Good evening, everyone. Thank you so much for joining us tonight for Inner Ear Gene
Therapy Recent Advances and Clinical Perspectives with Dr. Lukas Landegger. Thank you so much,
doctor, for joining us tonight. We appreciate it.
Before we get started, I want to say thank you to Darcy Kriens of Alternative Communication
Services for providing CART tonight. Everyone should have captions available right now,
if you click the closed caption button at the bottom of the screen, it should turn green
and you should see captions.
Tonight, you can hit the raise hand button if you have a comment or question, but I would
really prefer that you use the Q & A if you have a comment or question for me, and that's
the same place where you can pose a question to Dr. Landegger at the end of his presentation,
and I will post those questions verbally to him so that becomes part of our CART transcript.
Dr. Landegger earned his medical degree from the Medical University of Innsbruck in Austria.
He served as a military doctor in the Austrian Army. He joined the Molecular Neuro otology
Biotechnology Laboratory at Mass Eye and Ear in 2013.
Two days ago, Dr. Landegger completed the Boston Marathon, so I'm anxious to hear more
about that and I would not even be walking if I did that two days ago, but I'm really
glad that you're here alive and well and you finished, and I can't wait to hear about that,
too. So go ahead, and I'll let you get started.
>> LUKAS LANDEGGER: First of all, good evening. Thank you so much to everybody involved in
the organization of this talk. Thanks to the Hearing Loss Association of America for giving
me this platform. While I was preparing this talk, I kind of really had to figure out who
the audience was, and so primarily it will be patients from my understanding, however,
there will be some professionals in the audience as well, so what I try to do with these slides
is that I have a lot of information in the slides themselves. However, I really try to
walk the patients through it and highlight some of the most important information in
red so that the professionals can kind of follow up on this information and kind of
go through the primary sources, so go to all these papers that are mentioned on the slides.
I still want to give guidance to the patients, so as patients don't be overwhelmed by the
slides. I really will try to walk you through it step by step.
In this talk I'll try to present, obviously, inner ear gene therapy studies that have been
done here in our lab and other labs around the world. We'll try to just present some
of these most recent advances and give you an idea where we stand and when these potentially
could become available for clinical use. So to give you an overview of the talk we'll
first start with the definition of hearing loss and what the current standard of treatment
is. Then we will talk about inner ear gene therapy or gene therapy in general. Then we'll
briefly discuss different approaches and how genes could be targeted, primarily viral vectors
but also CRISPR Cas9. Some of them might have heard about the gene scissors that have been
mentioned in a lot of newspapers recently. We'll discuss certainly mouse models that
have been rescued, so mouse models of human disease that can be rescued with gene therapy,
and we'll briefly talk about stabilization of cells versus restoration of cells, which
is particularly important for age related hearing loss. The last part is what are the
hurdles on the way to the clinic as we said. Hearing loss, as we all know not as we all
know, but we know it's a big problem and it's the most common sensory deficit in humans.
Just last month the World Health Organization released a fact sheet on deafness and hearing
loss, and these numbers are really incredible if you haven't seen them before the estimate
is over 5% of the world's population has disabling hearing loss, and this number is expected
to basically double up until 2050 with about 900 million people being affected then. In
addition to that, about 1.1 billion young people are at risk of hearing loss.
And the reason for hearing loss are multifold, and can include genetic causes, complications
at birth, infectious diseases and ear infections, certain drugs especially chemo-therapeutic
drugs such as cisplatin or aminoglycosides which are certain types of antibiotics, noise,
aging, et cetera. An overview of how many patients are affected per life decade, you
see newborns at about 0.2%, school children goes to about 0.4% and then 16% in over 18
year olds, 34% in 65 to 69 year olds, and eventually we go up to 72% in octogenarians,
which is really remarkable. To understand hearing loss, we have to first
understand how hearing works in general. We have sound that comes in through the external
auditory canal, hits the eardrum, and the sound is then transmitted through the ossicles,
the smallest bones in the human body, to the fluid filled inner ear, specifically the stapes
or stirrup, that's the smallest one in the human body and connects to this oval window,
and then a fluid wave is created, but it's mechanical transduction and kind of tilts
or deflects the hairs of certain cell types that are called hair cells.
Once these hair cells or these hairs deflect, the stimulus is changed from a mechanical
stimulus to an electrical stimulus, and that electrical stimulus is then forwarded by the
auditory nerve to the brain where we then actually hear.
In this schematic, you see the cochlea where we hear, which is the snail shaped structure
here, and then we also have the vestibular part of the human inner ear that is responsible
like is the balance part of the human inner ear and you see the semicircular canals here
important for rotational movements, and we can see the utricle and saccule, altogether
five organs. They're responsible for acceleratory movements, either horizontally or vertically.
Then we can, based on where the hearing loss occurs, we can divide these types of hearing
loss into either conductive or sensorineural hearing loss.
Conductive loss means everything to this oval window here basically. So all the bones and
canal, et cetera, and we have multiple treatment options for that. However, the sensorineural
part of the system, the cochlea or inner ear and auditory nerve, right now it's basically
just the cochlear implant, although it's a really remarkable device and we'll talk about
the kind of a lot of pros, but the few things that are not perfect yet regarding this device
later in the talk. Another thing that could be used is an auditory
brainstem implant in case the nerve is missing, but we won't really talk about that in this
presentation. So the current treatment options are hearing aids. You're all familiar with
those and what they do. There's a lot of models, but we won't talk about this in this presentation.
Basically they simply amplify sound. Then we can change the sound transmission
itself and here so called middle ear prostheses or middle ear active implants are important
because for example, if we miss the ossicles, we can replace them by titanium prostheses,
so it's relatively straightforward, or these middle ear active implants.
What they do is they have a little microphone here behind the ear, and this microphone detects
all the frequencies that come in and then filters these frequencies and you have a little
magnet in the middle ear that attaches to the ossicles. And through the different frequencies
that are detected, the number of vibrations or kind of the vibration intensity itself
is determined, and that can then, again, facilitate hearing.
Then cochlear implants, you might have heard about them or even have one of them, and they're
really remarkable devices. What you have is, again, this outside microphone that detects
the different frequencies, and instead of manipulating the ossicles, what this device
does is that you have a coil that goes into the snail shaped structure, so into the cochlea,
and this device has certain outlets where you can kind of shoot electricity out that
directly stimulates the auditory nerve, and so you kind of circumvent these hair cells
that usually make the transition from the mechanical stimulus to the electrical stimulus.
It's really great that this actually works. What is gene therapy? So the idea is that
you kind of introduce normal genes into cells, and with those you can then replace missing
or defective genes so that the cells work again as they should. There's about 100 genes
that cause non-syndromic hearing loss that could potentially be targeted with gene therapy.
When we compare our field - the field of ENT, you know, ears nose and throat, to ophthalmology
it's relative sad because right now there's about 30 gene therapy trials for 10 diseases
of the retina (so the structure in the back of the eye); however, there's only one for
severe to profound hearing loss going on. The ophthalmologists already have one drug
FDA approved since December of 2017. So we really have to catch up in this way.
This is an image that shows how a virus transduces a cell, so how a virus gets taken up by a
cell. This is an adenovirus. Most of the talk is about an adeno associated virus, which
is a relatively similar virus, and the main difference is with adenovirus you can cause
a transient expression of the gene, with adeno associated virus usually the gene you want
to replace stays there pretty much until the cell dies, so pretty much forever. At least
that's the assumption right now - at the moment we don't really have the data in clinical
trials that show how long. There have been studies that have shown this expression for
several years over the decades. And this adenovirus attaches to the cell and
is taken up by the cell, and the virus itself cannot replicate or double itself basically
so what it needs is the machinery of the cell to actually kind of – yeah, replicate itself.
So what it does is that it delivers the gene that it has been loaded with into the inner
part of the cell, and then the effects take place that we could then potentially use for
the gene therapy. So what we briefly have to talk about genetics
as well, because those have implications for therapy, and so basically every human gets
one gene, so it has two copies of a certain gene. And one is received by the mother, and
the other one is received by the father. And if just one of those two has to be affected,
then we are talking about a dominant disease. So one of the two has to be affected so that
the patient has the disease, and then it's a dominant disease. However, if both have
to be affected, then it's a recessive disease. So dominant would mean my father gives me
a faulty gene, my mother gives me a healthy one = disease. Recessive disease means both
my mother and my father have to give me the faulty gene, so I have the disease. That is
important because that means how we can or that playing a role regarding how we can treat
these diseases. So the simple gene addition would be relevant
for a recessive disease, because in recessive cases, as we've just discussed, we basically
have no functioning gene, and so the delivery of a copy of a normal gene could then just
kind of make the cell function again. That's what has been done in most animal studies
so far. However, in a dominant case we can also use
so called gene we cannot use the gene addition therapy or strategy, but here we'd have to
use a gene disruption therapy because here we have this dominant gene that will independently
if there's a normal copy will still produce the faulty kind of protein, the faulty mechanism,
and so we kind of have to target that somehow. So by targeting that, the remaining gene can
then take over. And the last part is the gene editing part
where with a recessive or dominant missing, that's a completely irrelevant mutation. If
you have a minor part affected, you can then use a so called CRISPR Cas9, so the gene scissors,
again, to replace that specific part of the gene. The functional gene addition is also
something that we'll skip for this talk. So how would the gene therapy work specifically
for the inner ear? Well, we've talked about like how the hearing works, and so if we cut
a piece of the cochlea out here and look into it, then we see three fluid filled chambers.
The names are irrelevant, but in the scala media, we have the inner hair cells and three
rows of outer hair cells. One row of inners and three rows of outers. The inner hair cells
make this transition from the mechanical stimulus to the electrical stimulus, while these outer
hair cells have more of an amplifying function. And in one human ear we have about 15,000
hair cells, and it's the same cell type in the vestibular system, so the five organs
we discussed before with the utricle and et cetera. All of these have these stereocilia
on top and the hairs give them their characteristic look and name and we'll see a few pictures
afterwards. What's interesting in birds, for example,
these cells regenerate without any problems, while in mammals including humans they don't.
There's just one exception. In 2014 researchers found out in neonatal mice, newborn mice,
some of these hair cells do regenerate, and here supporting cells come into play. We'll
talk about them later. Those are the cells right next to the hair cells here.
And one potential surgical approach for gene therapy is the round window here. That's also
the place where usually the cochlear implant is introduced, at least nowadays is introduced.
So that would be a relatively straightforward process for the injection.
We've talked about the success story of the cochlear implant that has really enabled so
many patients to actually learn language and everything without any problems, however,
there's still some issues, namely the natural sound perception (so sound perception in general
is not that great), frequency sensitivity (enjoying music, for example, is relatively
hard), and speech discrimination in noisy environments. In a bar, for example, with
a lot of background noise, it's really hard with these devices to actually filter out
that one voice. The goal of gene therapy is to kind of restore natural hearing.
And this is the mouse inner ear, the mouse cochlea. It's relatively similar to the human
ear. We have the turns up here where we hear with the hair cells, and we have the oval
window here and the round window that could be used for gene therapy and is being used
for gene therapy by a lot of groups. It's right here. I'm sorry, I'm just trying to
remove this bar here from my screen. Okay. So the first study that I'm trying to
or I'll present is the VGLUT3 study, and it's one of the first rescue studies in mouse models.
This VGLUT3 is a receptor in inner hair cells and that's what we discussed in the last few
slides. It's right there at the connection between inner hair cells and the auditory
nerve. Mice lacking this transporter are actually
deaf, and it's only relevant in a few human patients but what makes this model interesting
or what made these models interesting is these adeno associated viruses that I mentioned
before actually specifically target these inner hair cells, so that's what needed here.
What's a relevant fact is these mice in general usually develop hearing around two weeks after
birth, whereas, humans are born with hearing. So that is interesting in terms of timing
afterwards because potentially that would mean that if a mouse is injected immediately
after birth, in humans we have to go into the womb or like the baby would have to be
injected in the womb. And if we see that these mouse pups who are
lacking the transporter are injected with VGLUT3, then they actually did not go deaf.
So this is a slide that or a figure that will be used in several of these studies, and what
you can see here on this Y axis is the loudness level. Down here it's like a whisper basically,
and up here it's like if a jet engine would start right next to you, so very loud.
These curves that you can observe are functions of basically an objective hearing test, so
once you see the curve, you can tell that the mouse heard that. You can see in wild
type mice, regular mice, healthy mice, we have these curves somewhere around here. In
knockout mice, the mice affected by this disease where the transporter is not there, we don't
have any response at all, so those are basically deaf. In these rescued animals where the VGLUT3
was injected with a virus, we can actually get responses again. It means that these mice
heard because the VGLUT3, the specific transporter, was introduced into the inner hair cells,
and in a different way that is depicted here, you can see 95 decibels is really, really
loud - no response at all while the wild type animals and the injected animals are actually
pretty good. So that was a really remarkable paper that came out in 2012.
What other functional rescue studies have there been? Quite a few published in the last
few years. However, what is common or what is like the same in all of them is that they
all talk about the inner hair cells and outer hair cells are really hard to target and you
can see that in these images where you can appreciate that all of these viruses kind
of just target the inner hair cells while the three rows of outer share cells that should
be out here somewhere remain dark. What is that dark part? So everything that's green
lights up with so the lighting up means that it's GFP, green fluorescent protein. If a
virus transduces a cell, gets into a cell, you can tell what it expresses, and basically
it expresses this green fluorescent protein and then the cell lights up. That is something
that researchers can use to determine where the vector goes.
For the rest of the talk, you can remember green cells are good, because that means that
the virus got into the cell, and we could potentially deliver something into the cell
including the healthy gene. So in this 2011 study, you can see that they tried five different
serotypes, and for all these adeno associated viruses, these inner hair cells were the most
effectively transduced cochlea cell types. So it's good that it worked in this specific
disease model before, but the difficulty is to get these outer ear hair cells I mentioned
before. Here a virologist comes into play, Luk Vandenberghe
and the institute affiliated with it comes into play. His lab looked at a computer model,
synthetic AAV, so they looked at the predicted ancestor of adeno associated virus types 1,
2, 8, and 9 and those are commonly used viruses. What they were looking for was that ancestor
because everybody has had a cold, and this adenovirus is actually the common cold virus.
The adenovirus and adeno associated viruses are relatively similar, so our immune system
actually recognizes the similarities and neutralizes some of these adeno associated viruses immediately
before they can target the cells they should target.
His lab hypothesized that this novel ancestor, predicted ancestor could actually circumvent
this pre existing immunity. They did a lot of high throughput screening, in vitro, in
vitro means in the petrie dish, and injected them into mice. So you can see AAV2, AAV8,
so these conventional adeno associated viruses in these columns, and Anc80 is the new virus
and you can see expression in the liver, muscle and retina, and Anc80 seems to outperform
all these other conventional adeno associated viruses.
But nobody had tried that in the ear, so we did that in the ear and we tried it on something
called cochlear explants. These are like microdissections of these mouse inner ears, and we can grow
them and culture and add certain viruses or whatever we want to them and see what they
do. Then in red, you can see hair cells, so a
specific hair cell marker. In blue you see a marker for neural structures, and in green
we have, again, this GFP, so the green fluorescent protein, which means that the virus went there.
Every column here represents one of the conventional viruses, and here the last two columns on
the right are Anc80, so that's this new virus. What you can see is that Anc80, so this new
adeno associated virus, really outperforms all of the other adeno associated viruses,
and we were very happy when we saw that for the first time. Specifically, it was not only
at the level of inner hair cells but also outer hair cells and supporting cells. I'll
show that to you in a few slides later. You can see that these micro-dissections are
really tiny, so it's really my thumb next to it. You see these white, little dots, those
are the explants. So mouse inner ears are not really very big. We then also tried this
together with or this work was primarily done in Jeff Holt's lab at Harvard Medical School.
They injected mice with the virus, the most promising vectors we identified in vitro in
the Petri dish. Anc80 still outperforms all the conventional viruses. They did a bunch
of studies regarding how the uptake of the virus would change the cells, and it was normal
in terms of how the cells reacted and how these animals then heard and then had these
objective hearing tests in a way. Again, for you to appreciate how tiny everything is,
we have a mouse pup here, and that's where you the injections then take place, so you
have to expose the round window back there. It takes about 10 minutes per pup once you
establish the approach. Some more images of this GFP expression. You
see along the whole length of the cochlea, we get a lot of viral expression in inner
hair cells and also the outer hair cells that could not be reached with the conventional
adeno associated viruses are finally transduced with Anc80 with a maximum follow up up to
a month and the expression was stable which was interesting because mice live between
2 to 3 years, something like that. It depends on the strain. So a month is a pretty substantial
amount of time. With the in vivo injections we showed that
from the very apex or the very top of the cochlea up until the very base of the cochlea,
so up all the way to the bottom of the cochlea, so throughout the cochlea we had a lot of
expression of this virus, which is very promising, and it was so strong that we sometimes even
saw it on the other side of the ear. Then we were wondering, how does it actually get
there? For that we used brain slices of the mice, so we cut the brain like this. You can
see the A here, so the section is called an axial section with this human head. For the
mouse in front here, we have the snout while here we have the cerebellum, which is the
posterior part of the brain back here. You can see that this is where we get the predominant
GFP expressions of green fluorescent protein expression, and you can see that these cells
here take it up, and so what we think is what happened is that the virus travels to the
other side through a structure that's called the cochlear aqueduct, which is a connection
between the fluid of the inner ear and the cerebrospinal fluid - that's the fluid where
the brain and spinal column kind of swims in it. That is actually known in rodents that
this is relatively patent, so we have to figure out how far that is translatable to larger
animals, because that would be another hurdle until it goes into clinic because you want
to avoid that it actually goes into the brain. We also looked at the vestibular system and
what you see in mouse tissue that we get a lot of green cells, so it's very positive
- we can actually reach them and what's very interesting is it was done by collaborators
in London, we also got it into human tissue. In some surgeries you actually have go through
the inner ear, and what they do in this case or to resect certain tumors you have to go
through the inner ear and you can get access to the precious human tissue. You see that
we have this excellent expression also in human tissue, so it seems to be a promising
candidate for clinical studies. Excuse me. This is another study that used Anc80 in adult
animals. In 7 week old animals they were injected through the posterior semicircular canal.
That could be an approach used in humans, specifically the lateral semicircular canal
that seems to be accessible. What you can see here is that, again, in these
adult animals that couldn't really be transduced at all until now with this new virus, you
get a lot of outer hair cells at the apex, not so much at the base (not so much at the
bottom of the cochlea). Still relatively promising. Other collaborators at the Harvard Medical
School used this virus in a model of Usher syndrome. That was Holt's group and Géléoc's
group. What Usher syndrome is, it's the leading cause of deaf blindness and is inherited recessively.
Both genes have to be affected then. What you can see in this figure is that it's a
scanning electron micrograph, so it's the highest resolution of the the highest resolution
of basically the common microscopes that you can see.
What you can see on the left side here is a wild type animal, so a healthy animal. What
you see in the middle is a diseased animal, so that's an animal with Usher syndrome. What
you see on the right side here is an animal that has been injected with this Anc80 that
had had protein that is missing had this gene that is missing in these animals, and you
can see that the hairs to the stereocilia that give the hair cells their name, are really
similar to these wild type healthy cells compared to the Usher cells.
So that was really remarkable these cells could be rescued to such an extent. They performed
many additional experiments and specifically performed these hearing tests, objective hearing
tests again and what you can see here is that the control animal, so the Usher animal with
the disease, did not show any thresholds at all with the hearing, so the louder it gets,
deaf animals no responses, while here on the right side - the animals that were injected
did actually have relatively nice hearing. For some of them the hearing was as good as
for wild type animals, as for healthy animals. Several other studies have come out since
then and like before them or around the same time, and you they targeted different Usher
models, so there's a lot of different subtypes. They all showed most of them showed rescue,
however, none of them was as substantial as with this novel virus presumably because the
standard adeno associated viruses did not target, or cannot target, the outer hair cells.
Are there any other approaches that allow viruses to target more hair cells? Yes.
Another lab here at Harvard is working on something called exosomes. They're small vesicles,
and for patients I would describe them as "bubbles filled with information" and
secreted from cells. They enable communication between cells. These other cells then take
exosomes up to process it, and these viruses have hijacked this approach to actually get
into the cells more easily. What this lab is doing now, and a very clever
strategy, is they package these conventional adeno associated viruses into these exosomes
and can target more cells with this approach. Then this CRISPR Cas9, these gene scissors
that we briefly had mentioned before, in a very interesting study that was published
at the end of the last year, they looked at they had a mouse model that lacked Tmc1. That's
something I'll explain in a minute. I want to show you this here in this frog
hair cell you see these stereocilia, so the "hairs" of the hair cells. What you can
see here is something called tip links. These are the little bridges between the "hairs"
of the hair cells and this Tmc1 and this transmembrane channel-like gene family 1 is part of this
gene complex here that is important to cause the kind of or the movement of these hair
bundles. In 2002 a study group created a mouse with a TMC mutation, and it showed that it
led to slow degeneration of the hair cells. They named this mouse Beethoven mouse, which
is not a great name because the composer had a completely different type of deafness. This
mutation is also relevant to humans and has been described in a Chinese family.
What these researchers did is they injected so called Beethoven mouse pups and compared
them to controls and this protein RNA complex, so CRISPR Cas9, targets only the affected
copy of the gene without influencing the other gene. If we can get the affected copy of the
gene, the diseased copy of the gene kind of out of the way, then in theory the normal
gene should take over and the cell should be functioning again. That's what these researchers
hypothesized. What you can see here on the right side, so
again, we have inner hair cells here, and then three rows of outer hair cells out here
all along the length of the cochlea. On the right side you see all the cells are still
viable, while here on the left side the uninjected animals, so these Beethoven mice, do have
degeneration at the lower part of the cochlea or the apex (or the top) is kind of still
there. Then these injected animals actually have preserved cells all throughout the cochlea.
So it was a substantial rescue after the injection. Then the researchers obviously again assessed
the hearing, and what you can see here, again, loudness on the Y axis - so loudest level
up here, very quiet level down here. What you can see is that these injected animals
actually heard better than the uninjected animals - deaf in some frequencies at least.
However, the rescue was not as good as for the uninjected animals, healthy animals. However,
this study is really proof of concept that this gene disruption be might be a potential
strategy of treatments of some form of this dominant hearing loss.
So far we only talked about stabilization. What about restoration actually? That is a
different an interesting difference between genetic hearing loss and age related hearing
loss because for age related hearing loss, we probably need a mix of gene therapy, molecular
therapy and stem cell therapy or just focus on yeah, there's a lot of overlap between
the three fields. As I said before in some of these newborn
mice, it is actually possible to make a transition from the supporting cells to hair cells, some
of these mice still regenerate hair cells. And usually that's through the switch of supporting
cells into hair cells, and that's been studied extensively and several different signaling
pathways have been identified by researchers all over the world.
In a relatively recent paper -- and that is lost after like the maturation of the mice
- so in adult mice, you cannot transition supporting cells to hair cells anymore. However,
in a relatively recent paper that also came out last year, a group actually tried to combine
several of these factors, and then was able to make the switch from supporting cells to
hair cells, so you can see here in blue the hair cells, the inner hair cells and three
rows of outer hair cells and here after noise damage they would be lost and could be regenerated
after the mix of different factors. So this group shows that for the first time in adult
animals, which is very relevant for age related hearing loss. The only clinical study at the
moment that targets or that is focused on gene therapy in the inner ear that I mentioned
before is actually targeting ATOH1. That's a study that the lead investigator,
the principal investigator is Hinrich Staecker in Kansas, but they also have sites at Johns
Hopkins in Baltimore and at Columbia in New York.
So to summarize, gene therapy is a potential solution to restore kind of natural hearing
and hopefully millions of people affected by this hearing loss, especially hereditary
hearing loss. Anc80 seems to be potent viral vector for cochlear gene therapy and several
mouse models that could be rescued and the best results for the major deafness genes
at the moment seem to be achieved with Anc80, because with Anc80 you can also reach the
outer hair cells and not just the inner hair cells.
Gene editing with CRISPR Cas9 is feasible as this last study showed that was published
at the end of last year, but now the really important part for the patient and also for
the physicians that are confronted with these questions all the time: "What are the hurdles
on the way to the clinic?" As we saw in the mouse model with the expression
in the cerebellum (so in the brain) - it's really necessary that there are studies in
larger animal models, specifically for dosing, because the inner ear is so much bigger in
larger animals and humans compared to mice, and also the safety issues that I mentioned
before. It's kind of the last step prior to starting multiple independent human experiments.
And what was interesting in the study that also came out last year was that a group showed
that they could actually inject a sufficient volume into the inner ears of rhesus monkeys
without worsening this objective hearing. They have these ABRs where they can then detect
the wave forms and see if the animal heard it or not.
I recently was attending a talk by an investigator working in ophthalmology, and he said that
the vector correlation, vector result correlation, is under 30% between mice and humans, while
it's over 75% between monkeys and humans. You can really see the result.
Like, I'm also not a big fan of large animal experiments, but if you look at these results,
then it really seems to be necessary to have a larger animal model to be sure that what
goes into human studies that is, yeah, associated with so much like risk, et cetera, can actually
work and in vivo as well and humans as well. Another question is can you specifically target
certain cell types? A way to do that is to give the vectors a kind of a different key.
This key is called promoter scientifically, because for some diseases you just want to
target inner hair cells for some diseases and you want to target outer hair cells for
some diseases and you want to target neuronal structures. If you have the keys for all the
different cell types, it's nice to be able to kind of customize a treatment for every
patient. For these adeno associated virus vectors,
the size of the gene you can actually put into them, there are some approaches to try
to circumvent that problem. Excuse me. Try to circumvent the problem with very promising
results that haven't been published yet, but I heard somebody talk about it the other day
at a conference. Yeah, there's several options that hopefully can avoid this issue. And then
the time window is another very important thing that I was talking about.
The degeneration of cells progresses in several animal models or in many animal and human
models, human diseases. So the question is, do you really have to treat patients in the
womb, or is it sufficient to kind of do it after birth? Would the results be better in
the womb, and if it has to be in the womb it's associated with a lot of risks and it's
really, really tricky to actually get that into the inner ear.
Then also the treatment of age related hearing loss. Are these results from the one mouse
study actually translatable, and what are the results from this multi centered trial
I mentioned before beyond the gene therapy trial in humans at the moment. And what's
really exciting is most gene therapy labs have now ordered this virus, and we really
hope to accelerate the translational research, and then there's several more applications
where definitely more research is necessary. And with that, I'd like to thank all the collaborators
that have worked with us on gene therapy projects and all our funding agencies and as Nancy
said, I did run the Boston Marathon two days ago, and it was really horrible weather. If
you want to support our research, then you still have time until April 30th if you click
on that link you can read some more about me and why I decided to kind of try this marathon.
It was my first marathon. Yeah, I finished it. I was very happy with
the time as well for these conditions, and thanks a lot for your attention. I'm happy
to answer any questions. >> NANCY MACKLIN: Congratulations on that.
There are a few questions that have come in that are very interesting. Your presentation
was very interesting. It provides so much hope, so promising, this research. Lauren
said, if you get a cochlear implant, are you not a potential candidate for gene therapy?
>> LUKAS LANDEGGER: That is an excellent question, and that was also a big discussion about,
yeah, 20 years ago or so. I wasn't part of that discussion, obviously, but back then
people started to implant both ears, so in Europe so primarily the first candidates only
received one sided cochlear implants, and then about 20 years ago or so in Europe primarily
they started to implant both sides of the both ears of the patient.
When that first started, then some researchers said this is madness, and you have to preserve
one ear for gene therapy. Then the surgeons asked, well, when will it be ready? Then they
said, yeah, the maximum is five years or so. That was 20 years ago. It's really hard to
make like any predictions when it will be ready, so I am not sure how many questions
I answered there, because that's usually a standard question that I get.
>> NANCY MACKLIN: Right. >> LUKAS LANDEGGER: Typically if there is
a cochlear implant in place in that ear, you'd rather not inject it at the moment at least.
However, in the future if there still are these supporting cells left, then potentially
if these approaches worked to really make the switch from supporting cell to hair cell,
and then potentially they might be candidates, but it's a tricky question to answer.
You look at the so in the slides I also posted the link to this current gene therapy trial,
and the criteria for the patient selection are very strict. In the first studies you
really have to determine what works in a very small patient pool, and then if it works in
those patients, then you can kind of expand it and try to include more patients.
>> NANCY MACKLIN: I think that's probably several people in the audience that would
like to just become in the clinical trial right now. Go from mouse to humans.
>> LUKAS LANDEGGER: Also after the big paper was published with the virus, I received a
lot of e mails and all the collaborators received a lot of e mails. People really appreciated
that people are willing to really participate in these trials, and hopefully we will be
there soon. Right now, unfortunately, there's only this one trial with very limited criteria.
You can definitely check out the website and see if you are a candidate for this.
>> NANCY MACKLIN: Okay. So we've identified about 100 genes associated with hearing loss.
Do these genes include both inner and outer hair cell information?
>> LUKAS LANDEGGER: It depends. It really depends on the disease. So, as I said, this
VGLUT3 is a specific inner ear hair cell problem, and that's why they fixed it with the AAVs
and they target it. However, a lot of diseases affect both inner and outer hair cells in
that these conventional vectors seem not to work so well. That's why this new vector seems
to be better specifically for these diseases for the animal models.
>> NANCY MACKLIN: Tony asked, he said, I have hereditary hearing loss on my father's side.
I'm considering getting genetic testing to identify the genes responsible for my hearing
loss. Do you think getting the tests could be beneficial at this time?
>> LUKAS LANDEGGER: I mean, it might be beneficial in terms of the prognosis for him. I mean,
that's personally, because based on the gene that's affected, it might tell you how will
I hear in like ten years? How will I hear in 15 years and so on? You can kind of see
it from the father's side already. Yeah, it's tricky to like say anything about it without
seeing the patient, and I haven't my clinical training is very limited at this point, so
I still have to finish my residency and so on. So I'm kind of hesitant to answer this
question and would rather recommend seeing somebody who really has experience with hearing
and genetics in the human background and geneticists, specifically, like genetic counseling.
>> NANCY MACKLIN: Fair enough. John says, it is my understanding that for people who
have lost hearing over a period of decades that changes have taken place in the brain.
For example, reduction of volume of gray matter in the cortex. If you are successful in restoring
hair cells, will the changes in the brain gradually be reversed?
>> LUKAS LANDEGGER: That is an excellent question as well. The question regarding tinnitus,
for example, the ringing in the ears and what the current hypothesis of tinnitus basically
is, is that if there's not enough information coming in from the ears, then the kind of
central gain is just like amped up, and then the brain kind of creates this noise itself.
In tinnitus even if you cut the auditory nerve that connects the inner ear and brain, then
it still doesn't go away. So it's probably not something that's caused just by the inner
ear itself. Again, from a limited clinical experience, but in patients that receive hearing
aids, they usually do better with the tinnitus as well. So some of it might come back, but
I think if you really have had have not done anything about a hearing loss for decades,
then it might be hard to actually do something with this information that the brain all of
a sudden receives. >> NANCY MACKLIN: All right. Ken said, are
patients with Meniere's disease candidates for gene therapy? I understand the hair cells
die off in Meniere's patients. Do they regenerate? >> LUKAS LANDEGGER: That's also a good question.
We look at the vestibular system, so in some of the genetic diseases the vestibular function
is affected. So in these mouse studies, for example, all of these mice were dizzy as well.
So there's some very interesting tests that you can do with mice to figure out whether
they're dizzy. You can kind of film them from the top of the cage and see how they run,
or you can put them on a rotating rod called the rotarod and determine how long they stay
on top of the rod. Or have them swim and see if they can keep the head out of the water.
With this regeneration in Usher mouse models and others, the vestibular function was it
was like restored as well. However, in these mouse models the hair cells
kind of were still in there, and it was just a gene that was lacking. The gene was lacking
and reintroduced with this viral vector. If the hair cells are gone, the vestibular
hair cells are gone, it will be relatively hard at the moment to kind of grow them back.
However, also in the vestibular system you have supporting cells that could regrow into
the hair cells in the future. I mean, I'm not we're not talking about years here. It's
decades probably if I'd have to say anything about a timeline. So, yeah. Tricky.
>> NANCY MACKLIN: Okay. Katherine said, can you talk about the role of deteriorated brain
pathways in people with long term loss? Would they be eligible for gene therapy or regeneration?
>> LUKAS LANDEGGER: That's kind of question that I answered before where, yeah, it's kind
of the gain, et cetera. >> NANCY MACKLIN: Okay. Got it. Is effectiveness
of Anc80 versus AAVs specific to mouse inner ear, or are there similar studies on other
organs or organisms? >> Organs, yes. There are different studies,
so the initial paper I highlighted where they showed it in the liver, muscle and retina,
so everywhere there Anc80 seems to outperform the other AAVs. It's synthetic, so it's the
first of a class of synthetic AAVs, so in different organs it works. Regarding different
species, right now there's nothing published on that, whether it's translatable. That's
why we're so interested in having larger animal models not just for Anc80s but AAVs in general.
>> NANCY MACKLIN: Did male and female respond equal to the therapy? The females did much
better. >> LUKAS LANDEGGER: That's an excellent question,
and the NIH requires us to analyze male and female mice now because traditionally most
of the studies were carried out in male mice because they have fewer hormonal influences
that play a role in noise exposure in general. What we did for the in vivo studies is we
tested it in male and female mice. In vivo studies means the pups that were injected,
we tested the male and female mice for the so that was the same number, and pretty much
the same effect. For the in vitro studies, we don't know. At postnatal day four it's
really hard to differentiate the sex. We don't specifically look for that.
After a few weeks it's relatively easy to differentiate the sex in mice, but in the
very small mouse pups it's relatively hard. >> NANCY MACKLIN: Okay. Has a gene been identified
to explain cookie bite hearing loss? >> LUKAS LANDEGGER: I have to admit I'm not
familiar with cookie bite. >> NANCY MACKLIN: With that term? I'm not
either. >> LUKAS LANDEGGER: Like the shape of the
audiogram? >> NANCY MACKLIN: I believe so.
>> LUKAS LANDEGGER: Probably. Cookie bite hearing loss. Yes, that's the shape of the
audiogram. I'm not familiar with some of the clinical terms in English. This is not my
native language. That is a good question, and I'm, I mean,
I'm sure there are one of like one of the hundreds of genes or several of the hundreds
of genes have such a form, but I like it's hard to give you a diagnosis now just based
on this audiogram. So I don't think that that's possible.
>> NANCY MACKLIN: Okay. Would hearing loss due to meningitis be similar to that of age
related hearing loss discussed, or is that totally different?
>> LUKAS LANDEGGER: That is also a good question, and, yeah. So it depends what is like what
was inflamed. If there was actually a if the inflammation took part in the ear as well
or if it's just the not just, but if it's primarily the central parts that are affected.
If it is the central part, so the part of the brain where the processing of the signals
actually takes place, then I would say that it would be different than the well, I'm not
actually on this question, I'm not sure. I don't think I can answer this question.
I'm sorry. I have to pass on that. >> NANCY MACKLIN: Okay. All right. And last
question. Is the talk about hair cell regeneration in birds, mice, and fish applicable in nature
or just in research clinical trials? >> LUKAS LANDEGGER: No. For mice only in the
very, very neonatal mice. But for birds and fish, that's applicable in nature. So they
really regenerate their cells (their hair cells) constantly basically.
>> NANCY MACKLIN: Okay. Is there a reason for the lack of therapy trials? Is it strictly
because of funding, or you mentioned that in the very beginning.
>> LUKAS LANDEGGER: Right. That is a good question. I mean, the eye is just way more
accessible than the ear. The inner ear is kind of encapsulated in one of the hardest
bones in the human body and it's really tricky to deliver something there. In the eye you
can use a syringe and inject it in there. Yeah, it was just easier to kind of access
that, and then funding for blindness in general is or like hearing research is a relatively
small community in general, whereas the blindness foundations are definitely larger. So that
might have played a role as well. >> NANCY MACKLIN: Okay. And if you had to
guess, when would you think that there would be human clinical trials?
>> LUKAS LANDEGGER: There is already one human clinical trial.
>> NANCY MACKLIN: For the mass you know, for more people to get involved in the trials.
>> LUKAS LANDEGGER: So I don't think there will be clinical trials for like everybody
with deafness. It will be a clinical trial for a certain disease, for Usher syndrome
or that specific type for example with hearing data and so on. I'd really hope that we'd
have something to offer patients of like for at least like one specific syndrome within
the next two decades or so, but it's really hard to make these predictions. There's one
person from 20 years ago that said it would only take them five years to translate into
clinic. So you really have to be conservative there.
>> NANCY MACKLIN: It seems that the research is so promising and on the verge of great
discovery. I know everybody is anxious, and we definitely like to keep up on this topic.
So I welcome you to present again, even if it is from Europe or wherever you may land
from here. Thank you so much for doing the webinar. It was rather short notice, I know,
and you really did a great job. Thank you again to Darcy, who provided CART
tonight, and we'll look forward to seeing you next month when we talk about HLAA2018
in Minneapolis coming up in June. Good night, everybody, and thanks again.
>> LUKAS LANDEGGER: Good night. Thank you.
For more infomation >> Academy of Art University - W...
For more infomation >> Audi A1 1.4 TFSI Pro Line S - Duration: 1:09. 
For more infomation >> Audi A1 1.4 TFSI Pro Line S - Duration: 1:09. 
For more infomation >> Home Video 2 2 - Duration: 27:21. 
For more infomation >> 真相大白了！公正党候选人爆出真相来了！原来根本都不是他的错，都是他们在搞鬼？ - Duration: 11:21. 
For more infomation >> La famille secrète d'Avicii : sa compagne dévoile son bonheur brisé - Duration: 3:24. 
For more infomation >> PSG: Unai Emery annonce son départ - Duration: 1:30. 
For more infomation >> skribbl.io: Mal´n wa ma - Duration: 1:47:35. 
For more infomation >> STORYTELLING HIGH STRINGS ►NEW WAY◄ SYNTH FX STREET {FREE} Hip Hop Beat ☯️Sacred Beatz☯️ - Duration: 4:17. 
For more infomation >> Guam #11 The last day of Guam trip, United airline [#26] - Duration: 5:55. 
For more infomation >> 唱跳实力兼备！D七少年团《Red Alert》练习室版及翻唱音源公开 - Duration: 2:32. 
For more infomation >> কিলোগ্রাম - Duration: 14:45. 
For more infomation >> Affaire Jeremstar : Pascal Cardonna promet de nouvelles révélations sur Snapchat - Duration: 3:26. 
For more infomation >> Cette huile est miraculeuse : elle fait repousser les cheveux et les sourcils - France 365 - Duration: 8:40. 
For more infomation >> 《創造101》Sunnee神複製舞步！尬贏宇宙少女宣儀奪A - Duration: 3:15. 
No comments:
Post a Comment