
of the spinal cord in the brain.
And finally, most recently we've recognized
that the tertiary structure of RNA can be targeted
with small molecules and there's emerging small molecules
that can also target RNAs and with quite high specificity.
And this leads to the possibility
of an orally bioavailable drug that a patient could take
by mouth.
The disease in which there's really been remarkable progress
in developing gene targeting therapeutics has been,
this motor neuron disease
that predominantly affects children
called spinal muscular atrophy.
This disease is considered a rare disease,
but because it's such a devastating disease
is the leading inherited cause of infant mortality.
One in 40 of us carry the disease gene and the incidence
is approximately one in 10,000 births.
Patients with SMA have a motor neuron disease.
Motor neurons are the large neuron whose cell body sits
in the ventral horn of the spinal cord,
and extends its wire or axon out to target skeletal muscle.
And it's motor neuron firing that allows our muscles
to contract.
When motor neurons die,
the muscle becomes very small and weak,
and unfortunately babies and children with SMA
can be profoundly weak.
Most people with SMA have the most severe form type 1 SMA,
and these babies never achieve head control,
never achieve the ability to sit and severe respiratory
and swallowing muscle weakness,
results in lethality usually before the age of two.
The genetic basis for SMA was identified in 1995.
And the diseases caused by recessive mutations
of what's called the survival motor neuron 1 gene.
Usually these are large deletion mutations
and therefore there's no functional RNA or protein
that arises from the SMN1 genes and patients with SMA.
But all patients with SMA retain at least one copy
of what's called the SMN2 gene.
And this gene is very similar to SMN1, but not identical.
There's a single important nucleotide change,
this is a cytosine to finding change in the sequence
of SMN2, and what that single base pair change does,
is when the SMN2 gene goes to make its RNA molecules,
the splicing of those pre-mRNAs is altered,
such that an axon, a segment of the RNA is removed.
And this shortened RNA goes on to make a shortened protein
that is nonfunctional.
Some of the time the axon seven sequence is retained
in the RNAs and that RNA mix of full length protein
that's completely normal.
But, overall patients with SMA have less SMN protein,
and it's this reduction in SMN protein that causes disease.
But this unique genetics of SMA
provided a remarkable opportunity to develop different types
of strategies for targeting the disease with therapeutics.
One way has been to just replace the SMN1 gene,
replace what's missing.
And this has been achieved
using adeno-associated virus 9.
The drugs Zolgensma was approved by the FDA in may of 2019,
and this virus delivers SMN
and the SMN is expressed in motor neurons.
The drug is delivered once by an IV injection
to children two and less.
The other therapies that have been developed,
actually target RNA.
In this case, we're targeting the RNAs,
the rise from the SMN2 gene.
The first drug that was developed and approved for SMA
is called nusinersen or Spinraza.
This is a splice switching, antisense oligonucleotide,
and this drug binds to the pre-mRNA
arising from SMN2 and encourages axon seven retention,
thus making a normal SMN RNA and protein.
This drug is delivered to patients by spinal infusion
or intrathecal injection four times in the first two months
and every four months thereafter.
And finally, the third drug on the horizon
is called risdiplam.
This is a small molecule that's orally bioavailable,
and this drug is currently being reviewed by the FDA
with anticipated approval this year.
So we now have four different, sorry,
three different drugs for SMA soon to be approved.
And these each have different administration routes
biodistribution, some potential toxicities.
But in all cases, these drugs have shown efficacy
in patients.
And at times this efficacy can be quite remarkable.
This is a sister and a brother who were cared for,
by my colleague, Thomas Crawford,
and unfortunately this little girl was born before the era
of treatment.
In this picture, she's a year old and has no ability
to control her head, or to sit or to stand,
and she died of respiratory failure at the age of 15 months.
Her brother, who was born later,
received treatment before he developed any symptoms
at three weeks of life.
And you can see here at 10 months that he sitting,
and at 26 months Sidi's actually taking steps.
These are motor milestones that would have never
been anticipated for this boy.
So this is really a remarkable result
for this individual patient.
But unfortunately, as we gain experience
with these treatments, we realize that they're not
as this efficacious in all patients.
The therapeutic effect actually is quite variable,
with some patients having really marked improvements
in motor milestones and others showing almost no benefit.
There are probably many factors
that underlie this variability,
and we need to understand all of these factors,
but one of them is that there is clearly
an effect of the timing of treatment.
When treatment is delivered very early,
very soon after birth, there can be a marked improvement
in motor milestone achievement.
Whereas when drug is delivered later in disease,
the benefits can be quite modest.
But we've been interested in the last several years
about really what is the cellular molecular biology
that underlies this variable treatment effect.
It's been understood really, since 1891 when Werdnig
first described this disease,
that the ventral roots are very thin
in SMA babies and children.
The ventral root is where the motor neuron axon
exits the spinal cord on its way to the muscle.
You can see here a picture of a spinal cord
that we dissected at the time of autopsy
in a child who died of SMA.
And you can see the very thin ventral roots,
almost looking like a thread in this baby with the disease.
When you look at those ventral roots and cross section
and compare their size between a control child
and two babies with SMA,
you can see the marked diminution in size
in the SMA children.
But what is the cellular basis for the smallness
of these SMA ventral roots?
We've really undertaken a reverse translation study
where we've integrated our understanding
of the human disease and study of human tissues,
together with basic models of the disease,
including mouse and cellular models in order to understand
this process better.
And here in schematic form,
I summarize a lot of work in recent years,
that's taught us that in fact what is happening
to SMA motor axons,
is that many of them are not developing normally
in the first place.
You can see here that in utero,
during fetal stages of development,
motor axons are very, very small,
they're clustered in these bundles of a budding axons
with a few immature Schwann cells surrounding them.
But these axons have to grow enormously
during the course of development in radial diameter
and become myelinated, so that they can deconduct rapidly.
What we see in SMA both in humans and in mouse models,
is that during, in utero fetal development,
there's impairment in the growth of many of these axons.
And thus, they persist in this very small size.
And then after birth,
those axons that don't develop normally that are retarded
in their development, die very, very quickly
in the days following burst,
as you can see here in the red.
And when these axons die,
they release a cytoskeletal protein from the neurons,
what we call neurofilament.
And importantly, this data not only is teaching us
about the basic cellular biology of the disease,
but it's provided us with an opportunity
to develop a biomarker.
We can actually measure using highly sensitive techniques,
neurofilament protein levels in the peripheral blood.
And you can see here in mouse models of the disease
that there's a spike in neurofilament release,
right after birth in the mouse model.
And we can also see this in human patients.
This provides us a very important opportunity
to be able to monitor the neurodegenerative events
in SMA patients, in order to optimize treatment.
So, the urgency of treatment,
has led to a very practical change in how we think
about diagnosing SMA patients.
Traditionally, patients were not diagnosed
until they were overtly symptomatic
at which point genetic testing might be obtained.
But now it's been recognized that because
we have effective treatment that's most effective
when delivered earliest,
we now are advocating population-wide newborn screening
for this disease.
And this is occurring in the United States,
where each state is now enacting newborn screening,
and also in other countries around the world.
In studies recently published in Australia and Germany,
you can see that the time from neonatal diagnosis
to drug delivery, is 26 and 24 days.
And in many ways, this is quite quick,
this represents three to four weeks,
but unfortunately for those most severely affected patients,
this time delay may even be suboptimal.
In that it was clear in these studies that some patients
have become overtly symptomatic in this time interval,
and would have benefited from earlier therapy.
One of the things that does delay treatment in some cases
is the drug cost.
Both of these drugs, both nusinersen Spinraza,
as well as Zolgensma are very expensive.
And these are quotes from two newspaper articles
that were published at the time,
that each of these drugs were approved.
And it's clear that we need to think carefully
about these drug costs and how they're influencing
our clinical care, and ways in which we might reduce cost.
So, just to conclude, we're on the verge of three FDA
approved gene targeting therapeutics,
for this motor neuron disease SMA,
but we have much to do, much at the basic research level
and much at the translational level,
to optimize our therapeutics
and develop complimentary treatments.
But importantly, continually to advance treatment
in SMA will also provide critical insights
for other neurogenetic disorders
and allow us to apply these therapeutic platforms
more widely.
And I'll just end by the slide that acknowledges
to my own research laboratory and the many collaborators
with whom we work, as well as to the many patients
and families with whom we've interacted,
and who so generously provided human tissues
at the time of autopsy.
And happy to take any questions if there's time.
Thank you.
>> Great, thank you very much.
Due to time, we'll just keep it limited to one question.
So, Orla she had asked what has been the success rate of,
so don't get, I can't pronounce it,
Zolgensma?
>> Dr. Charlotte: Zolgensma yes.
>> And how did scientists overcome
the usual rejection response to the viral vector
when delivering it?
>> Dr. Charlotte: I'll start with
the second question perhaps.
So infants that have preexisting antibodies to AAV9
are currently excluded from treatment, with Zolgensma.
So once you've been treated with Zolgensma,
you uniformly develop antibodies to AAV9
and thus cannot be redosed with AAV9.
So that's an important caveat of that treatment.
The drug currently as I mentioned,
only FDA approved for children two years and less.
It's not available to older patients,
whereas nusinersen Spinraza is available
to the patients of any age.
So, you know, in answering the treatment success,
you know, it can be like the other,
like nusinersen Spinraza can be very impressive
in terms of its treatment effects,
but if delivered later is much less so.
There's much more we could talk about on that,
but I'll just leave it at that for the sake of time.
>> Okay, thank you well...