Sigma-2 receptor (TMEM97) ligands for ocular healing

Abstract

Provided herein are methods, compositions, and kits to promote ocular healing. In particular, provided herein are reagents and methodologies to promote ocular healing comprising a sigma-2 receptor (TMEM97) ligand.

Description

[0001]Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 SIGMA-2 RECEPTOR (TMEM97) LIGANDS FOR OCULAR HEALING FIELD Provided herein are methods, compositions, and kits to promote ocular healing. In particular, provided herein are reagents and methodologies to promote ocular healing comprising a sigma-2 receptor (TMEM97) ligand. BACKGROUND Ocular diseases including corneal diseases are a substantial public health concern. For example, loss of vision, quality of life, and function due to corneal pathologies affect millions of people worldwide. Many conditions affect corneal clarity, including traumatic, inflammatory, infectious, chemical exposures and hereditary conditions. The corneal epithelium protects the corneal stroma and mediates responses to the external environment by preventing pathogen entry and responding to injury. Corneal and ocular surface injuries are common and range from painful, short-lived injuries to chronic non-healing wounds that lead to infection, inflammation, and loss of vision or loss of an eye. These injuries affect more than 1 million patients per year. Current standards of care include observation and prophylaxis for infection with antibiotics for minor injuries, or therapeutic amniotic membrane contact lenses or surgical tarsorrhaphy for severe or recurrent injuries. Accordingly, patients will benefit from a non-invasive treatment that accelerates recovery times and reduces the time during which they have poor vision, pain, and are at risk of infection. SUMMARY Provided herein are methods, compositions, and kits to promote ocular healing. In particular, provided herein are reagents and methodologies to promote ocular healing comprising a sigma-2 receptor (TMEM97) ligand. Exemplary, non-limiting compositions, kits and methods are described below. In some embodiments, the present invention provides method of treating, ameliorating, or preventing recurrence of an ocular condition in a patient, comprising administering to the patient a therapeutically effective amount of a sigma-2 receptor (TMEM97) ligand and a pharmaceutically acceptable carrier. In some embodiments, the TMEM97 ligand is an oxysterol. Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 In some embodiments, the oxysterol is oxysterol 20(S)-hydroxycholesterol (20(S)-OHC). In some embodiments, the TMEM97 ligand is a small molecule. In some embodiments, the small molecule is glycerol phenylbutyrate (PBU). In some embodiments, the small molecule comprises a 2,7-diazaspiro[4.4]nonane scaffold flanked by benzyl and homobenzyl substituents at 2 nitrogens with a benzyl substituent substituted with a geminal ethyl ester group (AD223). In some embodiments, the small molecule is 2-(4-morpholinethyl)-1- phenylcyclohexanecarboxylate hydrochloride (PRE084). In some embodiments, the ocular condition is one or more conditions selected from a corneal injury, an ocular ulcer, an ocular infection, an ocular condition of aging, a foreign body, a thyroid ocular disease, a corneal dystrophy, a chemical exposure and / or an ocular immune condition. In some embodiments, the patient is a mammal. In some embodiments, the mammal is a human. In some embodiments, the administering is topical administering. In some embodiments, the present invention provides a kit comprising a pharmaceutical composition comprising a TMEM97 ligand and a component for topical administration of the TMEM97 ligand. In some embodiments, the TMEM97 ligand is 20(S)- OHC, PBU, AD223 or PRE084. In some embodiments, the component comprises a dropper. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one TMEM97 ligand and a pharmaceutically acceptable carrier, and / or a pharmaceutically acceptable formulation. In some embodiments, the TMEM97 ligand is 20(S)-OHC, PBU, AD223 or PRE084. In some embodiments, the present invention provides a pharmaceutical composition comprising a topical formulation of a TMEM97 ligand. In some embodiments, the TMEM97 ligand 20(S)-OHC, PBU, AD223 or PRE084. In some embodiments, a pharmaceutical composition of the present invention further comprises an antibiotic, an anti-inflammatory agent, a sterol, and / or a growth factor. In some embodiments, a pharmaceutical composition of the present invention is provided in dosage form. In some embodiments, the present invention provides use of a kit or a pharmaceutical composition of the present invention. In some embodiments, the present invention provides use of a kit or pharmaceutical composition of the present invention for the treatment of an eye condition or disease. Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 DESCRIPTION OF THE FIGURES Figures 1A-F show that 20(S)-OHC induces human corneal epithelial (HCE) cell migration and wound healing. Figure 1A shows a Boyden chamber assay for cell migration. Cells are tested for chemotaxis towards 20(S)-OHC at 0.1 - 20 µg / mL in 0.5% FBS media for 20 h. Images showing HCE cells are stained with hematoxylin and eosin (inset). Cell migration is displayed in fold change relative to untreated samples. The increase in migration of cells exposed to 20(S)-OHC is significant and dose-dependent. Figure 1B shows that knockout (KO) of TMEM97 inhibits 20(S)-OHC induced migration. HCE cells were transfected with a TMEM97 CRISPR plasmid system. After cell selection, TMEM97 KO efficiency was assessed by Western blot using an α-TMEM97 antibody versus control cells (inset). Migration rates using a Boyden chamber assay comparing wild type (Wt, black bar) and TMEM97 KO (white bar) show significant loss of response to 20(S)-OHC in TMEM97 KO HCE cells supporting the role of TMEM97 for 20(S)-OHC induced migration. Figure 1C shows that the R-epimer of 20-OHC induces insignificant migration compared to the S- epimer, and that migration is induced in a dose-dependent manner with 20(S)-OHC treatment but not with 20(R)-OHC. Figure 1D shows that 20(S)-OHC is well-tolerated by HCE. The viability of 20(S)-OHC-treated HCE cells was measured using an MTT assay (black, LD50 = 9.24 ± 1.2 µg / mL), and cytotoxicity was evaluated using an LDH assay (white shows LDH release in cell lysate, Ctrl is use of lysis buffer). The results are displayed in percentage of untreated (MTT) or control (LDH) samples. Concentrations of 20(S)-OHC that induce migration have limited cytotoxicity and minimal effects on metabolic activity. Figure 1E shows that 20(S)-OHC accelerates cell migration in standardized scratch assays using time- lapse microscopy.20(S)-OHC application leads to a statistically significant and dose- dependent improvement in scratch closure rates compared to untreated controls. Scale bar = 500 µm. The line graph depicts scratch closure % over time. Figure 1E images show wound healing 12 hours after scratching with and without the presence of 20(S)-OHC (inset). Figure 1F shows direct binding analysis by surface plasmon resonance (SPR) of binding of 20(S)- OHC with recombinant TMEM97. In sensorgrams of 20(S)-OHC binding to TMEM97, the estimated Kd value is 11.5 µM. Kd values were calculated from 2 rate constants determined by fitting the data with a 1:1 Langmuir kinetic model. The average Kd values and standard deviations were calculated from 2-4 independent experiments. Statistical significance was determined by a student’s t test. *p < 0.05 and **p < 0.01. Figures 2A-B shows that application of 20(S)-OHC accelerates corneal wound closure rates in a murine corneal epithelial injury model. Figure 2A shows slit-lamp Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 biomicroscopic images of murine corneas using a cobalt filter and fluorescein dye. Staining of the wounded areas is shown among the experimental groups (N = 5 for each group) with treatment of 10 μg / ml of 20(S)-OHC or vehicle (Balanced Salt Solution, BSS). Figure 2B shows wound areas at multiple time points measured using ImageJ software. Measurement of relative remaining corneal wound area at each time point compared to baseline showed statistically significant improvement in 20(S)-OHC treatment groups compared to BSS treated mice. Statistical significance was determined by a student’s t test. **p < 0.01, ***p < 0.001. relative wound area = wound area at time x / wound area at time 0. Figures 3A-E show that glycerol phenylbutyrate (PBU) induces human corneal epithelial (HCE) cell migration and murine corneal epithelial wound healing. Figure 3A shows cells tested for chemotaxis with PBU at the indicated concentrations (0.1 – 1000 µM) in 0.5% FBS media for 20 h in a Boyden assay chamber. The increase in migration of cells exposed to PBU is significant and dose-dependent. Figure 3B shows that PBU is well tolerated by HCE. Cell viability was measured using an MTT assay (black). Cytotoxicity in treated cells was evaluated using an LDH assay (white, Ctrl is LDH in cell lysate). PBU over a range of concentrations showed limited cytotoxicity and minimal effect on metabolic activity in HCE. Figure 3C shows SPR analysis demonstrating that PBU binds to recombinant TMEM97 protein with high affinity (Kd = 67 nM). Kd values were calculated from 2 rate constants determined by fitting the data with a 1:1 Langmuir kinetic model. Figure 3D shows that PBU treatment accelerates corneal wound closure rates in a murine corneal epithelial injury model. Slit-lamp biomicroscopic images of murine corneas using a cobalt filter and fluorescein dye staining of the wounded areas are shown among the experimental groups (N = 5 for each group) with treatment of 10 μM PBU or vehicle (Balanced Salt Solution, BSS). Figure 3E shows wound areas at multiple time points measured using ImageJ software. Measurement of relative remaining corneal wound area at each time point compared to baseline showed statistically significant improvement in PBU treatment groups compared to BSS treated mice. Statistical significance was determined by a student’s t test. **p < 0.01, ***p < 0.001. relative wound area = wound area at time x / wound area at time 0. Figures 4A-B show assessment of cell migration activation using small molecule modulators of TMEM97 in human corneal epithelial cells (HCE). Figure 4A shows HCE cells treated with each compound (10 μM) in 0.5% FBS media for 20 h. Cell migration was measured using a Boyden chamber assay. AD223 and PRE084 showed significant activation of cell migration. Figure 4B shows cell viability measured using the MTT assay (black). Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 Cytotoxicity in treated cells was evaluated using the LDH assay (white, Ctl is LDH release in cell lysate). Small molecule compounds showed no substantial toxicity at this concentration. Each value represents the mean ± S.D. and is representative of results obtained from three independent experiments. Statistical significance was determined by Student’s t test. *p < 0.05 and **p < 0.01. Figures 5A-E show that AD223 induces human corneal epithelial (HCE) cell migration and murine corneal epithelial wound healing. Figure 5A shows cells tested for chemotaxis toward AD223 at the indicated concentrations (0.1 –100 µM) in 0.5% FBS media for 20 h in a Boyden assay chamber showing a significant and dose-dependent increase in migration of cells exposed to AD223. Each value represents the mean ± S.D. and is representative of results obtained from three independent experiments. Statistical significance was determined by Student’s t test. *p < 0.05 and **p < 0.01. Figure 5B shows that AD223 was well tolerated by HCE cells. Cell viability was measured using an WST-1 assay with a minimal effect on metabolic activity in HCE cells treated with AD223 over a range of concentrations. Figure 5C shows a SPR analysis showing that AD223 binds recombinant TMEM97 protein with high affinity (Kd = 1.1 nM). Kd values were calculated from 2 rate constants determined by fitting data with a 1:1 Langmuir kinetic model. Figure 5D shows that AD223 accelerates cell migration in standardized scratch assays using time-lapse microscopy. AD223 application leads to a statistically significant and dose-dependent improvement in scratch closure rates compared to untreated controls (Un). Scale bar = 500 μm. Figure 5E shows a graph depicting scratch closure % over time showing a statistically significant improvement in scratch closure rates [versus untreated control (Un)] with AD223 treatment (10 and 20 μM) of concentrations at 12 to 24 h. Statistical significance was determined by a student’s t test. *p< 0.05, and **p< 0.01. Figures 6A-B show that AD223 accelerates corneal wound closure rates in a murine corneal epithelial physical injury debridement model. Figure 6B shows slit-lamp biomicroscopic images of murine corneas using a cobalt filter and fluorescein dye staining of the wounded areas shown between experimental groups (N= 5 for each group) with treatment of 100 µM of AD223 or vehicle (Balanced Salt Solution, BSS). Figure 6B shows wound areas at serial time points measured using ImageJ software. Measurement of relative remaining corneal wound area at each time point compared to baseline showed statistically significant improvement in AD223 treatment groups compared to BSS treated mice. Statistical significance was determined by a student’s t test. *p< 0.05, **p< 0.01. relative wound area= wound area at time-x / wound area at time 0. Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 Figures 7A-F shows that 20S-OHC mitigates corneal damage induced by alkali injury in a murine model. Seven-week-old C57BL / 6 mice received corneal injuries using NaOH- soaked filter paper (1.5 mm,0.5N NaOH, 30 sec) and were treated with BSS or 20S-OHC (10 or 20 µg / ml) three times daily. 20S-OHC accelerates corneal wound healing. (Figure 7A) Slit-lamp biomicroscopic images of fluorescein-stained murine corneas were captured across experimental groups (n = 5 per group). (Figure 7 D) Wound areas at multiple time points were measured using ImageJ software. The percentage of remaining corneal wound area at 18 and 24 hours showed significant improvement in the 20S-OHC-treated group compared to BSS. Wound area (%) = (wound area at time x / wound area at time 0) × 100. 20S-OHC reduces corneal neovascularization. (Figure 7B) White-light images show the neovascularization induced by alkali injury. (Figure 7E) Neovascularization was graded on a scale from 0 to 4. Where 0- no vessels on the corneal limbus;1- vessels advance over the corneal limbus, covering 0-25% of the burned area; 2-vessels that will reach 25-50% of the burned area; 3- vessels that will reach 50-75% of the burned area; 4- vessels that will extend to the entire burned area. Treatment with 20 µg / ml of 20S-OHC strongly inhibited alkali induced corneal neovascularization.20S-OHC reduces corneal opacification induced by alkali burns. (Figure 7C) White-light images depict corneal epithelial injuries in BSS- and 20S-OHC-treated groups. Corneal opacity was significantly lower in 20S-OHC-treated mice than in the BSS group. (Figure 7F) A histogram quantifies corneal opacity at different time points using a grading scale (0–4). Where 0- no opacity, completely clear cornea; 1 - slightly hazy, iris and lens visible; 2 - moderately opaque, iris and lens still detectable; 3- severely opaque, iris and lens hardly visible; 4- completely opaque, with no view of iris and lens. All values are expressed as mean ± SEM (n = 5 per group). Statistical significance was determined by two-way ANOVA with multiple comparisons. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Figure 8 shows that 20S-OHC treatment improves histological features after alkali injury. H&E staining shows different features associated with injury, including immune cell infiltration, stromal edema, and reduced epithelial thickness with injury compared with uninjured (healthy) and substantial normalization in the 20S-OHC treated versus the control (BSS treated) group. (Panel A) There was significantly fewer immune cell infiltration, reduced stromal thickness, and increased epithelial thickness in corneas treated with 20S- OHC versus controls. (Panels B, C). Immunohistochemistry (IHC) staining of corneal sections using CD45 and F4 / 80 antibodies showed that immune cells infiltrated the corneal stroma on day 14 after alkali burn. Both CD45 + hematopoietic immune cells and F4 / 80+ Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 macrophages numbers were elevated in injured versus uninjured animals and underwent relative normalization in the 20S-OHC group compared with the BSS (control) treated group. Immunofluorescent staining showed higher α-SMA expression in myofibroblasts in the injured area (BSS) compared to the healthy and 20-S-OHC-treated groups, indicating more myofibroblasts in the injury site. (Panel D) Figure 9 shows the effects of 20(S)-OHC in a corneal stromal injury model. Eight- week-old C57BL / 6 mice were treated 3 times daily with either BSS or 20S-OHC (20 µg / ml) after superficial keratectomy and corneal stromal injury. Panel A shows slit-lamp biomicroscopic images of fluorescein-stained murine corneas were captured across experimental groups.20S-OHC accelerates corneal wound healing at 24 hours. Panel B shows white-light images showing corneal scaring in BSS- and 20S-OHC-treated groups. At 10 days, mice treated with 20S-OHC showed reduced corneal opacification compared to the BSS groups, indicating the effects of 20(S)-OHC in promoting corneal wound healing and reducing corneal opacification. Yellow arrow denotes the scarring lesion. Figures 10A-B show the effects of 20(S)-OHC in a corneal alkali burn injury model. Triple treatment per day was conducted for 2 weeks comparing 20(S)-OHC (20ug / mL) (n = 5) to BSS as a control (n = 5). DEFINITIONS Throughout the specification and claims, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. The phrase “in some embodiments” as used herein does not necessarily refer to the same embodiment, though it may. Thus, as described below, various embodiments of the invention may be readily combined, without departing from the scope or spirit of the invention. In addition, as used herein, the term “or” is an inclusive “or” operator and is equivalent to the term “and / or” unless the context clearly dictates otherwise. The term “based on” is not exclusive and allows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of “a,” “an,” and “the” include plural references. The meaning of “in” includes “in” and “on.” The term “one or more,” as used herein, refers to a number higher than one. For example, the term “one or more” encompasses any of the following: two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, twenty or more, fifty or more, 100 or more, or an even greater number. Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 The term “one or more but less than a higher number,” “two or more but less than a higher number,” “three or more but less than a higher number,” “four or more but less than a higher number,” “five or more but less than a higher number,” “six or more but less than a higher number,” “seven or more but less than a higher number,” “eight or more but less than a higher number,” “nine or more but less than a higher number,” “ten or more but less than a higher number,” “eleven or more but less than a higher number,” “twelve or more but less than a higher number,” “thirteen or more but less than a higher number,” “fourteen or more but less than a higher number,” or “fifteen or more but less than a higher number” is not limited to a higher number. For example, the higher number can be 10,000, 1,000, 100, 50, etc. For example, the higher number can be approximately 50 (for example, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 32, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2). As used herein, the terms “patient” or “subject” refer to organisms to be subject to various tests described herein. The term “subject” includes animals, preferably mammals, including humans. In a preferred embodiment, the subject is a primate. In an even more preferred embodiment, the subject is a human. Further with respect to diagnostic methods, a preferred subject is a vertebrate subject. A preferred vertebrate is warm-blooded; a preferred warm-blooded vertebrate is a mammal. A preferred mammal is most preferably a human. As used herein, the term “subject” includes both human and animal subjects. Thus, veterinary therapeutic uses are provided herein. As such, the present disclosure provides for the diagnosis of mammals such as humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms for consumption by humans; and / or animals of social importance to humans, such as animals kept as pets or in zoos. Examples of such animals include but are not limited to carnivores such as cats and dogs; swine, including pigs, hogs, and wild boars; ruminants and / or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels; pinnipeds; and horses. Thus, also provided is the diagnosis and treatment of livestock, including, but not limited to, domesticated swine, ruminants, ungulates, horses (including racehorses), and the like. As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of a federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and, more particularly, in humans. The term "carrier" and / or “formulation” refers to a diluent, adjuvant, excipient, or Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 vehicle with which the therapeutic is administered and includes, but is not limited to, such sterile liquids as water and oils. A "pharmaceutically acceptable salt" or "salt" is a product of a disclosed compound that contains an ionic bond and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for administering to an individual. A pharmaceutically acceptable salt can include, but is not limited to, acid addition salts including hydrochlorides, hydrobromides, phosphates, sulphates, hydrogen sulphates, alkylsulphonates, arylsulphonates, arylalkylsulfonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactates, and tartrates; alkali metal cations such as Li++, Na++, K+, alkali earth metal salts such as Mg++ or Ca++, or organic amine salts. A "pharmaceutical composition" is a formulation comprising an oxysterol in a form suitable for administration to an individual. A pharmaceutical composition is typically formulated to be compatible with its intended route of administration. In some embodiments, the pharmaceutical composition is formulated for topical administration. As used herein, the term "therapeutically effective amount" generally means the amount necessary to ameliorate at least one symptom of a disorder or condition to be prevented, reduced, or treated as described herein. The phrase "therapeutically effective amount" as it relates to the oxysterol of the present disclosure means the oxysterol dosage that provides the specific pharmacological response for which the oxysterol is administered in a significant number of individuals in need of such treatment. It is emphasized that a therapeutically effective amount of an oxysterol that is administered to a particular individual in a particular instance will not always be effective in treating the conditions / diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art. As used herein, “small molecule” refers to a molecule of low molecular weight, for example, a molecule with a molecular weight equal to less than 1000 Daltons. In some embodiments, a small molecule is an organic molecule. In some embodiments, a small molecule is an inorganic molecule. In some embodiments, a small molecule binds to a larger target molecule, for example a protein, and alters an activity or property of a larger target molecule. Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 As used herein, the term “second agent” refers to a therapeutic agent other than an oxysterol in accordance with the present invention. In certain instances, the second agent is an anti-inflammatory agent, an antibiotic, a steroid, and / or a growth factor. The term “co-administration” refers to the administration of at least two agent(s) (for example, an oxysterol ) or therapies to a subject. In some embodiments, the co- administration of two or more agents / therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the formulations and / or routes of administration of the various agents / therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when agents / therapies are co- administered, the respective agents / therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents / therapies lowers the requisite dosage of a known potentially harmful (for example, toxic) agent(s). DETAILED DESCRIPTION Provided herein are methods, compositions, and kits to promote ocular healing. In particular, provided herein are reagents and methodologies to promote ocular healing comprising a sigma-2 receptor (TMEM97) ligand. Exemplary, non-limiting compositions, kits and methods are described below. Corneal diseases are a significant public health concern. Loss of vision, quality of life, and function due to corneal pathologies affect nearly 5 million people worldwide (Lin A, Rhee MK, Akpek EK, Amescua G, Farid M, Garcia-Ferrer FJ, Varu DM, Musch DC, Dunn SP, Mah FS; American Academy of Ophthalmology Preferred Practice Pattern Cornea and External Disease Panel. Bacterial Keratitis Preferred Practice Pattern. Ophthalmology.2019 Jan;126(1):P1-P55.). Many conditions affect corneal clarity including traumatic, inflammatory, infectious and hereditary conditions. The corneal epithelium protects the corneal stroma and mediates responses to the external environment by preventing pathogen entry and by responding to injury. Corneal and ocular surface injuries are common and range from painful, short-lived injuries to chronic non-healing wounds that may lead to infection, inflammation, and loss of vision or loss of an eye. These types of injuries affect more than 1 million patients per year (Channa R, Zafar SN, Canner JK, Haring RS, Schneider EB, Friedman DS. Epidemiology of Eye-Related Emergency Department Visits. JAMA Ophthalmol.2016 Mar;134(3):312-9.). Conventional standards of care include Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 observation and prophylaxis for infection with antibiotics for minor injuries, or therapeutic amniotic membrane contact lenses or surgical tarsorrhaphy for severe or recurrent injuries (Vaidyanathan U, Hopping GC, Liu HY, Somani AN, Ronquillo YC, Hoopes PC, Moshirfar M. Persistent Corneal Epithelial Defects: A Review Article. Med Hypothesis Discov Innov Ophthalmol.2019 Fall;8(3):163-176., Walkden A. Amniotic Membrane Transplantation in Ophthalmology: An Updated Perspective. Clin Ophthalmol.2020 Jul 22;14:2057-2072., Portnoy SL, Insler MS, Kaufman HE. Surgical management of corneal ulceration and perforation. Surv Ophthalmol.1989 Jul-Aug;34(1):47-58.). No effective treatments to actively promote wound healing for epithelial defects are available to patients. Thus, there is a need for improved approaches to promote appropriate wound healing. Patients would benefit from a non-invasive treatment that would accelerate recovery times and reduce the time during which they have poor vision, pain, and are at risk of infection. Corneal epithelial wounds can predispose to bacterial infections, such as bacterial keratitis, especially in contact lens wearers. Such inflammatory and infectious sequelae of acute corneal wounds can lead to severe visual loss, pain and even endophthalmitis (Kaye AD, Renschler JS, Cramer KD, Anyama BO, Anyama EC, Gayle JA, Armstead-Williams CM, Mosieri CN, Saus JA, Cornett EM. Postoperative Management of Corneal Abrasions and Clinical Implications: a Comprehensive Review. Curr Pain Headache Rep.2019 May 30;23(7):48., Ljubimov AV. Diabetic complications in the cornea. Vision Res.2017 Oct;139:138-152.). Persistent epithelial defects (for example, chronic corneal wounds) may result from even relatively minor acute corneal trauma, especially in patients with co-morbid conditions like diabetes, post-herpetic keratopathy, neurotrophic keratopathy, limbal stem cell deficiency (LCSD), as a chronic sequela of dry eye disease, exposure keratopathy (from facial nerve palsy or other causes), or alkali and other chemical injuries. A high proportion of diabetic patients have corneal pathology ranging from insensate corneas to epithelial fragility and recalcitrant wounds. Moreover, chemical injuries and chronic conditions are associated with aberrant wound healing, poor epithelialization, corneal melting from proteases refractory inflammation, infection, eventual neovascularization from angiogenesis, scarring, and costs of care of over $90,000 over 5 years (Awasthi P, Singh P, Raj A. Surgical Management and Recent Advances in Chemical Injury: A 5-year Review. Semin Ophthalmol.2022 Jan 2;37(1):49-56., Ahmmed AA, Ting DSJ, Figueiredo FC. Epidemiology, economic and humanistic burdens of Ocular Surface Chemical Injury: A narrative review. Ocul Surf.2021 Apr;20:199-211., Kamil S, Mohan RR. Corneal stromal wound healing: Major regulators and therapeutic targets. Ocul Surf.2021 Jan;19:290-306.). Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 The sigma-2 receptor (TMEM97) is an endoplasmic reticulum (ER)-resident receptor protein that participates in cholesterol processing, cancer, and neurodegenerative diseases with impacts on multiple aspects of ocular biology and pathology. TMEM97 is a scaffolding protein that interacts with cholesterol homeostasis regulators such as NPC1, PGRMRC1, and TSPO, as well as signal transducers such as LRP6, STIM1, and TEX264 (Cheng YS, Zhang T, Ma X, Pratuangtham S, Zhang GC, Ondrus AA, Mafi A, Lomenick B, Jones JJ, Ondrus AE. A proteome-wide map of 20(S)-hydroxycholesterol interactors in cell membranes. Nat Chem Biol.2021 Dec;17(12):1271-1280., Ebrahimi-Fakhari D, Wahlster L, Bartz F, Werenbeck- Ueding J, Praggastis M, Zhang J, Joggerst-Thomalla B, Theiss S, Grimm D, Ory DS, Runz H. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells. Hum Mol Genet.2016 Aug 15;25(16):3588-3599., Riad A, Zeng C, Weng CC, Winters H, Xu K, Makvandi M, Metz T, Carlin S, Mach RH. Sigma-2 Receptor / TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. Sci Rep.2018 Nov 15;8(1):16845., Thejer BM, Infantino V, Santarsiero A, Pappalardo I, Abatematteo FS, Teakel S, Van Oosterum A, Mach RH, Denora N, Lee BC, Resta N, Bagnulo R, Niso M, Contino M, Montsch B, Heffeter P, Abate C, Cahill MA. Sigma-2 Receptor Ligand Binding Modulates Association between TSPO and TMEM97. Int J Mol Sci.2023 Mar 28;24(7):6381., Cantonero C, Camello PJ, Abate C, Berardi F, Salido GM, Rosado JA, Redondo PC. NO1, a New Sigma 2 Receptor / TMEM97 Fluorescent Ligand, Downregulates SOCE and Promotes Apoptosis in the Triple Negative Breast Cancer Cell Lines. Cancers (Basel).2020 Jan 21;12(2):257., Peterson C, Chandler HL. Insulin facilitates corneal wound healing in the diabetic environment through the RTK-PI3K / Akt / mTOR axis in vitro. Mol Cell Endocrinol.2022 May 15;548:111611., An H, Ordureau A, Paulo JA, Shoemaker CJ, Denic V, Harper JW. TEX264 Is an Endoplasmic Reticulum-Resident ATG8-Interacting Protein Critical for ER Remodeling during Nutrient Stress. Mol Cell.2019 Jun 6;74(5):891-908.e10.) In some embodiments, the present invention provides methods, compositions and kits for TMEM97 ligand administration to promote healing in, for example, ocular tissues. In some embodiments, methods of the present invention comprise administering to a patient a therapeutically effective amount of a TMEM97 ligand, a pharmaceutically acceptable carrier and / or pharmaceutically acceptable formulation. In some embodiments, the TMEM97 ligand is an oxysterol. In some embodiments, the oxysterol is oxysterol 20(S)- hydroxycholesterol (20(S)-OHC). In some embodiments, the TMEM97 ligand is a small molecule. In some embodiments, the small molecule is glycerol phenylbutyrate (PBU). In Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 some embodiments, the small molecule is compound AD223. Compound AD223 comprises a 2,7-diazaspiro[4.4]nonane scaffold flanked by benzyl and homobenzyl substituents at two nitrogens wherein the benzyl substituent is substituted with a geminal ethyl ester group. Structure activity relationship studies suggest that the ester function provides for sigma-2 receptor over sigma-1 receptor selectivity, with additional hydrogen bond interactions with the sigma-2 receptor. In some embodiments, the small molecule is PRE084. (2-(4- morpholinethyl)-1-phenylcyclohexanecarboxylate hydrochloride) In some embodiments, the small molecule is not a histidine-rich peptide, for example, histatin. In some embodiments, methods of the present invention comprise administering to a patient a therapeutically effective amount of a TMEM97 ligand and a pharmaceutically acceptable carrier, and / or pharmaceutically acceptable formulation. In some embodiments, the TMEM97 ligand is an oxysterol. In some embodiments, the oxysterol is oxysterol 20(S)- hydroxycholesterol (20(S)-OHC). In some embodiments, the TMEM97 ligand is a small molecule. In some embodiments, the small molecule TMEM97 ligand is PBU, AD223 and / or PRE084. In some embodiments, the administration comprises topical administration of a topical formulation comprising, for example, eyedrops, a gel, a lotion, an ointment, an emulsion, a coating (for example, a coating on a contact lens or other medical device). In some embodiments, the administration comprises an injectable administration, for example, an intraepithelial injection. In some embodiments, administration comprises co-administration of a TMEM97 ligand with, for example, one or more of an antibiotic, a steroid, an anti-inflammatory agent, a growth factor (for example, fibroblast growth factor (FGF) or nerve growth factor (NGF), a therapeutic lubricant for keratoconjunctivitis (i.e., “dry eye” that is common among elderly persons), a stem cell, an exosome, an antiviral (for example, an anti-HSV anti-viral), a gene therapy, for example, a viral vector gene therapy for a hereditary or acquired corneal dystrophy, an mRNA / siRNA, a CRISPR associated gene therapy or gene editing system, a pro- or anti-angiogenic factor, an anti-oxidant, and / or a vitamin, for example, vitamin C or and AREDs treatment comprising a supplement of antioxidant plant pigments lutein and zeaxanthin, vitamin C and E and zinc and copper. In some embodiments, the administration comprises co-administration of two or more TMEM97 ligands, for example, co-administration of 20(S)-OHC with AD223 and / or PBU. In some embodiments, the present invention provides a therapeutic for the prevention and or treatment of a disorder of the eye. In some embodiments, the eye disorder is an ocular injury, for example a corneal injury, an inflammatory condition of the eye, an ocular ulcer, an Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 ocular infection (for example, a viral, bacterial, parasitic or fungal eye infection), an ocular condition of aging, a foreign body, a thyroid ocular disease (for example, exophthalmos), neurotrophic pain or other ocular pain, limbal stem cell deficiency, a corneal dystrophy, a corneal endothelial disease, corneal neovascularization, an ocular immune condition, an autoimmune ocular condition, and / or an intraocular disease. In some embodiments the dose of TMEM97 ligand is from 0.001 mg / mL to 10,000 mg / mL (for example, 0.01 mg / mL to 1,000 mg / mL (for example, 0.1 mg / mL to 100 mg / mL)). In some embodiments, the dose of TMEM97 ligand is from 1.0 mg / mL to 10 mg / mL. In some embodiments, the dose of TMEM97 ligand is 10 mg / mL. In some embodiments, the present invention comprises a kit comprising, for example, one or more of a TMEM97 ligand, a vial, a dropper, a gel administration tip, instructions, a sponge and / or a compress. Pharmaceutical compositions that include at least one TMEM97 ligand described herein and at least one pharmaceutically acceptable carrier may also include one or more other active agents. The TMEM97 ligands described herein can be utilized in any pharmaceutically acceptable dosage form, including but not limited to injectable dosage forms, liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, dry powders, tablets, capsules, controlled release formulations, fast melt formulations, delayed release formulations, extended-release formulations, pulsatile release formulations, mixed immediate release and controlled release formulations, etc. Solutions or suspensions used for corneal, parenteral, intradermal, or subcutaneous application can comprise one or more of the following components: (1) a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; (2) antibacterial agents such as benzyl alcohol or methyl parabens; (3) antioxidants such as ascorbic acid or sodium bisulfite; (4) chelating agents such as ethylenediaminetetraacetic acid; (5) buffers such as acetates, citrates or phosphates; and (6) agents for the adjustment of tonicity such as salts (for example, sodium chloride) or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. A parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. In some embodiments, compositions of the present invention are provided in a formulation compatible with ophthalmic administration. See, for example: Navarro-Partida J, Castro-Castaneda CR, Santa Cruz-Pavlovich FJ, Aceves-Franco LA, Guy TO, Santos A. Lipid-based nanocarriers as topical drug delivery systems for intraocular diseases. Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 Pharmaceutics.2021 May 9;13(5):678; Wroblewska KB, Jadach B, Muszalska-Kolos I. Progress in drug formulation design and delivery of medicinal substances used in ophthalmology. International Journal of Pharmaceutics.2021 Sep 25;607:121012; López- Cano JJ, González-Cela-Casamayor MA, Andrés-Guerrero V, Herrero-Vanrell R, Molina- Martínez IT. Liposomes as vehicles for topical ophthalmic drug delivery and ocular surface protection. Expert opinion on drug delivery.2021 Jul 3;18(7):819-47; Jerkins GW, Pattar GR, Kannarr SR. A review of topical cyclosporine A formulations—a disease-modifying agent for keratoconjunctivitis sicca. Clinical Ophthalmology.2020 Feb 20:481-9; Periman LM, Mah FS, Karpecki PM. A review of the mechanism of action of cyclosporine A: the role of cyclosporine A in dry eye disease and recent formulation developments. Clinical Ophthalmology.2020 Dec 2:4187-200; Ghezzi M, Ferraboschi I, Delledonne A, Pescina S, Padula C, Santi P, Sissa C, Terenziani F, Nicoli S. Cyclosporine-loaded micelles for ocular delivery: Investigating the penetration mechanisms. Journal of Controlled Release.2022 Sep 1;349:744-55; Osi B, Khoder M, Al-Kinani AA, Alany RG. Pharmaceutical, biomedical and ophthalmic applications of biodegradable polymers (BDPs): literature and patent review. Pharmaceutical Development and Technology.2022 Mar 16;27(3):341-56; Rahnfeld L, Luciani P. Injectable lipid-based depot formulations: where do we stand?. Pharmaceutics. 2020 Jun 19;12(6):567; Castro-Balado A, Mondelo-García C, Zarra-Ferro I, Fernández- Ferreiro A. New ophthalmic drug delivery systems. Farmacia Hospitalaria.2020 Jul 1;44(4):149-57; Navarro-Partida J, Castro-Castaneda CR, Santa Cruz-Pavlovich FJ, Aceves- Franco LA, Guy TO, Santos A. Lipid-based nanocarriers as topical drug delivery systems for intraocular diseases. Pharmaceutics.2021 May 9;13(5):678; Toffoletto N, Saramago B, Serro AP. Therapeutic ophthalmic lenses: a review. Pharmaceutics.2020 Dec 28;13(1):36; and Wei J, Mu J, Tang Y, Qin D, Duan J, Wu A. Next-generation nanomaterials: advancing ocular anti-inflammatory drug therapy. Journal of nanobiotechnology.2023 Aug 19;21(1):282,, each of which is herein incorporated by reference in its entirety. Pharmaceutical compositions suitable for injectable use may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous and tissue administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The pharmaceutical composition should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The term "stable", as used herein, means remaining in a state or condition that is suitable for Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 administration to a subject. For example, in some embodiments, where the formulation comprises an emulsion, the emulsion is sufficiently stable to allow for short- or long-term storage prior to use. Sterile injectable solutions can be prepared by incorporating the active reagent (for example, a TMEM97 ligand) in an appropriate amount in an appropriate solvent with one or a combination of ingredients enumerated above, as desired, followed by filtered sterilization. Generally, dispersions are prepared by incorporating at least one oxysterol into a sterile vehicle that contains a basic dispersion medium and any other desired ingredient. In some embodiments, a TMEM97 ligand is prepared with a carrier that protects against rapid elimination from the body. For example, a controlled release formulation can be used, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. Additionally, suspensions of a TMEM97 ligand may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as castor oil, sesame oil, or synthetic fatty acid esters, such as ethyl oleate, triglycerides, or liposomes. Non-lipid polycationic amino polymers may also be used for delivery. Optionally, the suspension may also include suitable stabilizers or agents to increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. In some embodiments, it is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of an oxysterol calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of TMEM97 ligands described herein are dictated by and directly dependent on the characteristics of the particular TMEM97 ligand and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active agent for the treatment of individuals. Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 EXPERIMENTAL EXAMPLES EXAMPLE 1 – 20(S)-OHC modulates gene expression related to cholesterol metabolism and phosphoinositide signaling in human corneal epithelium. Transcriptome analysis was used to test differential gene expression in human corneal epithelia (HCE) treated with 20(S)-OHC. Significantly altered TMEM97- dependent pathways include cholesterol metabolism and PI3K-Akt signaling that are both important regulators of corneal epithelial function. Human corneal epithelial (HCE) cells were treated with 10 µg / mL of 20(S)-OHC for 8 hours. Cells were harvested and total RNA was prepared with a RNeasy Plus Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. RNA sequencing and statistical analysis were performed by Novogene (Sacramento, CA) on total RNA from HCE. Signaling pathway findings in RNA seq data were validated using assays for the activity of Akt, where Akt phosphorylation was analyzed by Western blot at several different time points using phospho-Akt (Ser473) antibody according to techniques reported previously. Transcriptome analysis showed that 113 genes were significantly differentially expressed following 20(S)-OHC treatment of HCE. Among these, 52 genes were upregulated and 61 genes were downregulated. Enrichment analysis showed that the differentially expressed genes are correlated with cholesterol metabolism and sterol biosynthesis in addition to enrichment in the PI3K-Akt signaling pathway. Following treatment with 20(S)- OHC, Akt activation was assayed at serial time points using Western blot analysis, with most prominent activation observed at 2 hours after treatment. These data indicate that 20(S)-OHC stimulates TMEM97-dependent Akt signaling, and that cholesterol metabolism is altered by 20(S)-OHC treatment. EXAMPLE 2 – AD223 induces human corneal epithelial (HCE) cell migration and murine corneal epithelial wound healing. HCE cells were tested for chemotaxis toward AD223 at the indicated concentrations (0.1 –100 µM) in 0.5% FBS media for 20 h in a Boyden assay chamber showing a significant and dose-dependent increase in migration of cells exposed to AD223 (Figure 5A). AD223 was well tolerated by HCE cells (Figure 5B). Cell viability was measured using an WST-1 assay with a minimal effect on metabolic activity in HCE cells treated with AD223 over a range of Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 concentrations. SPR analysis shows that AD223 binds recombinant TMEM97 protein with high affinity. (Figure 5C) AD223 accelerates cell migration in standardized scratch assays using time-lapse microscopy. with improvement in scratch closure % over time. (Figure 5D and 5E) EXAMPLE 3 - AD223 accelerates corneal wound closure rates in a murine corneal epithelial physical injury debridement model. Slit-lamp biomicroscopic images of murine corneas using a cobalt filter and fluorescein dye staining of the wounded areas shown between experimental groups (N= 5 for each group) with treatment of 100 µM of AD223 or vehicle (Balanced Salt Solution, BSS). (Figure 6A) Wound areas at serial time points were measured using ImageJ software. (Figure 6B) Relative remaining corneal wound area at each time point compared to baseline showed significant improvement in AD223 treatment groups compared to BSS treated mice. EXAMPLE 4 - 20S-OHC mitigates corneal damage induced by alkali injury in a murine model. Seven-week-old C57BL / 6 mice received corneal injuries using NaOH-soaked filter paper (1.5 mm,0.5N NaOH, 30 sec) and were treated with BSS or 20S-OHC (10 or 20 µg / ml) 3 times daily. 20S-OHC accelerates corneal wound healing. (Figure 7A) with slit-lamp biomicroscopic images of fluorescein-stained murine corneas were captured across experimental groups (n = 5 per group). (Figure 7 D) Wound areas at multiple time points were measured using ImageJ software. The percentage of remaining corneal wound area at 18 and 24 hours showed significant improvement in the 20S-OHC-treated group compared to BSS20S-OHC reduces corneal neovascularization. (Figure 7B) White-light images show the neovascularization induced by alkali injury. (Figure 7E) Neovascularization was graded on a scale from 0 to 4. Treatment with 20 µg / ml of 20S-OHC strongly inhibited alkali induced corneal neovascularization.20S-OHC reduces corneal opacification induced by alkali burns. (Figure 7C) White-light images depict corneal epithelial injuries in BSS- and 20S-OHC- treated groups. Corneal opacity was significantly lower in 20S-OHC-treated mice than in the BSS group. (Figure 7F) EXAMPLE 5 - 20S-OHC treatment improves histological features after alkali injury. H&E staining shows different features associated with injury, including immune cell infiltration, stromal edema, and reduced epithelial thickness with injury compared with Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 uninjured (healthy) and substantial normalization in the 20S-OHC treated versus the control (BSS treated) group. (Figure 8, Panel A) There was significantly fewer immune cell infiltration, reduced stromal thickness, and increased epithelial thickness in corneas treated with 20S-OHC versus controls. (Figure 8 Panels B, C). Immunohistochemistry (IHC) staining of corneal sections using CD45 and F4 / 80 antibodies showed that immune cells infiltrated the corneal stroma on day 14 after alkali burn. Both CD45 + hematopoietic immune cells and F4 / 80+ macrophages numbers were elevated in injured versus uninjured animals and underwent relative normalization in the 20S-OHC group compared with the BSS (control) treated group. Immunofluorescent staining showed higher α-SMA expression in myofibroblasts in the injured area (BSS) compared to the healthy and 20-S-OHC-treated groups, indicating more myofibroblasts in the injury site. (Figure 8, Panel D) EXAMPLE 6 – Effects of 20(S)-OHC in a corneal stromal injury model. Eight-week-old C57BL / 6 mice were treated 3 times daily with either BSS or 20S- OHC (20 µg / ml) after superficial keratectomy and corneal stromal injury. Figure 9, Panel A shows slit-lamp biomicroscopic images of fluorescein-stained murine corneas were captured across experimental groups.20S-OHC accelerates corneal wound healing at 24 hours. Figure 9, Panel B shows white-light images showing corneal scaring in BSS- and 20S-OHC-treated groups. At 10 days, mice treated with 20S-OHC showed reduced corneal opacification compared to the BSS groups, indicating the effects of 20(S)-OHC in promoting corneal wound healing and reducing corneal opacification. EXAMPLE 7 - Effects of 20(S)-OHC in a corneal alkali burn injury model. Figures 10A-B show the inhibitory effects of 20(S)-OHC on pre-existing neovascular vessels and corneal opacity following a prior alkali-induced corneal injury. Ten days after alkali injury, treatment three times each day was initiated and continued for 2 weeks to compare 20(S)-OHC (20 µg / mL) (n = 5) to balanced salt solution (BSS) as a control (n = 5). These data show that 20(S)-OHC provides a marked benefit in lesion regression, progression and mitigation after 14 days of 20(S)-OHC administration. Client Docket No.2024-214-03 Attorney Docket No. UM-42960.601 EXPERIMENTAL METHOD Slit lamp biomicroscopy General anesthesia was induced, and baseline slit lamp biomicroscopy and photography was performed to ensure animals do not have corneal pathology prior to experimentation. A circular 2 mm corneal epithelial wound was created using an Alger brush and post-operative analgesia was provided. Topical dosing of control and experimental agents was applied to the right eye only, with the left eye serving as an internal control. Slit lamp photography was performed every 6 h for 2-3 days or until wounds were completely healed typically within 2 days. Sacrifice of the animals and preservation of the eyes was performed at the conclusion of imaging, and samples will be utilized for secondary analyses. INCORPORATION BY REFERENCE All publications, published patent documents, and patent applications cited herein are hereby incorporated by reference to the same extent as though each individual publication, published patent document, or patent application was specifically and individually indicated as being incorporated by reference.

Claims

CLAIMS We claim:

1. A method of treating, ameliorating, or preventing recurrence of an ocular condition in a patient, comprising administering to said patient a therapeutically effective amount of a sigma-2 receptor (TMEM97) ligand and a pharmaceutically acceptable carrier.

2. The method of claim 1, wherein said TMEM97 ligand is an oxysterol.

3. The method of claim 2, wherein said oxysterol is oxysterol 20(S)-hydroxycholesterol (20(S)-OHC).

4. The method of claim 1, wherein said TMEM97 ligand is a small molecule.

5. The method of claim 4, wherein said small molecule is glycerol phenylbutyrate (PBU).

6. The method of claim 4, wherein said small molecule comprises a 2,7- diazaspiro[4.4]nonane scaffold flanked by benzyl and homobenzyl substituents at 2 nitrogens with a benzyl substituent substituted with a geminal ethyl ester group (AD223).

7. The method of claim 4, wherein said small molecule is 2-(4-morpholinethyl)-1- phenylcyclohexanecarboxylate hydrochloride (PRE084).

8. The method of claim 1, wherein said ocular condition is one or more conditions selected from a corneal injury, an ocular ulcer, an ocular infection, an ocular condition of aging, a foreign body, a thyroid ocular disease, a corneal dystrophy, and / or an ocular immune condition.

9. The method of claim 1, wherein said patient is a mammal.

10. The method of claim 1, wherein said mammal is a human.

11. The method of claim 1, wherein said administering is topical administering.

12. A kit comprising a pharmaceutical composition comprising a TMEM97 ligand and a component for topical administration of the TMEM97 ligand.

13. The kit of claim 12, wherein said TMEM97 ligand is 20(S)-OHC, PBU, AD223 or PRE084.

14. The kit of claim 12, wherein said component comprises a dropper.

15. A pharmaceutical composition comprising at least one TMEM97 ligand and a pharmaceutically acceptable carrier, and / or a pharmaceutically acceptable formulation.

16. The pharmaceutical composition of claim 15 wherein said TMEM97 ligand is 20(S)- OHC, PBU, AD223 or PRE084.

17. A pharmaceutical composition comprising a topical formulation of a TMEM97 ligand.

18. The pharmaceutical composition of claim 17 wherein said TMEM97 ligand 20(S)- OHC, PBU, AD223 or PRE084.

19. The pharmaceutical composition of claims 17 or 18, further comprising an antibiotic, an anti-inflammatory agent, a sterol, and / or a growth factor.

20. The pharmaceutical composition of any of claims 17-19 in dosage form.

21. Use of a kit or pharmaceutical composition of any of claims 12-20.

22. Use of a kit or pharmaceutical composition of any of claims 12-20 for the treatment of an eye condition or disease.