1. Inhibition of microfibrillar-associated protein 4 as a potential therapy targeting choroidal neovascularization in age-related macular degeneration
Bartosz Pilecki
Institute of Molecular Medicine
University of Southern Denmark

2. 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)
Dry AMD atropy of Retinal epithelial cells – blurred central vision
Wet AMD rapid worsening af vision, blind spots

3. RPE – retinal pigment epithelium
AMD pathogenesis
Photo receptors
RPE BM
Choroid
RPE – retinal pigment epithelium
BM – Bruchs membrane

4. 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
Luc: 21,4 letter more with 0.5 mg luc in trial III
Eylea: ph III: samme efficacy as luc
Ref. Datamonitor

5. 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Mediates endothelial cell adhesion and integrin signaling activation (Ormhøj et al, unpublished)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

6. Neovascularization and inflammation of the eye
αMFAP4 actions in AMD
Endothelial cells
Inflammatory cells
Extracellular matrix
Neovascularization and inflammation of the eye
Integrin
receptor
Activation
MFAP4
MFAP4
MFAP4 blocking antibody

7. 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
Brown Norway rats, 5 microliters, app. 60 micrograms – (12 mg/ml, 2 EU/ml)
1 injection; hyperemia (rødfarvning), chemosis (swelling), discharge (liquid flows from the eye) (Draize examination) uptill 23 days
Electroretinogram
Weight
Behaviour
HE histology
Figure adapted from Singh-SR, Gene Therapy, 2009

8. αMFAP4 reduces lesion size at day 7, in contrast to αVEGF Trend for superiority of high dose αMFAP4
fundus flourescein angiogr

9. αMFAP4 andαVEGF have similar effects in reduction of lesion size at day 14 Trend for superiority of high doseαMFAP4

10. αMFAP4 andαVEGF have similar effects in reduction of inflammation at day 14 Trend for superiority of high doseαMFAP4

11. 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

12. 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

13. School of Medicine, University of Nottingham, UK:
Acknowledgements:
School of Medicine, University of Nottingham, UK:
Zoe Blackley
Nikita Ved
David Bates
UFFE
GRITH
ANDERS
KARIN
CHARLOTTE
KIRSTEN
VICKI
BARTEK
SEBASTIAN
LINE
CHRISTINE
KIMMIE
SOFIE
ANDERS
ANITA