Transcript New Antiinflammatory Strategy to Treat Murine Dry

New Antiinflammatory Strategy
to Treat Murine Dry-Eye Disease
André Okanobo, MD, Mohammad Dastjerdi, MD, Sunil Chauhan,
DVM, PhD, Nambi Nallasamy, BS, Zahra Sadrai, MD, Reza Dana, MD,
MPH, MSc.
Schepens Eye Research Institute,
Harvard Medical School, Boston, MA
Financial Disclosures :The Schepens Eye Research Institute and Mass. Eye and
Ear Infirmary hold rights to the intellectual property for the use of IL-1 blockade
in ocular surface disease.
Financial support: Prevent Blindness America and NIH K24EY019098
Inflammation and Dry Eye
• Dry eye was originally considered to be simply a lack,
or diminishment, of tear production
• We now know that inflammation plays a critical role
in the pathophysiology
• This is supported by clinical data using antiinflammatory therapies which lead to significant
amelioration of the signs and symptoms of DED
mRNA expression
of IL-1α
IL-1 and IL-1Receptor Are Upregulated in Dry Eye
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5
4
3
2
1
0
Normal Eye
Dry Eye
IL-1R Expression; Cross-Section Cornea Epifluorescent Microscope
Dry Eye
Normal
AC
AC
AC
40x
EP
40x
EP
40x
40x
Propose
• Given that IL-1–mediated mechanisms play a
critical role in corneal inflammation, we
propose that local blockade of IL-1 may offer a
novel approach to the management of dry eye
disease
Interleukin-1 (IL-1)
Proinflammatory forms
Anti-inflammatory form
• IL-1α
• IL-1β
• IL-1 receptor antagonist (IL-1Ra)
IL-1R
IL-1R
IL-1
IL-1AcP
IL-1
IL-1AcP
IL-1Ra
Kinase, Phosphatase, etc.
Signal
Transduction
Induction of Dry Eye Disease
• Controlled Environment Chamber
– humidity below 25%
– constant temperature of 21-23ºC
– airflow of 15 L/minute
• Topical atropine and SC scopolamine
Barabino S, et al. The controlled environment chamber: a new mouse
model of dry eye. Invest Ophthalmol Vis Sci. 2005;46(8):2766-2771.
Topical formulation and treatment regiment
•Formulation prepared by MEEI pharmacy
•Masked Fashion
Control Environment Chamber
Treatment
DAY Induction of Dry Eye
0
CFS
1
2
3
4
5
CFS
6
7
8
9
CFS
CFS
10
Euthanized
Groups (n=6 eye)
1. IL-1Ra
2. CsA
3µl (3x/day)
3. Methylprednisolone
4. Vehicle (1% carboxymethylcellulose)
5. Untreated (no eye drops)
CFS: Corneal Fluorescein Staining
Corneal Staining
mRNA expression levels of IL-1β in the cornea
Enumeration of macrophages in the cornea
Normal
0.05% CsA
Untreated (Dry eye)
5% IL-1Ra
CMC (Vehicle)
1% Methylprednisolone
IL-1Ra inhibits lymphangiogenesis in dry eye
Normal
Dry Eye
IL-1Ra 5%
LYVE-1(Lymphatics Vessels) / CD31(Blood Vessels)
Conclusion
• IL-1Ra ameliorates dry eye disease comparable to
methylprednisolone
– Signs: CFS scores were significantly improved
• Our data suggests that this is due to the marked
inhibition of corneal inflammation:
– Down regulated levels of IL-1β mRNA
– Reduced infiltration of macrophages
– Inhibition of lymphangiogenesis
• Thus the use of topical IL-1Ra appears to be a
promising therapeutic modality to dry eye disease
and possibly in other inflammatory conditions of the
cornea and ocular surface