Therapeutic Compositions For Treatment Of Inflammation Of Ocular And Adnexal Tissues

Abstract

The present invention comprises a composition with means to inhibit the function of the inflammatory cytokine IL-1 and methods for using this composition to treat inflammatory disease of ocular and adnexal tissues by topical administration. The present invention also discloses devices for delivering this composition to target tissues.

Description

RELATED APPLICATIONS[0001]This application claims priority to U.S. application Ser. No. 12 / 298,380, filed Aug. 15, 2008, which claims priority to International Application No. PCT / US08 / 09776, filed Apr. 28, 2010, which claims priority to U.S. Provisional Application Nos. 60 / 965,135, filed Aug. 16, 2007 and 61 / 130,687, filed Jun. 2, 2008, the contents of which are each herein incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]This invention relates generally to the field of ophthalmology.BACKGROUND OF THE INVENTION[0003]Inflammation of the ocular and adnexal tissues can occur by a variety of mechanisms and is associated, either primarily or secondarily, with a large number of disease conditions. Current treatments for inflammation of these tissues involve the systemic administration of antibiotics, steroids, and immune-system inhibitors. The difficulty of using these systemic drugs becomes apparent through damaging long-term side effects in the case of steroids, ...

AI Technical Summary

Benefits of technology

[0004]The present invention overcomes these obstacles by administering a topical composition comprising one or more antagonists of IL-1 function, or a combination of IL-1 and other inflammatory antagonists, to locally decrease or prevent inflammation of the ocular and adnexal tissues.

[0022]A preferred approach uses a recombinant DNA construct in which the short polynucleotide sequence is placed under the control of a strong polymerase III or polymerase II promoter. The use of such a construct will result in the transcription of sufficient amounts of polynucleotide that will form complementary base pairs with the endogenous transcripts of nucleic acids of the invention and thereby prevent translation of endogenous mRNA transcripts. The invention encompasses the construction of a short polynucleotide using the complementary strand as a template. For example, a vector can be introduced in vivo such that it is taken up by a cell and directs the transcription of an interfering RNA or precursor to a double stranded RNA molecule. Alternatively, the template for the short polynucleotide transcript is placed under the transcriptional control of a cell-type specific promoter or other regulatory element. Thus, diffusion or absorption of a topically administered composition beyond the intended ocular or adnexal target tissue does not cause deleterious or systemic side effects. The vector remains episomal or becomes chromosomally integrated, as long as it can be transcribed to produce the desired polynucleotide.

[0025]Compositions comprise one or more extracellular or intracellular antibodies, also called intrabodies, raised against one or more of the following: IL-1a, IL-1b, IL-1Ra, IL-1R1, IL-1R2, Il-1Ra3, IL-1RAP, or IRAK1. Extracellular antibodies are topically administered with a pharmacologically appropriate aqueous or non-aqueous carrier. Sequences encoding intracellular antibodies are subcloned into a viral or mammalian expression vector, packed in a lipophilic device to facilitate transport across the plasma membrane, and topically administered to ocular or adnexal tissue with a pharmacologically appropriate aqueous or non-aqueous carrier. Once inside the plasma membrane, host cell machinery transcribes, translates, and processes the intrabody code to generate an intracellular function-blocking antibody targeted against IL-1a, IL-1b, IL-1Ra, IL-1R1, IL-1R2,1′-1Ra3, IL-1RAP, or IRAK1. In the case of secreted molecules, intracellular antibodies prevent post-translational modification or secretion of the target protein. In the case of membrane-bound molecules, intracellular antibodies prevent intracellular signaling events upon receptor engagement by IL-1 cytokines.

[0035]The invention comprises a method of contacting a composition, with means to inhibit IL-1R activity, to an ocular or adnexal tissue surface of a subject who presents symptoms or associated conditions of posterior blepharitis. Unlike all other treatments for this condition, this method comprises a composition that is topically administered to the subject and affects local disease mechanisms without the side effects present with systemically administered treatments. The composition is not only effective immediately, but also safe for long-term administration.

[0042]In another embodiment, the composition is capable of increasing the abundance of the naturally-occurring IL-1 Receptor antagonist (IL-1Ra). The composition comprises a polynucleotide, a polypeptide, an antibody, a compound, or a small molecule that binds to a region of the IL-1Ra gene, mRNA transcript defined by SEQ ID NO: 5, 7, 9, 11, or 13, a polypeptide isoform of IL-1Ra defined by SEQ ID NO: 6, 8, 10, 12, or 14, or a recombinant IL-1Ra protein defined by SEQ ID NO: 16. Alternatively, the composition contains mRNA transcripts or polypeptides encoding a region or the entirety of the IL-1Ra gene.

[0044]The composition comprises a molecule with means to inhibit IL-1α- or IL-β-mediated modulation of matrix metalloproteinase (MMP) overexpression, which degrades collagen matrices within tissues and retards wound healing.

Problems solved by technology

The difficulty of using these systemic drugs becomes apparent through damaging long-term side effects in the case of steroids, long-term drug resistance in the case of antibiotics, or insufficient long-term persistence at the target site in the case of signaling inhibitors.

Moreover, the systemic inhibition of signaling within the immune system can have deleterious outcomes for individuals already afflicted with disease, whose susceptibility to additional complications is increased as a result of the systemic use of these treatments.

Images