Transcript Pilecki 20-01

Inhibition of microfibrillar-associated
protein 4 as a potential therapy targeting
choroidal neovascularization in agerelated macular degeneration
Bartosz Pilecki
Institute of Molecular Medicine
University of Southern Denmark
20.01.2016
Age-Related Macular Degeneration
(AMD)
 Leading cause of blindness in
people over 50
 Affects > 30 million people
worldwide
 Characterized by the loss of
central vision due to the
gradual deterioration of the
macula (angiogenesis,
inflammation, fibrosis)
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AMD pathogenesis
Photo
receptors
RPE
BM
Choroid
RPE – retinal pigment epithelium
BM – Bruchs membrane
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Current treatment options
 Intravitreal injection of vascular endothelial growth factor (VEGF)
inhibitors has become the standard treatment for wet AMD
 Anti-VEGF therapy does not affect inflammation and fibrosis and
gives rise to side effects
 Laser-based therapies are the only solution for the subpopulations
of non-responders to anti-VEGF monotherapy (15-25%)
 New treatment strategies are warranted
Ref. Datamonitor
Microfibrillar-associated protein 4
 Extracellular matrix elastin-binding protein (Pilecki, Holm et al
2016)
 RGD-dependent integrin ligand
 Promotes integrin-dependent smooth muscle cell proliferation
and macrophage chemotaxis (Schlosser, Pilecki et al 2016;
Pilecki et al, 2015)
 Mediates endothelial cell adhesion and integrin signaling
activation (Ormhøj et al, unpublished)
Suggests a potential involvement of MFAP4 in AMD pathogenesis
αMFAP4 actions in AMD
Extracellular matrix
MFAP4
Endothelial cells
Inflammatory cells
Integrin
receptor
Neovascularization
and inflammation of
the eye
MFAP4
MFAP4 blocking antibody
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Choroidal neovascularization (CNV)
rodent model
 CNV is the hallmark lesion of advanced
AMD
 Similar to the CNV that occurs in human
ocular disease
 Laser-induced injury
 Administration of αVEGF, αMFAP4 and IgG
control at days 0 and 7
 Endpoints analyzed at days 7 and 14 after
surgery
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Figure adapted from Singh-SR, Gene Therapy, 2009
αMFAP4 reduces lesion size at day 7,
in contrast to αVEGF
Trend for superiority of high dose αMFAP4
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αMFAP4 andαVEGF have similar effects in
reduction of lesion size at day 14
Trend for superiority of high doseαMFAP4
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αMFAP4 andαVEGF have similar effects in
reduction of inflammation at day 14
Trend for superiority of high doseαMFAP4
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Summary:
 No adverse tolerability, assessed by electroretinography,
physical defects, gross observations of ocular irritation and
histological observation of retinal tissue
 Treatment with αMFAP4, particularly at higher dose, was able
to consistently reduce lesion size and density and limit
leukocyte infiltration into the burn area
 Effects of αMFAP4 were already detectable 7 days after lesion
formation
αMFAP4-based therapy can potentially be used to treat the
pathological angiogenesis and inflammation in AMD
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Perspectives:
 Efficacy of prophylactic αMFAP4 treatment
 Combinational αMFAP4/αVEGF treatment
 In vitro MFAP4/anti-MFAP4 effects on ocular angiogenesis,
vessel permeability, cell proliferation and cytokine secretion
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Acknowledgements:
School of Medicine,
University of
Nottingham, UK:
Zoe Blackley
Nikita Ved
David Bates
UFFE
KARIN CHARLOTTE
BARTEK
KIMMIE
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GRITH
ANDERS
KIRSTEN
VICKI
SEBASTIA
N
LINE
CHRISTI
NE
SOFIE
ANDERS
ANITA