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(Investigative Ophthalmology and Visual Science. 2003;44:5228-5234.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0312
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Topical Treatment with Antisense Oligonucleotides Targeting Tumor Necrosis Factor-{alpha} in Herpetic Stromal Keratitis

Susanne Wasmuth,1,2 Dirk Bauer,2 Yanning Yang,3 Klaus-Peter Steuhl,1 and Arnd Heiligenhaus2

1From the Department of Ophthalmology, University of Essen, Essen, Germany; 2Ophtha-Lab, St. Franziskus Hospital, Münster, Germany; and the 3Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China.

PURPOSE. Tumor necrosis factor (TNF)-{alpha} is a pleiotropic factor that is critical for the development of inflammation. The authors investigated whether topical application of TNF-{alpha}-antagonizing molecules, antisense oligonucleotides (ASON), might be an effective way of modifying the course of immune-mediated herpetic stromal keratitis (HSK).

METHODS. ASON targeting TNF-{alpha} mRNA were examined for their efficiency in interfering with the production of this cytokine in vitro. In vivo uptake was determined by FITC-labeled ASON. HSV-1 corneally infected mice were injected three times with ASON. Mice from the control groups received unrelated control oligonucleotides (CON) or buffer. The clinical course of HSK, the delayed-type hypersensitivity (DTH) reaction, the uptake of [3H]thymidine from cells derived from the spleen, virus-neutralizing antibody titers in the serum, and viral replication in the infected eyes were determined. The eyes were examined histologically. The corneal TNF-{alpha} content was measured by ELISA.

RESULTS. The TNF-{alpha} ASON reduced the lymphocytic cytokine expression in vitro. In vivo, the FITC-labeled molecules were detected in the cornea even after 10 days. In the TNF-{alpha} ASON mice the incidence of HSK decreased, and the severity of the disease was diminished. The corneal content of TNF-{alpha} was reduced, and the number of inflammatory cells was decreased. The other investigated parameters were not significantly altered by TNF-{alpha} ASON treatment.

CONCLUSIONS. The data suggest that TNF-{alpha} ASON diminishes the release of TNF-{alpha} from cultured lymphocytes and from lymphocytes in the HSV-1–infected cornea. This topical treatment mitigates the course of HSK, whereas the systemic antiviral effector functions were not impaired.






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