Richard Lee – Landscape of Translational Research in Ocular Eye Disease

So Miles said I am a clinician I work in Bristol and London in
Moorfields also laboratory scientist and so I work in the field of what we call
Translational Medicine and my task today is to try and explain how translational
medicine works. I’m going to be talking about inflammatory eye diseases as a whole
so birdshot is a type of inflammatory eye disease but even uveitis is itself a
rare disease and its classified as an orphan indication for treatment by the
various drug regulatory authorities so I’m going to show what’s going on
internationally and various institutions and people who are involved in this sort
of research in inflammatory eye diseases, just to give a flavour in 10 to 15 minutes
and also show how we’re trying to contribute to that through government
funded programmes in the United Kingdom and after my talk there’s going to be a
session where the panel members of the speakers already seen will come up and
we’ll try and put that in the context of that Birdshot Chorioretinopathy, so when
we think about medical research we professionally tend to put the
research on this sort of spectrum we can actually play some of the talk you have
heard today against this diagram so basic research would typically be considered
to be some of the fundamental biology that tells us about how cells work and
we’ve we’ve heard of that in mitochondria and there are many examples
where basic understanding of the way the immune system works goes on to inform
what we do as clinical practitioners. Then we can refine some of those
concepts in a more clinically applicable way so we can think of them in the
context of specific diseases that we’ve been talking today about birdshot chorioretinopathy and there are wider efforts in the field of uveitis as a whole. If there is a new drug target that we
think could be beneficial so for example if ERAP is found to be very critical in the
biological mechanism of Birdshot and somebody finds a
way of modulating the function of the ERAP and that’s demonstrated in
preclinical studies we then go into early clinical trials and needs are what is called proof of
concept studies where a new agents new drug typically is considered and
evaluated in a small population of patients doctors know what patients are taking
patients know what they’re taking and we’re looking for early signals of
biological effects and we often don’t know which drug dose to use and at this point
it’s an early scoping exercise but if that proof of principle is
demonstrated we then can scale up by scaling up we tend to go to large
phase 3 trials as they are called which normally not undertaken by single institutions and at
this point the ball is often handed over from academia to large-scale
pharmaceutical companies and often run not only nationally internationally and it is the data from those later phase trials which then goes on to inform the regulators
about whether to license a drug for a particular indication so in this
circumstance so if we have got a new ERAP modulator that we think is going to help Birdshot we’ve done our proof of concept study, we have gone in to a late stage clinical trial we’ve managed to
get all the birdshotters internationally which is a great challenge in a rare
disease to participate in a phase 3 study and that data is then submitted to
regulators authorities in the united sates the FDA in Europe the EMA and they decide whether to license the drug and then then within each of our health care systems we then have to decide whether that licensed drug is going to be used and that means is it
affordable and cost effective and the way that’s applied varies
enormously internationally in the UK we speak to our commissioners NHS England and as Miles says there has been a dialogue with many professionals for a couple of years specifically around
some of the biologic therapies to try and presented the evidence as
favorable as possible to the commissioner to prove benefit and cost effectiveness
and so this is the spectrum that we work on but it’s quite simplifies and I
just put it in the paradigm of a new drug and this drug development but in
reality lot of what we heard today isn’t as simple as that someone doesn’t just come with
a concept and take it through that takes decades what often happens is we have a
clinical observation so in Carlos’s talk we heard that he thinks that certain
types of treatments will help in Birdshot in particular and maybe not in other
forms of uveitis the same way and the whole spectrum can then cross
inform and the arrows don’t need to go in one direction but there are two particular
parts of this pathway in which the government funding in the UK through the
National Institute for Health Research which is the main research and
development funding in the National Health Service There’s two particular areas where investment is made and this is in trying to catalyze the jump from ideas which may have
benefit for patients to get into early phase clinical trials and that’s what we call gap one and then there’s
the jump to get from late phase trials to be clinically applicable and that’s that gap 2, and that gap 2 we tend to call Applied Healthcare Research and the gap one
we’re getting into early phase trials to look at proof of concept is experimental
medicine or translational medicine and we are fortunate in the UK to have specific
investment in ophthalmology in experimental medicine through a
Biomedical Research Centre which is based at Moorfields Eye Hospital as I
said for birdshot actually things are mixed up as data come from
different parts of this pathway at different times. So when we look
internationally there are a range of a very active and talented clinicians globally
who have an interest in Inflammatory eye diseases and if you look at the medical
literature and against some of the presentation seen examples of this there
are different levels of evidence or evidence quality as some of the regulators or
healthcare commissioners will call it. So I as a doctor may see a patient with
unusual condition and I may want to document and report it to my colleagues
in the literature and that would be a case report but it’s unusual for a case
report to then inform spending and inform commissioning of care. Groups of doctors
sometimes work together in consortia but more typically the way research
works and you heard this today as well is that individual expertise is gained in
individual centers and that tends to be for inflammatory eye diseases centres of
excellence and expertise and the main ones to focus on are in the United States the United
Kingdom but typically the investment for that research has come to
individual researchers and their teams within individual institutions and so
I’m just going to add to the names you heard today from the UK environment
and UK community just how about some of the people internationally who work in
inflammatory eye diseases and none of them specifically focused on Birdshot alone
but Birdshot is incorporated within the programmes of work they undertake. This first group
of researches those that we’re not mature enough with inflammatory eye diseases to have a clear distinction between applied health care research and experimental medicine
as you would do some of the large disease like rheumatology but the researchers that I have presented
here are largely looking at application of treatments to patients in a clinical
environment and on the west coast of the States, they have Eric Suhler, I am just going to mention these name if you put them into PubMed you find things out about inflammatory eye diseases There’s Quan Nguyen who is based in Nebraska and then
on the east coast of Steve Foster who’s up on the top left, Douglas Jabbs, John Kempen and Nida Sen. If you put those names into PubMed you get a range of publications which will tell you about inflammatory
eye disease and show you how the conditions were interested in the field
are trying to report what they see in clinic and trying to assimilate that
data so that it is useful to the community as a whole and then if we go back to the
morel laboratory orientated research and the people who are who are focused more
experimental medicine I’m going to add a few other names in the USA: Jim
Rosenbaum on the left and Narsing Rao who also does clinical research, Russell Van Gelder,
the arrow goes off to Adelaide in Australia for Justine Smith and Bob Nussenblatt at National Eye Institute in the USA and so these are a community of
individuals who between them sometimes collaborate but often work on projects which
are centered on their own institution then if you look across Europe and
leaving the UK out because you seen much of the UK expert base here today in
France you have Bahram Bodaghi, in Spain Alfredo Ada and we’ve heard about the
activity in in Utrecht already from Jonas and Manfred Zierhut in Germany
Carl Herbort in Switzerland and Ilknur Tugal-Tutkun in Turkey, and so together his is a community but there aren’t actually that many pictures. I can fit onto the map reasonably well
and it is a rare disease and if you do this and Rheumatology if you do this in
Cardiovascular medicine or Oncology you wouldn’t be able to see the pictures on
the page and so we are a small piece of the jigsaw within medical research as a
whole. So I’m going to focus now on where the British government is investing in
research in this first translational gap to get new ideas in disease specific treatments into the
clinic and the context of that is the Biomedical Research Center which is
based at Moorfields, the inflammation part of the Biomedical Research Centre
is actually split and the first example as best practiced in this research domain
really being spread across institutions in the NHS and so it is formally partnered
with Bristol, University of Bristol and and Andrew Dick and both work between both London and Bristol in delivering this program of early phase research and
patient care. We’ve been very lucky though really because the government
based on the funding to also look further afield and this is our attempt
to challenge the usual status quo of institutional specific and research specific funding
and through close affiliation with the National Eye Institute in the United
States which is the US government-funded experimental medicine
base we formed a consortium called UNITE which is the University’s National Institute
Transatlantic Eye consortium for Human Ocular Immunology. Our basis is
looking in research in human beings and patients. We established this in
2012, photograph on the left-hand side and this is trying to make sure that we
scale up because it’s only a few individuals here for all the patients
that we have in the room today if expanded across the inflammatory eye diseases, if we’re really to have an impact and make changes to the
opportunities in inflammatory diseases in a meaningful time frame we have to
work together and that’s essentially the collaborative basis of the consortium
and the laboratories are truly joined. It isn’t a traditional scientific
collaboration the teams in the United Kingdom the teams in the US who are working in the labs and also the clinical teams, video conference on a weekly basis and
the programme of work is entirely joined up so that the government funded core research in
the UK and USA comes together in a coordinated way for inflammatory
eye diseases as a whole and then a year later in 2013 that was extended non
clinical more laboratory research level to the State Laboratory for Ophthalmology in
China and so this is is attempting to
bring together for ocular inflammatory eye diseases the expertise and research base and
resources and technologies from which you seen applied in the early talks of both
the UK government funded program US and the Chinese and a lot of this
simply wouldn’t have been possible without modern communications but
actually it’s very easy using simple software which most of you have on your computers, to communicate with people across the globe and coordinate programs of scientific
work. This is quite involved an in-depth now and I’m not proposing for a second to
go through every bullet point here it is to show the range of activity has been
undertaken through this consortium across these site, exchange of people,
exchange of PhD student for example we have postdoctoral fellows and
inflammatory eye diseases and not just uveitis we also know that inflammation
contributes to abnormalities in the retina and macular degeneration which affects older
people as Pearse described earlier and we also know that it plays a key role in diabetic retinopathy among
other sight threatening conditions. So there’s a range of programmes here and this needs quite a framework of administrative support and we’ve also moved into early phase clinical
trials and this is also a challenge to make sure that the systems we use to
collect data are robust and standardized across the UK and the US. And to bring
us together a number of meetings between the investigators and all these efforts
are actually trying to create a platform which will deliver patient benefit but
we need directions on how to deliver that benefit and we’ve heard a lot today about the sorts
of questions that you would like to be answered and that’s informed much what
we’ve done and done already but there’s much further to discuss around that which we will do
later. There were two key programmes work of work under the consortium that I wanted to highlight for you. One’s called ocular immune-phenotyping by phenotyping all
that means is characterizing we are describing the way the eyes look today
there’s been much discussion about the definition of Birdshot, what Birdshot is, do you need to be A 29 positive or not to have a diagnosis of birdshot and as doctors we
do sub-classify in order to try and optimize therapy and also be able to
give better advice on prognosis for individual groups of patients with
individual types of eye inflammation and so in this programme of work this is just
explained through a flowchart how a patient with eye inflammation would
essentially be sub-classified in a research programme, so that once they
present to one of our hospitals they have the opportunity to participate, so
it simply describes their disease, sometimes using the sorts of technologies
that you saw Pearse display but the same time is clinically characterizing yhr disease using some of these high-end technologies would also want to be
looking at the way the immune systems working in these patients and currently we
do that by taking blood samples and maybe more advanced ways of doing that
which I wish I will mention in the last slide so you’ve already seen in the Supercell
talk from from Birmingham the flow cytometry data of this sort and just to recap on some of that it’s
possible to take a blood sample from anybody in this audience and put it
through a machine and to visualize every single cells from that blood sample and
for each individual cell at the same time we can work out which proteins that
cells is expressing both on the cell surface and internally. There is a huge
challenge in then reconciling all that data and you heard Jonas talk about
bio-informatics and how this information can be tabled together but ultimately
looking for the molecular signatures that he was talking about in the context
of birdshot chorioretinopathy and what we’re trying to achieve is a
particular description or characterization of the way the eye looks and aline that
to the way we think the immune system works, alongside that as we know that somebody has a particular immune deviation abnormality associated with particular
appearance in the eye were hopeful that we would then be able
to be more effective in terms of the diagnostic tests we use and also more
effective in terms of the treatment that we use in a
targeted fashion to personalize it because even though we’re all talking about the
Birdshot Chorioretinopathy today it’s clear that every one of your independent
experience of Birdshot is slightly different so this is trying to get to a
more individualized level and to be more personalised and what we do I’m going skip over this as Jonas has talked
about it but this is really quite remarkable for each individual who
participate in these sorts of studies we can look it over 40,000 genes and
combine that data across groups of patients and this sort of technology is
really enabling us now to probe at a personalized level, difference and
characteristics of our immune responses and we hope that we can then alignment
to therapy. We are also very lucky to have advanced imaging and although we have a
disadvantage in ophthalmology of not being able to take samples of material
very easily from the eyes to look at under the microscope which would tell us quite a
lot about the biology of the abnormality in the eye for Birdshot for example we are able to now look at it in high resolution. Pearse alluded to the next generation of
imaging applications that are going to be coming to the clinic what I’m showing
you here is a research tool called adaptive optics, what you’ve got on the left
hand side of the screen as you look at it is a live human retinal, individual
photoreceptors both cones and rods visualized in real time and what I’m
showing you in the video individual cells going through the blood
vessels of a patient’s retina in real in real time we’ve got a project which is
starting in in the UK in the new year which is going to try and track retina labeled cells with a retina and that
will enable us to look at the immune response for the first time live in
human being to understand some of these things we think we’ve left the
laboratory before a really applicable to somebody with inflammatory eye disease
these concepts are very exciting but I also feel very cautious in these supports of
environments about giving a promise that we can apply this world of new
technology to make a step change in the care you receive. This is a long way away from some of the
questions we’ve heard about the practicalities of receiving
immunosuppressive drugs for example.

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