inhibition of corneal fibrosis with a mir-29 mimic · confidential pg. 1 restoring biological...
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Pg. 1Confidential
Restoring Biological Harmony for Patients with Debilitating DiseaseRestoring Biological Harmony for Patients with Debilitating Disease
Inhibition of corneal fibrosis with a miR-29 mimic
Corrie Gallant-Behm, PhD, MQARS
Oligonucleotide Therapeutics Society 14th Annual Meeting
October 1, 2018
Pg. 2
microRNA Therapeutics Regulate Systems Biology to Modify Disease
▪ microRNA-targeted therapy is focused
on disease modification by restoring
homeostasis to dysregulated processes
▪ microRNAs regulate complex biological
systems
▪ microRNA-targeted therapies are
intrinsically focused on disease-relevant
pathways
▪ microRNA therapeutics particularly
suited for complex, multigenic disorders
Pg. 3
miR-29 Pathways and Systems Control
Growth factors
Collagen transcription/translation
Post-translational modification
& triple helix formation
N- and C-terminal cleavage
& secretion
Fibril cross-linking
Mature collagen fibrils
miR-29
Inflammation
TGF-b +
Diseased ECM
TGF-b2, TGF-b3, EGF, IGF2, IGFBP5,
PDGFA, PDGFC
COL1A1, 1A2, 3A1, 5A1, 5A2, 5A3,
6A4, 6A5, 6A6, 8A1, 8A2, 9A1,
11A1, 12A1, 14A1, 22A1, 28A1
HSP47, P4HA2, P4HA3, PLOD2
PCOLCE2
LOXL2
in vivo Validated Targets
Pg. 4
miR-29 Pathways and Systems Control
Remlarsen(MRG-201)(promiR-29)
Growth factors
Collagen transcription/translation
Post-translational modification
& triple helix formation
N- and C-terminal cleavage
& secretion
Fibril cross-linking
Mature collagen fibrils
TGF-b2, TGF-b3, EGF, IGF2, IGFBP5,
PDGFA, PDGFC
COL1A1, 1A2, 3A1, 5A1, 5A2, 5A3,
6A4, 6A5, 6A6, 8A1, 8A2, 9A1,
11A1, 12A1, 14A1, 22A1, 28A1
HSP47, P4HA2, P4HA3, PLOD2
PCOLCE2
LOXL2
in vivo Validated Targets
Pg. 5
Fibrotic Diseases in Which Reduced miR-29 Has Been Implicated
▪ Keloid scar. Phase 2 clinical trial ongoing: NCT03601052
▪ Hypertrophic scar. Phase 1 clinical trial complete: NCT02603224
▪ Scleroderma.
▪ Cardiac fibrosis.
▪ Pulmonary fibrosis – IPF, CTD-associated.
▪ Liver fibrosis – cirrhosis, NASH, viral.
▪ Kidney fibrosis – diabetic nephropathy, IgA.
▪ Retinal fibrosis.
▪ Glaucoma. Trabeculectomy bleb failure. Multiple opportunities in ophthalmology
▪ Fuch’s Endothelial Corneal Dystrophy.
Pg. 6
The Eye is a Preferred Target Organ for microRNA Therapeutics
▪ Delivery to multiple compartments of the eye, and via multiple routes of administration including injection and topical drops
▪ Stability due to reduced nuclease concentration enables long duration of action and infrequent dosing
▪ Reduced liability for toxicities due to local administration with limited systemic exposure
Pg. 7
Remlarsen Uptake in Alkali Burned Cornea
▪ Animal model: Rat alkali burn
▪ Distribution of Remlarsen (MRG-201) to all layers of the cornea, including corneal endothelium after drop administration
EpitheliumStroma
FITC-remlarsenDAPI
Pg. 8
▪ Uptake of remlarsen in alkali burned cornea is high, but diminishes after re-
establishment of the corneal epithelium and/or tear film post-burn
Remlarsen Uptake in Alkali Burned Cornea
0
2 0
4 0
6 0
8 0
1 0 0
1 0 0 01 5 0 02 0 0 02 5 0 03 0 0 0
m iR -2 9 b le v e ls in ra t c o rn e a
miR
NA
ex
pre
ss
ion
(fo
ld c
ha
ng
e)
* * * *
S a lin e : + + + +
R e m la rs e n : + + + +
2 4 h 4 8 h 4 D 7 D
C o n tr o l S a lin e D a y 1 0 D a y 1 4 D a y 2 1 D a y 2 8
0
5
1 0
1 5
m iR - 2 9 L e v e ls
miR
NA
ex
pre
ss
ion
(fo
ld c
ha
ng
e)
R e m la r s e n
14x
11x
1.7x
Pg. 9
Remlarsen as an Anti-Fibrotic in the Cornea
▪ Damage is reduced in remlarsen treated alkali burned eyes▪ Epithelium re-established more quickly
▪ Less damage to the stroma, decreased cellularity
▪ Reduced inflammation
Unburned corneaNo treatment Saline treated burned cornea Remlarsen treated burned cornea
Day 4
Pg. 10
Remlarsen as an Anti-Fibrotic in the Cornea
▪ Wound healing is accelerated in remlarsen treated alkali burned eyes▪ Epithelium re-established more quickly
▪ Reduced stromal thickness results
D a y 4 D a y 7 D a y 1 0 D a y 1 4
0
2 0
4 0
6 0
Ep
ith
eli
um
th
ick
ne
ss
(u
M)
S a lin e
M R G -2 0 1
T re a tm e n t e ffe c t a c ro s s a ll t im e s : p < 0 .0 0 1
p < 0 .0 1
D a y 4 D a y 7 D a y 1 0 D a y 1 4
0
1 0 0
2 0 0
3 0 0
Str
om
al
thic
kn
es
s (
uM
)T re a tm e n t e ffe c t a c ro s s a ll t im e s : p < 0 .0 5
p < 0 .0 5
Saline Remlarsen
Pg. 11
Remlarsen as an Anti-Fibrotic in the Cornea
▪ Scarring is reduced in remlarsen treated alkali burned eyes
Day 14
1 2 3 4 5Normal Scar
Unburned cornea
No treatment
Saline treated burned cornea
Remlarsentreated burned
cornea
0 .0 0
0 .2 5
0 .5 0
0 .7 5
1 .0 0
H a z in g /s c a r r in g
Pro
po
rti
on
of
sa
mp
les
* * *
10 14 21 28D a y :
R e m la rs e n : - + - + - + - +
Pg. 12
Remlarsen as an Anti-Fibrotic in the Cornea
▪ a-SMA staining is reduced by remlarsen treatment
Saline Remlarsen
Least stainingin cohort
Most stainingin cohort
a-smooth muscle actin
S a lin e R e m la r s e n
0
2 0 0
4 0 0
6 0 0
D a y 1 4
a
SM
A+
co
un
ts
S a lin e R e m la r s e n
0
5 0
1 0 0
1 5 0
2 0 0
D a y 2 8
a-S
MA
+ c
ou
nts
Pg. 13
▪ miR-29b PD biomarkers are repressed following twice daily remlarsen drop treatments
▪ Consistent in multiple studies
▪ Multiple collagens and pro-fibrotic factors are affected
Remlarsen Demonstrates Target Engagement in Cornea in vivo
S a lin e R e m la r s e n
0 .0
0 .5
1 .0
1 .5
D a y 7
mR
NA
Ex
pre
ss
ion
(Fo
ld C
ha
ng
e)
0.0350p =
S a lin e R e m la r s e n
0 .0
0 .5
1 .0
1 .5
D a y 1 0
mR
NA
Ex
pre
ss
ion
(Fo
ld C
ha
ng
e)
0.0003p =
S a lin e R e m la r s e n
0 .0
0 .5
1 .0
1 .5
D a y 1 4
mR
NA
Ex
pre
ss
ion
(Fo
ld C
ha
ng
e)
p < 0 .0 0 0 1
COL1A1
COL1A2
COL5A2
FN1
TGFB2
MMP2
Study 1 Study 2
Pg. 14
▪ miR-29b mimics are well taken up by a damaged/ulcerated cornea following drop
administration
▪ Remlarsen uptake is sustained in the alkali burn model until the corneal epithelium and
tear film are fully established post-burn
▪ Remlarsen treatment reduces the severity of alkali burn, accelerates repair vs. vehicle
▪ Remlarsen treatment reduces corneal hazing/scarring, decreases the corneal stromal
thickness, and reduces a-SMA staining post-burn
▪ Remlarsen engages its pharmacodynamic targets and reduces collagen/ECM
expression in vivo
▪ Remlarsen represents a potential therapeutic for corneal scarring regardless of the
etiology:
▪ Infectious keratitis, surgery, trauma, genetic disease
▪ Translatable to other compartments of the eye – trabecular meshwork, conjunctiva, retina, choroid
Conclusions
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