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Printable Handouts
Navigable Slide Index
- Introduction
- Prevalence of AMD in Ireland
- Forms of AMD
- NLRP3 inflammasome
- A model of NLRP3 inflammasome activation
- Drusen activates the NLRP3 inflammasome
- Laser-induced CNV model of wet AMD
- Protective effect of NLRP3
- NLRP3 protection via IL-18 production
- Summary (1)
- Mature IL-18 causes geographic atrophy
- Iboctadekin: recombinant human IL-18
- Mature hIL-18 does not cause RPE cell death
- RPE cells & hIL-18 treatment
- IL-18 & cell death in primary RPE cells
- IL-18 & cell death in mice
- Over expression of pro-IL-18/pro-IL-1β
- Pro-IL-18 expression induces LC3 cleavage
- Cell swelling is independent of NLRP3
- Is RPE cell swelling specific to pro-IL-18?
- Translational potential of IL-18 for wet AMD
- IL-18 & treatment of nAMD
- Treatment potential of IL-18
- Summary (2)
- IL-18 prevents CNV & vascular leakage
- What about non-human primates?
- Mature hIL-18 is not toxic to primate RPE
- Laser-induced CNV in non-human primates
- Treatment of laser-induced CNV in macaques
- hIL-18 reduces grade IV CNV
- Safety concerns
- RPE is intact post IL-18 injection
- How is it working?
- IL-18 negatively regulates the VEGF axis
- IL-18 potently down-regulates VEGFR2 mRNA
- Summary (3)
- Acknowledgements
Topics Covered
- Prevalence & forms of AMD
- The NLRP3 inflammasome in AMD
- Laser-induced CNV
- IL-18 anti-angiogenic properties
- IL-18 regulation of vascular permeability in choroid
- IL-18 in human & primate retinal pigment epithelium (RPE)
- IL-18 regulation of VEGF activity, secretion & expression levels
- IL-18 regulation of CNV development
- IL-18 utility as an additive therapy for wet AMD
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Campbell, M. (2016, October 31). Protective inflammasome activation in AMD [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved October 4, 2024, from https://doi.org/10.69645/TGFW4407.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Matthew Campbell has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Other Talks in the Series: Macular Degeneration
Transcript
Please wait while the transcript is being prepared...
0:00
My name is Matthew Campbell.
I'm based at the Smurfit Institute
of Genetics
in Trinity College Dublin in Ireland.
And today, I'm going to talk about
some research results
that we have that suggest that aspects
of the NLRP3 inflammasome
may have a protective effect
in the degenerative eye disease,
age-related macular degeneration,
or AMD for short.
0:21
AMD is a very prevalent
cause of central retinal blindness.
And to give you the perspective
of AMD in a country
the size of Ireland
with a population of about 4.5 million,
in this country,
we have a prevalence
of AMD at about 7.2%.
So that's roughly aligned
with the similar prevalence of AMD
that's observed in Western Europe,
and in the US where about
10% of individuals
over the age of 50 present
with AMD of some sort.
In Ireland, over 1 million people
are over the age of 50 years,
and of that, over 70,000 people
have some sort of AMD.
So this is a very, very
common form of blindness.
The life expectancy for men
in Ireland is approximately 78 years,
and for women, it's 82 years.
So again, this is very well aligned
with figures in Western Europe
and even the US.
And interestingly, life expectancy
has been going up by approximately
six hours every day since 1900.
And so it stands to reason
that with a growing increase
in the aging population,
the cases of AMD
are going to continue to rise,
and this is going to present
with a very major problem
in the years ahead.
1:26
So AMD can present
in two major forms.
One form is called dry AMD,
and the other form is called wet AMD.
Now, by far, the most common form
of AMD is dry AMD.
And the classic hallmark
pathological feature of dry AMD
is the presence of sub retinal deposits
in Bruch's membrane
called Drusen.
Now drusen are extracellular deposits
that are processed
through the retinal pigment epithelium
and they appear
as yellowish-white deposits
in retinal fundus photos.
Now in 10% of cases of dry AMD,
it can progress to a form of AMD
called wet AMD
or neovascular AMD
whereby the underlying choroid
behind the retina
will begin to proliferate
into the center of the retina.
And these proliferative vessels
can actually
become very, very permeable,
and in some instances,
they can actually hemorrhage and bleed,
leading to almost instant
central retinal blindness.
So it's very clear that
AMD is a very prominent problem
in the aging population
and new therapies need to be developed.
So in terms of the pathological hallmark
of how ophthalmologists determine
whether somebody has AMD or not,
the classic pathological hallmark
featured in retinal photos
is the presence of drusen.
And what drusen can do,
it can distort and damage the retina
as it builds up
between the choroid and the retina.
And when you actually dissect drusen
from donor AMD eyes
and examine drusen under a microscope,
it's particulate, it's oily,
it's extracellular in nature.
And we asked the question
back in 2010 and 2011,
well, drusen is extracellular,
and it's oily,
and it's an extracellular deposit
or aggregated material,
does it activate the NLRP3 inflammasome.