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 anti-inflammatory therapies which lead to significant amelioration of the signs and symptoms of DED

IL-1 and IL-1Receptor Are Upregulated in Dry Eye Normal 40x Dry Eye IL-1R Expression; Cross-Section Cornea Epifluorescent Microscope EP AC

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-1 receptor antagonist (IL-1Ra) IL-1R IL-1R IL-1 IL-1 IL-1AcP IL-1AcP IL-1Ra Signal Transduction Kinase, Phosphatase, etc.

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 0 1 2 3 4 5 6 7 8 9 10 Induction of Dry Eye Treatment CFS Control Environment Chamber DAY Euthanized Groups (n=6 eye) IL-1Ra CsA Methylprednisolone 4. Vehicle (1% carboxymethylcellulose) 5. Untreated (no eye drops) 3µl (3x/day) CFS: Corneal Fluorescein Staining

Corneal Staining

mRNA expression levels of IL-1β in the cornea

Enumeration of macrophages in the cornea

IL-1Ra inhibits lymphangiogenesis in dry eye Normal LYVE-1(Lymphatics Vessels) / CD31(Blood Vessels) IL-1Ra 5%

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