# US 10,117,906 B2 · Methods for reducing corneal nerves damage, corneal lymphangiogenesis or immunity to corneal antigens in dry-eye associated ocular surface diseases by IL-1Ra > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,117,906 B2 - Document ID: US10117906B2 - Status: Granted - Kind: B2 - Application number: 12/685,510 - Filed: 2010-01-11 - Published: 2010-07-22 - Granted: 2018-11-06 - Earliest claimed: 2009-01-09 - Assignees: The Schepens Eye Research Institute, Inc. - Applicants: Reza Dana; Mohammad Dastjerdi; Sunil Chauhan - Inventors: Reza Dana; Mohammad Dastjerdi; Sunil Chauhan - Web page: https://patentgrep.com/patent/US10117906B2 ## CPC - A61K 38/1709: {from mammals} - A61K 9/0048: {Eye, e.g. artificial tears} - A61K 38/1793: {for cytokines; for lymphokines; for interferons} - A61K 38/2006: {IL-1} - A61P 27/02: Ophthalmic agents - A61P 37/00: Drugs for immunological or allergic disorders - C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones} - C12N 2310/14: interfering nucleic acids [NA] - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) ## Abstract The invention provides methods and compositions for minimizing, preventing, or treating damage to corneal nerves by administering to a subject with such damage or at risk of exposure to such damage a composition which blocks an activity of an IL-1 cytokine and/or an IL-17 cytokine. ## Claims ### Claim 1 A method for protecting or inducing outgrowth of corneal nerves in a subject in need thereof, comprising the steps of: (a) identifying a subject with corneal nerve damage or loss by identifying in the subject a symptom from the group consisting of: abnormal tear production or dryness; abnormal blinking; difficulty or loss of ability to focus; decreased or lost visual acuity; or decreased or lost corneal sensitivity or identifying a subject with a sign of corneal nerve damage or loss, wherein the sign of corneal nerve damage or loss is a decrease of corneal innervation or sensation, a reduction in the number of nerve fibers or bundles innervating the cornea, death of neurons innervating the cornea, a decrease or loss of neurotransmitter release, a decrease or loss of nerve growth factor release, abnormal tearing reflexes, abnormal blink reflexes, abnormal nerve morphology, appearance of abnormal nerve sprouts, abnormal tortuosity, increased bead-like nerve formations, thinning of nerve fiber bundles, or thickening of nerve fiber bundles; wherein said subject is characterized as having corneal nerve damage or loss that results from neurotrophic keratitis, herpes simplex, zoster keratitis, diabetes mellitus, trigeminal nerve damage, ocular or orbital or head surgery, head trauma, aneurysm, intracranial neurologic disease, keratorefractive procedures, photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), ocular surface disease, dry eye syndrome, or peripheral neuropathy; and (b) locally administering to the cornea of said subject a composition that inhibits an activity of an inflammatory interleukin-1 cytokine, thereby enhancing corneal nerve outgrowth or reducing the development of abnormalities in nerve morphology or density, wherein said composition consists of a vehicle and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 16. ### Claim 2 (depends on 1) The method of claim 1, wherein said activity comprises binding of an inflammatory IL-1 cytokine to an IL-1 receptor. ### Claim 3 (depends on 1) The method of claim 1, wherein said polypeptide is present in a concentration of 0.1-10% (mg/ml). ### Claim 4 (depends on 1) The method of claim 1, wherein said polypeptide is present in a concentration of 2.5% (mg/ml) or 5% (mg/ml). ### Claim 5 (depends on 1) The method of claim 1, wherein the form of said composition is a solid, a paste, an ointment, a gel, a liquid, an aerosol, a mist, a polymer, a film, an emulsion, or a suspension. ### Claim 6 (depends on 1) The method of claim 1, wherein said composition is administered topically. ### Claim 7 (depends on 1) The method of claim 1, wherein said method does not comprise systemic administration or substantial dissemination to non-ocular tissue. ### Claim 8 (depends on 1) The method of claim 1, wherein said vehicle is selected from the group consisting of a physiological acceptable salt, poloxamer analogs with carbopol, carbopol/HPMC, carbopol-methyl cellulose, a mucolytic agent, carboxymethylcellulose (CMC), hyaluronic acid, cyclodextrin, and petroleum. ### Claim 9 (depends on 8) The method of claim 8, wherein said mucolytic agent is N-acetyl cysteine. ### Claim 10 A method for minimizing damage or loss of corneal nerves in a subject in need thereof, comprising the steps of: (a) identifying said subject at risk of exposure to corneal nerve damage or loss that results from neurotrophic keratitis, herpes simplex, zoster keratitis, diabetes mellitus, trigeminal nerve damage, orbital or head surgery, head trauma, aneurysm, intracranial neurologic disease, keratorefractive procedures, photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), ocular surface disease, dry eye syndrome, or peripheral neuropathy; and (b) locally administering to the cornea of said subject a composition that inhibits an activity of an inflammatory interleukin-1 cytokine prior to said exposure, thereby decreasing nerve degeneration and reducing the development of abnormalities in nerve morphology or density, wherein said composition consists of a vehicle and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 16. ### Claim 11 A method for reducing corneal lymphangiogenesis associated with a dry-eye associated ocular surface disease in a subject in need thereof, comprising the steps of: (a) identifying a subject with corneal lymphangiogenesis, wherein said subject has a dry-eye associated ocular surface disease; and (b) locally administering to the cornea of said subject a composition that inhibits an activity of an inflammatory interleukin-1 cytokine, thereby inhibiting the ability of lymphatic vessels to expand within or invade corneal tissue and reducing corneal lymphangiogenesis associated with a dry-eye associated ocular surface disease, wherein said composition consists of a vehicle and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 16. ### Claim 12 (depends on 11) The method of claim 11, wherein said activity comprises binding of an inflammatory IL-1 cytokine to an IL-1 receptor. ### Claim 13 A method for minimizing corneal lymphangiogenesis associated with a dry-eye associated ocular surface disease in a subject in need thereof, comprising the steps of: (a) identifying said subject at risk of developing lymphangiogenesis onset associated with a dry-eye associated ocular surface disease, wherein said subject is at risk of developing a dry-eye associated ocular surface disease; and (b) locally administering to the cornea of said subject a composition that inhibits an activity of an inflammatory interleukin-1 cytokine prior to said development, thereby inhibiting the ability of lymphatic vessels to form or expand within, or to invade corneal tissue, wherein said composition consists of a vehicle and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 16. ### Claim 14 A method for reducing the induction of immunity to corneal antigens in a cornea in a dry-eye associated ocular surface disease of a subject in need thereof, comprising the steps of: (a) identifying a subject with said induction of immunity to corneal antigens in dry-eye associated ocular surface disease; and (b) locally administering to the cornea of said subject a composition that inhibits an activity of an inflammatory interleukin-1 cytokine, thereby inhibiting the ability of lymphatic vessels to expand within or to invade corneal tissue and reducing the induction of immunity to corneal antigens, wherein said lymphatic vessels permit the transport of immune cells between said corneal tissue and lymphoid tissues and the initiation of an immune response to corneal antigens, wherein said composition consists of a vehicle and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 16. ### Claim 15 A method for minimizing induction of immunity to corneal antigens in a cornea of a subject in need thereof, comprising the steps of: (a) identifying said subject at risk of developing said immunity to corneal antigens in dry-eye associated ocular surface disease; and (b) locally administering to the cornea of said subject a composition that inhibits an activity of an inflammatory interleukin-1 cytokine prior to said development, thereby inhibiting the ability of lymphatic vessels to expand within or to invade corneal tissue and minimizing said induction of immunity to corneal antigens, wherein said lymphatic vessels permit the transport of immune cells between said corneal tissue and lymph nodes and the initiation of an immune response to corneal antigens, wherein said composition consists of a vehicle and a polypeptide consisting of the amino acid sequence of SEQ ID NO: 16.