Inflammation is generally treated with a standard anti-inflammatory regimen that includes steroids and/or non-steroidal anti-inflammatory drugs (NSAIDS). Allergic conjunctivitis, ocular inflammation, dermatitis, rhinitis, and asthma have historically been treated with a regimen of oral, intranasal or topical antihistamines in addition to or oral or intranasal steroids. Systemic treatment typically requires higher concentrations of the drug compound to be administered to afford an effective concentration to reach the necessary treatment site. Antihistamine compounds are known to have central nervous system activity; drowsiness and drying of mucus membranes are a common side-effect of antihistamine use. Steroids and NSAIDS have potential side effects including intraocular pressure increase, cataract, glaucoma or corneal melting.
Dry eye, also known as conjunctivitis sicca or keratoconjunctivitis sicca, is a common ophthalmological disorder involving breakdown of the pre-ocular tear film, resulting in dehydration of the exposed outer surface of the eye. To date, dry eye has been treated with topical administration of artificial tear solutions. Some of these solutions contain mucomimetic substances to temporarily replace or replenish the mucin layer in mucin deficient patients. Use of methylprednisolone has been proposed in a short-term “pulse” treatment to treat exacerbations of dry eye. The proposed “pulse” therapy is required to avoid complications associated with traditional steroid therapy for inflammatory conditions such as increased intraocular pressure and cataract formation.
The cytokine TNFα is a target for anti-inflammatory therapy of dry eye and uveitis. In a rabbit model of lacrimal gland inflammation-induced dry eye, inhibition of corneal staining and restoration of tear breakup time has been achieved by specific modulation of ocular surface TNFα levels. Dry eye therapy resulted by inhibiting TNFα synthesis (RDP58) or by specifically neutralizing TNFα using a monoclonal antibody (REMICADE®) or a soluble receptor (ENBREL®). Each of these TNFα directed treatments resulted in levels of efficacy obtained with topical ocular anti-inflammatory steroids.
U.S. Patent Publication 2005/0227935, published Oct. 13, 2005, to McSwiggen et al. relates to RNA interference mediated inhibition of TNF and TNF receptor gene expression. However, said publication teaches none of the particular target sequences for RNA interference as provided herein.
Embodiments of the present invention address the need in the art for further agents and treatment methods for dry eye and inflammation and provide alternative therapies therefor.