Methods for treating neurotrophic keratitis

Abstract

Disclosed are methods for the treatment of ocular diseases and disorders, e.g., neurotrophic keratitis (NK). The methods may comprise administering a therapeutically effective amount of a TrkA agonist to a subject in need thereof. The TrkA agonist may comprise MIM-D3. The disclosed methods may reduce corneal opacity in an affected eye of the subject following treatment.

Description

METHODS FOR TREATING NEUROTROPHIC KERATITIS CROSS-REFERENCE TO RLATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 696,424 that was filed September 19, 2024, the entire contents of which are hereby incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not applicable. BACKGROUND

[0003] Neurotrophic keratitis (NK) is a degenerative corneal disease resulting from trigeminal nerve damage, leading to impaired corneal sensitivity, persistent epithelial defects, and risk of ulceration.[1][2][3] The distinct roles of two nerve growth factor (NGF) receptors TrkA and p75NTR in corneal healing, with a focus on their impact in neurotrophic keratitis (NK) is further described.

[0004] TrkA activation by mature NGF promotes corneal epithelial survival and regeneration, while p75NTR activation—especially in the context of nerve injury and excess precursor proNGF can drive apoptosis and myofibroblast transformation, leading to fibrosis and scarring.

[0005] NGF Biology

[0006] NGF exerts its biological effects in the cornea through two neurotrophin receptors: the high-affinity selective tropomyosin receptor kinase A (TrkA) and the low-affinity non- selective p75 neurotrophin receptor (p75NTR).[4][5]

[0007] TrkA activation is responsible for transducing most of NGF's known pro- survival, proliferation, and migration activity, supporting epithelial regeneration and stem cell maintenance. In contrast, p75NTR can mediate both pro-apoptotic and pro-fibrotic signaling, particularly in the context of injury or when TrkA signaling is diminished. [6][7][8]

[0008] The interplay between these receptors is complex: TrkA signaling typically suppresses p75NTR-mediated apoptosis, but when TrkA is low or absent, p75NTR activation by NGF or proNGF can drive both apoptosis and myofibroblast transformation, contributing to tissue fibrosis and scarring. [9]

[0010]

[0009] This duality is especially relevant in the corneal stroma, where chronic NGF exposure in a high p75NTR environment can simultaneously increase apoptosis in some myofibroblasts while promoting the persistence and pathological activity of others, leading to ongoing matrix deposition and fibrosis.

[0010] NGF in Limbal Stem Cells

[0011] Corneal epithelial maintenance and wound healing depend on limbal stem cell (LSC) activity. In human and rodent corneas, most NGF expression occurs in the limbus, and its receptors TrkA and p75NTR are expressed by limbal basal epithelial cells including LSC.

[0011]

[0012]

[0013] NGF has been shown to stimulate LSC in vitro and supporting limbal stem cell renewal and corneal epithelial healing directly.

[0014]

[0015]

[0016] p75NTR is more broadly expressed and upregulated in fibroblastic keratocytes during injury, where it can drive myofibroblast differentiation, α-SMA expression, and collagen synthesis via MRTF-A and TGF-β1 pathways.

[0010] The balance between these pathways is critical for determining the outcome of corneal wound healing. [6]

[0012] LSC are significantly reduced in number and function in animal model of ocular denervation.

[0017] Loss of NGF and other trophic support leads to premature differentiation and depletion of these stem cells, further compromising epithelial integrity.

[0018]

[0013] NGF in Limbal Schwann Cells

[0014] Corneal nerves and Schwann cells in peripheral nerves, including those in the limbal region of the cornea, play a role in regulating stem cell activity. Schwann cells are known to synthesize NGF as well as its precursor, pro-NGF.

[0019] The synthesis and secretion of NGF by Schwann cells has been demonstrated in both in vivo and in vitro models, with evidence showing that Schwann cells contain NGF immunoreactivity and express NGF mRNA, particularly after nerve injury. Importantly, the processing of pro-NGF to mature NGF in Schwann cells involves proprotein convertases such as furin and PC7, which are co-localized with NGF in these cells, indicating thatSchwann cells secrete both pro-NGF and mature NGF forms.

[0019] Neural degeneration disrupts this process, causing a relative accumulation of proNGF and a deficiency of mature NGF. [8] This imbalance shifts neurotrophin signaling from TrkA-mediated survival to p75NTR-mediated apoptosis and fibrosis. [8]

[0010] The central corneal epithelium, with low TrkA and higher p75NTR, is more susceptible to apoptosis in the setting of excess proNGF.

[0015] While most studies have focused on Schwann cells in peripheral nerves, recent work has confirmed the regulatory role of Schwann cells in the limbal niche of the cornea, where they contribute to epithelial renewal and likely participate in paracrine signaling via neurotrophic factors such as NGF.

[0020] Mirmoeini showed in experimental genetic ablation of Schwann cells in rats, leaving corneal sensory innervation intact, there was a markedly inhibited corneal epithelial renewal (mimicking NK) suggesting that Schwann cells provide trophic support in the limbal niche to support normal homeostatic epithelial turnover.

[0020]

[0016] Corneal clarity is required for vision. Corneal epithelial maintenance and wound healing3,4depend on LSC activity5-8. During wound healing in other tissues, such as skin, the progenitor cells, residing within the wound bed itself, differentiate and migrate vertically to heal the wound9,10. A similar model of homeostatic or injury induced epithelial renewal was previously proposed for cornea, suggesting that epithelial stem cells differentiate vertically to replenish the upper layers of the epithelial cells12. More recent single cell RNA sequencing (scRNA-seq) and lineage tracing mouse studies showed that LSC are restricted to the limbal niche, which is also the mostly richly-innervated part of the cornea13-17. Unlike in skin, during corneal epithelial renewal in both mice and humans, LSC progeny (transient amplifying cells, or TACs), migrate centripetally towards the corneal centre (x axis), then further differentiate and migrate vertically (y axis) as terminally differentiated epithelial cells4,18-21. In the niche, LSCs are located in the basal epithelium of the limbus7,22, where they interact with mesenchymal cells, T-cells, and Schwann cells (SCs)11,13,23,24(FIG. 1). During epithelial maintenance, or after injury, LSC progeny differentiate into transient amplifying cells (TACs) that migrate toward the central cornea to further differentiate into the epithelial cells, which replenish the corneal epithelium18-21,25-28(FIG.1). Normally, LSCs reside in a growth-arrested or slow-cycling state29-32, exhibit morphological characteristics of stem cells, and express genes associated with asymmetric cell division2,33-36. In summary, the available evidence supports that limbal Schwann cells secrete pro-nerve growth factor, which is subsequently processed to mature NGF and plays a role in maintaining LSC activity and corneal epithelial homeostasis and regeneration.

[0017] Here, the inventors address the process of LSC differentiation and centripetal migration (corneal epithelial renewal) that occurs during homeostatic epithelial recycling or re- epithelialization following injury.

[0018] Clinical management of NK and the use of nerve growth factor (NGF): In an attempt to slow the inevitable progression toward corneal opacification and blindness, NK patients are frequently treated with tarsorrhaphy (sewing the eyelids shut to try to prevent injuries) or are fitted with large custom protective contact lenses. However, neither of these approaches addresses the underlying lack of innervation, and so they fail to prevent progression of NK. Since 2012, the inventors have developed an approach of treating NK patients with corneal neurotization surgery, using a nerve graft to direct cutaneous sensory fibers into the denervated corneas. This approach improves corneal wound healing and corneal innervation47, but 40% of patients fail to gain normal sensation following surgical corneal neurotization, often leading to recurrent ulceration48. To try to induce innervation pharmacologically, clinicians have prescribed recombinant human nerve growth factor eyedrops (rhNGF, OXERVATE). NGF is a potent neurotrophin for sympathetics and nociceptors49, and likely stimulates epithelial renewal indirectly via supporting / improving corneal innervation. In fact, some cenegermin-treated patients experienced increased corneal sensitivity, suggesting that reinnervation may have been induced by the applied rhNGF50,51. Besides its neurotrophic activity, NGF may stimulate LSCs in vitro1, and therefore may support corneal epithelial renewal directly. Unfortunately, the treatment of NK was not revolutionized, as was hoped, by the introduction of cenegermin52-55. It is not efficacious in 30% of cases, requires extremely high concentration with dosing 0.002% (20ug / mL) every two hours, six times a day , and treatment is frequently unaffordable for many patients (nearly $100,000 per course)52,54,56. More importantly, the absolute amount of corneal ulcer healing cenegermin induces is relatively low, even in cases of partial corneal denervation53. The discrepancy between NGF’s expected potential dual activity (i.e. inducing axonal growth plus stimulation of LSCs) and its disappointing efficacy in treating NK suggests a critical gap in the mechanistic understanding of NGF’s activity in the cornea. Therefore, this critical clinical and scientific knowledge gap is closed with the disclosed compositions and methods.

[0019] NGF signaling: NGF induces a wide spectrum of cellular responses in neuronal and non-neuronal cells via binding to and activating the two structurally and functionally distinct receptors TrkA and p75NTR49. Usually, these two receptors act antagonistically, while the outcome of their activity is defined by the activation state (ligated vs non-ligated with NGF), relative level of theirexpression on the cell surface, and / or the receptor-expressing cell type (neurons, stem cells, terminally differentiated cells, cancer cells etc)49,57. For example, in nerves, TrkA is responsible for transducing most of NGF’s known pro-survival, growth and differentiation signaling81. In low-level or absent TrkA activity, p75NTR mediates much of its negative effects on growth and survival by activating c- Jun N-terminal kinases (JNK) 1 and 3. NGF and both its receptors may regulate regeneration in a variety of injured tissues, including the corneal epithelium57-61. In human and rodent corneas, most NGF expression occurs in the limbus2,62, and its receptors TrkA and p75NTR are expressed by limbal basal epithelial cells including LSCs1,2,62,63, suggesting that NGF may regulate LSC activity. In denervated corneas, p75NTR signaling may overpower that of TrkA, particularly in situations of relatively high p75NTR. If that is the case, then rebalancing the effects of the two NGF receptors may be key to unlocking novel therapeutics for NK.

[0020] Despite being the only FDA-approved therapeutic for NK, the corneal cellular source(s) of NGF are not definitively known, nor is the mechanism of NGF’s effects on the corneal epithelium fully understood.

[0021] The cornea, the most densely innervated part of the body, is ordinarily protected by sensory nerves, responsible for protective pain sensation, tearing and blink reflexes. The densely packed axons in the basal epithelial layer of the limbus run adjacent to LSCs and their free nerve endings contact epithelial cells. Besides protecting from injury, sensory nerve fibers with their accompanying cells likely play a crucial role in LSC proliferation and survival, which suggests that corneal nerves are critical regulators of epithelial renewal. NK can be caused by a number of factors such as Herpes Simplex (HSV) and Herpes Zoster (VZV) infections: Viral infections are a frequent cause of corneal nerve damage, Topical drug toxicity: Prolonged use of certain eye drops, particularly topical anesthetics, can damage corneal nerves, Chemical and thermal burns: Direct injury to the cornea from chemicals or heat, Contact lens abuse: Improper or prolonged use of contact lenses can lead to nerve damage, Irradiation: Radiation therapy to the eye or surrounding areas can affect corneal nerves and systemic conditions: Diabetes mellitus and central nervous system conditions can also contribute to neurotrophic keratitis, CNS traumas, intracranial tumours, ocular trauma or surgery, congenital causes, LASIK, or cataract surgery.

[0022] Updated classifications for neurotrophic keratitis (NK) include a 6-stage NKSG classification and a 3-stage Mackie classification, both based on increasing severity of epithelial defect, stromal changes (like edema or haze), and potential for ulceration, melting, or perforation, whichimpacts visual acuity. The NKSG classification includes altered sensation (Stage 1), punctate epithelial keratitis (PEK) without haze (Stage 2), persistent epithelial defects (PED) without haze (Stage 3), PEK or PED with haze (Stage 4), PED with corneal ulceration (Stage 5), and corneal perforation (Stage 6).

[0023] In patients with deficient corneal sensory innervation due to some of the above mentioned factors infections, permanent blindness may develop. Microtraumas, corneal abrasions, and other corneal surface injuries initially go undetected because the patients do not sense pain, leading to non-healing corneal ulcers, scarring, and permanent opacification. NK, historically, has lacked a definitive cure. Accordingly, novel methods to treat NK are needed in the art. SUMMARY

[0024] In an aspect of the current disclosure, methods of treating a corneal disease or disorder in a subject in need thereof are provided. In some embodiments, the methods comprise administering a therapeutically effective amount of a TrkA agonist to the subject to treat the corneal disease or disorder in the subject.

[0025] In an aspect of the current disclosure, methods of reducing the opacity of a cornea in a subject following a corneal injury are provided. In some embodiments, the methods comprise administering a therapeutically effective amount of a TrkA agonist to the subject to reduce the opacity of the cornea in the subject following a corneal injury.

[0026] In an aspect of the current disclosure, methods comprising performing a corneal neurotization on a subject and administering a therapeutically effective amount of a TrkA agonist to the subject are provided.

[0027] In an aspect of the current disclosure, TrkA agonists for use in a method of treating a corneal disease or disorder in a subject in need thereof are provided. In some embodiments, the methods comprise administering a therapeutically effective amount of the TrkA agonist to the subject to treat the corneal disease or disorder in the subject.

[0028] In an aspect of the current disclosure, TrkA agonists for use in a method of reducing the opacity of a cornea in a subject following a corneal injury are provided. In some embodiments, themethods comprise administering a therapeutically effective amount of a TrkA agonist to the subject to reduce the opacity of the cornea in the subject following a corneal injury.

[0029] In an aspect of the current disclosure, methods of preventing neurotrophic keratitis (NK) in a subject in need thereof are provided. In some embodiments, the methods comprise administering a therapeutically effective amount of a TrkA agonist to the subject to prevent NK in the subject. BRIEF DESCRIPTION OF THE FIGURES

[0030] FIG. 1 shows structural and cellular composition of the limbal niche. The corneoscleral limbus contains the Palisades of Vogt and limbal epithelial crypts, forming the limbal niche (or limbus). Limbal stem cells (LSCs) differentiate into transient amplifying cells (TAC) that, subsequently, differentiate into epithelial cells. LSCs together with TAC, form the basal epithelial cellular layer. LSCs lie in close contact with mesenchymal stem cells (MSCs), myelinating Schwann cells (SC), ensheathing Aδ fibers, and non-myelinating SC associated with C fibers. LSC, MSC, and SC populations engage in juxtaparacrine molecular crosstalk. The limbal MSCs are attached to the basement membrane, interact with blood vessels, and their projections pass through the basement membrane in contact with LSCs. Schwann cells associated with unmyelinated sensory axons, penetrate the basement membrane, and extend neurites which terminate in the epithelial surface. Adapted from Feinberg et al.2023.

[0031] FIG. 2 shows clinical images of neurotrophic keratitis (NK). Clinical appearance of anesthetic corneas, showing central corneal opacity with overlying epitheliopathy. Conjunctival injection, corneal neovascularization, and corneal stromal scar with an overlying epithelial defect are demonstrated. Top left: A cornea with a shallow corneal ulcer. The clinician has applied fluorescein, which delineates the de-epithelialized corneal stroma. Top right: Another patient with a history of recurrent corneal ulceration leading to early opacification of the corneal stroma. Bottom left: A patient with severe NK leading to corneal perforation and infection. Bottom right: A patient with recurrent ulcerations leading to total opacification of the cornea. Feinberg et al.2023.

[0032] FIG. 3 shows a conceptual model of TrkA and p75NTRmediated corneal epithelial renewal. The locally expressed NGF activates TrkA that supports LSC maintenance, proliferation and migration, is antagonized by the locally expressed proNGF that activates p75NTR. Both NGF and proNGF-activated p75NTRsupports LSC maintenance by inhibiting their differentiation. This allowsbalancing between LSC stemness and differentiation that are required for corneal homeostatic and injury induces epithelial renewal.

[0033] FIGs.4A, 4B, 4C, 4D, 4E, and 4F show A) Schematic of the experiment in B,C. B) Representative live photographs of fluorescein-stained rat denervated or normally innervated (inrv) de-epithelialized corneas, demonstrating the course of corneal epithelial healing with (hNGF - 5ug / 10ul, tavelirmide (MIM-D3) - 0.145ug / 10ul) or without (“veh”) topical treatments 96 hours post de-epithelialization.0h indicates corneal condition five days post denervation (immediately after de- epithelialization). C) Representative live bright field images 120 hours post-de-epithelialization, as in B. D) Quantitative corneal healing as in B 72 hours after de-epithelialization. Each data point represents the fluorescein-negative (healed) area per cornea, per condition. E) Quantitative representation of the extent of corneal scarring / opacification as in C. The y axis quantifies the severity of opacification with 0 indicating a completely clear cornea and 5 indicating a completely opaque severely scarred cornea, as per the bright field image sample in F. Each data point represents an unbiased double-blinded grading of corneas per experimental condition, graded by at least eight independent raters. For D and E the numbers of mice per experimental condition were: hNGF n=8; veh n=7; inrv n=7; tavilemide n= 5

[0034] FIGs.5A, 5B, 5C, 5D, 5E, 5F, 5G, 5H, 5I, 5J, and 5K show topical tavilermide (MIM- D3) induces healing of deepithelialized NK cornea. A) Representative images of harvested experimental corneas, immunostained for bIII tubulin (red) and labeled with dapi (blue), demonstrate presence of corneal epithelial nerves in normally innervated (of untreated right eye) but their absence in denervated central corneas (left eye), exposed to the indicated experimental conditions. B) Quantitative representation of the results as in A, demonstrating density of the neurons-specific labeling per defined area of 285x240μm area of the central cornea. ImageJ software plugin NeuronJ was utilized for measurement of the total axonal lebgth (in mm) per area (mm2). Denervated vehicle- only “veh” treated corneas used as a reference (veh n=2; NGF n=4, tavilermide n=4). C) Schematic description of the preliminary experiments as in E-I. D) Representative live bright field image of rat cornea, five days after denervation, prior to de-epithelialization. E) Representative live photographs of fluorescein-stained denervated de-epithelialized corneas, demonstrating progress in corneal epithelial healing 48 hours post de-epithelialization, comparing vehicle-only and rhNGF (n=4) topical daily treatment. 0h indicates corneal condition five days post-denervation, immediately after de- epithelization. The treatment of the cornea began immediately after de-epithelialization and wasadministered every 24 hours, as noted in C. F) Representative live bright field images of corneas 120 hours post-de-epithelialization under the conditions as in E. Arrow denotes a thick scar in the NGF- treated cornea. G,H) Epithelial healing and assessment of corneal clarity, of tavilermide topically treated corneas (n=4) during 48 hours after de-epithelialization. Fluorescein-positive line in H (arrowhead) denotes corneal scratch, resulted from self-wounding incurred after full epithelial recovery, as per G. I) Fluorescent and bright field images of the cornea as in G,H, 120 hours after de- epithelialization, demonstrating complete epithelial healing with a small scar (arrow) formed at the place of self-mutilation (corneal scratching), as in H. J) Quantitative corneal healing as in C-F up to 72 hours after de-epithelialization. Each data point represents the fluorescein-negative (healed) normalised area per cornea, per condition.0h indicates corneal condition five days post denervation (immediately after de-epithelialization). K) Quantitative representation of subjective non-biased assessment of the extent of corneal scarring / opacification as in F. The y axis quantifies the severity of opacification with 0 indicating a completely clear cornea and 5 indicating a completely opaque scarred cornea. Every data point represents an average of eight subjective judgments per cornea. The statistical analysis is based on four level ANOVA test - the estimated overall effect size for the omnibus test is 0.56, giving an estimated effect size for Bonferroni-corrected pairwise comparisons of 1.82. The error bars represent standard error: *p<0.05; **p<0.01; ***p<0.005.

[0035] FIG. 6 shows Images of fluorescein-stained denervated de-epithelialized corneas, demonstrating progress in corneal epithelial healing 48 hours post de-epithelialization, comparing topical tavilermide-treated corneas (500 μg, Group 4, n=4) to vehicle (Group 2, n=4) and rhNGF (5μg, Group 3, n=4) and of vehicle treated innervated positive control (Group 1, n=3). At the bottom, representative live bright field images of corneas 120 hours post-deepithelialization under the same conditions. Asterix at animal #4 in the rhNGF group denotes suspected partial denervation.

[0036] FIG.7 shows Table 1 which provides experimental details on animal study subjects. DETAILED DESCRIPTION

[0037] The inventors discovered that specific activation of TrkA, e.g., with MIM-D3 (tavilermide) which is a selective partial agonist that does not activate p75NTR, significantly improves both the rate of healing and quality of corneal epithelial recovery after injury in NK. Based on the inventors’ preclinical study on rodent model of NK, topical treatment with MIM-D3 is expected toprovide improved clinical outcomes in patients with NK compared with those in which NGF is used alone.

[0038] Clinical Significance

[0039] The only clinically approved topical treatment for NK is rhNGF (OXERVATE, Dompe, Milan, Italy). Despite evidence for clinical efficacy and safety, rhNGF treatment of NK patients presents concerns including complicated formulation and requires 6 times a day dosing every 2 hours, the treatment fails in over 30% of patients, and it is associated with significant eye pain compared to vehicle treated patients.

[0021] Human recombinant NGF (rhNGF) binds both TrkA and p75NTR receptors, stimulating nerve regeneration, supporting limbal stem cell survival, and promoting epithelial healing—but potentially triggering inflammation and apoptosis through p75NTR activation.[8]

[0022] In contrast, tavilermide [lab name MIM-D3], a selective partial TrkA agonist, is designed to preserve the regenerative and survival benefits for limbal stem cells and corneal nerves while avoiding p75NTR-mediated apoptosis and inflammation, offering a more targeted and potentially safer and more effective therapeutic approach.

[0023]

[0024]

[0040] Specific activation of TrkA with MIM-D3 induces corneal epithelial maintenance and wound healing and restores corneal clarity in the condition of NK.

[0041] Patients with NK can suffer from recurrent corneal ulcers, which cause blindness if not treated. The novel treatment strategy, based on specific activation of TrkA will treat and prevent corneal ulceration in NK, thereby preserving and improving vision for these patients to much greater degree than presently possible using existing treatments.

[0042] Unlike NGF that activates both receptors TrkA and p75NTR, a specific activation of TrkA, e.g., by MIM-D3, supports the activity of LSC, thereby induces corneal epithelial wound healing in the condition of NK (i.e., completely or partially denervated cornea). And MIM-D3 achieved a better outcome than a combination of NGF and p75NTR inhibitor (WO2025 / 091016). A surprising and unexpected result considering that the use of a selective TrkA agonist was expected to yield results equivalent to the combination of NGF and p75NTR inhibitor.

[0043] Based on the inventors’ mechanistic understanding of regulation of LSC activity, in the inventors’ proof of concept preliminary study the inventors demonstrated that a specific activation of TrkA receptor by MIM-D3 small molecule induces fast corneal wound healing and restores cornealclarity in NK condition. The inventors are planning to further develop MIM-D3 topical treatment - based technology of treating completely anesthetic or partially denervated cornea in deafferent stages and / or severities of NK. Methods of treating a corneal disease or disorder in a subject in need thereof

[0044] Accordingly, in an aspect of the current disclosure, methods of treating a corneal disease or disorder in a subject in need thereof are provided. In some embodiments, the methods comprising administering a therapeutically effective amount of a TrkA agonist to the subject to treat the corneal disease or disorder in the subject. In some embodiments, the corneal disease or disorder is neurotrophic keratitis (NK).

[0045] The methods may comprise administering a therapeutically effective amount of a composition comprising a TrkA agonist and at least one excipient to the subject. In some embodiments, the disclosed methods do not comprise administering NGF or a p75NTRinhibitor to the subject.

[0046] A “subject in need thereof” as used herein may refer to a subject that is suffering from a corneal disease or disorder, e.g., NK. The subject may have suffered a corneal abrasion or a or surgical corneal epithelial debridement.

[0047] The TrkA agonist may be administered as a composition comprising an active ingredient targeted to either the TrkA or p75NTRpathways, wherein the active ingredient consists of a TrkA agonist, e.g., MIM-D3. The compositions may further comprise an excipient.

[0048] As used herein, a “TrkA agonist” refers to a composition that agonizes TrkA (tropomyosin receptor kinase A) and induces downstream signaling from the receptor. The TrkA agonist may be a “TrkA-specific agonist” which, as used herein, refers to a TrkA agonist that does not significantly activate p75NTR. Significant activation of p75NTRmay be determined by methods known in the art, e.g., Western blotting, quantitative polymerase chain reaction (qPCR), etc. to detectactivation of, e.g., NF B signaling, methods for which are known in the art. A skilled person maydetermine TrkA selectivity over p75NTR by applying standard biochemical and functional assays such as i) biophysical binding and kinetics (cell-free or cellular), competition, or displacement studies and ii) cellular functional assays that report TrkA versus p75 activation in TrkA+p75+ cells compared to p75+ cells (i.e. canonical receptor phosphorylation) or cellular survival assays (see, e.g., Mallartchouck et al mol. Pharm.2007, 57:385-391; Lesauteur et al. J Neurosc.199616(4):1308-1316).

[0049] Agonism / activation of TrkA is expected to induce PI3K, Ras, and / or PLC signalingpathways in cells. Methods for detecting activation of PI3K, Ras, and / or PLC are known in the art.

[0050] TrkA agonists include, but are not limited to, MIM-D3 (tavilermide), Udonitrectag lysine salt, E2511, ACD856, ENT-A013, or A1. Details concerning the structure, action, and associated other properties are found below and in the citations within Table 1, each of which are incorporated by reference herein.

[0051] As used herein, “MIM-D3” refers to a compound also known as “tavilermide” which has the chemical structure: .

[0052] Table 1 – Exemplary TrkA agonists. Compound

[0053] Lesions to denervated corneas may heal over time but the healing process may introduce opacity into the cornea, causing further problems and reduction in quality of life in subjects. The inventors discovered that administration of the TrkA agonist reduces opacity in subjects during the course of healing (FIGs. 5F, 6). Accordingly, the methods may reduce corneal opacity in the subject.

[0054] Further, methods of reducing opacity of a cornea in a subject following a corneal injury are provided. In some embodiments, the methods comprise administering a therapeutically effective amount of a TrkA agonist to the subject to reduce the opacity of the cornea in the subject following a corneal injury.

[0055] As used herein, a “therapeutically effective amount” or an “effective amount” refers to an amount that is sufficient to achieve at least one therapeutic goal in the subject, e.g., corneal healing, reduction in corneal opacity. A therapeutically effective amount may comprise about 0.0125 mg / ml to about 50 mg / ml or any subrange or value therein.

[0056] The effective amount may be formulated for topical administration, e.g., topical ophthalmic administration. The formulation may comprise about 0.1 to about 100 mg / ml or about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50 or more mg / ml TrkA agonist, e.g., MIM-D3 (tavilermide). The formulation may comprise about 50 mg / ml TrkA agonist, e.g., tavilermide.

[0057] The TrkA agonist may be administered topically to the eye of a subject. Thus, the formulation for topical ophthalmic administration may have a concentration of, e.g., 50 mg / ml TrkA agonist, e.g., MIM-D3, and a single drop may range from about 20-70 microliters for a final dose of about 1 mg (20 microliter drop) to about 3.5 mg (70 microliter drop) of TrkA agonist. The proper formulation and drop size may be determined by a physician / pharmacist. For example, either or both of the concentration of the formulation and the drop size could be modified to achieve a desired dose.

[0058] The inventors demonstrated two separate doses were effective in the rat model of NK: 10 microliter drops of 50 mg / ml solution of MIM-D3 (0.5 mg) and 10 microliter drops of 14.5 mg / ml solution (0.145 mg), each of the doses were effective at improving corneal epithelial healing and prevention of opacity in the cornea. An individual dose may be calculated as shown by determining a drop size or an average drop size administered to the subject.

[0059] The disclosed methods may comprise administering the TrkA agonist about once per day, about twice per day (BID), about three times per day (TID), about four times per day, about every other day, about every third day, about every fourth day, about every fifth day, about every sixth day, about once per week, or any other suitable interval, as determined by a physician. In certain embodiments, the TrkA agonist is administered once per day. The TrkA agonist may be administered every hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every 8 hours, every 9 hours, every 10 hours, every 11 hours, every 12 hours, every 13 hours, every 14 hours, every 15 hours, every 16 hours, every 17 hours, every 18 hours, every 19 hours, every 20 hours, every 21 hours, every 22 hours, every 23 hours, every 24 hours, or more, or any interval as determined by a physician.

[0060] The inventors denervated rats and, 5 days later, deepithelialized the corneas of the rats (induced a corneal lesion or injury; FIG.5C). The rats were then administered a TrkA agonist. The inventors discovered that the TrkA agonist was effective at inducing corneal healing and reducing opacity, which is observed during the course of healing of control denervated corneas (FIG.5F, 6). Thus, the TrkA agonist may be administered at least 1 day to about at least 1 year, or any subrange or value therein, to the subject following a denervation of the subject, e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 month, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months following denervation of the subject.

[0061] The disclosed methods may further comprise administering at least one additional therapy to the subject. In one embodiment, the additional therapy comprises corneal neurotization. The corneal neurotization may be performed on the subject to treat denervation in one or both eyes of the subject. The TrkA agonist may be administered prior to neurotization, subsequent to neurotization, or both prior to and subsequent to neurotization.

[0062] In related embodiments, methods comprising performing corneal neurotization on a subject and administering a TrkA agonist to a subject are provided.

[0063] The at least one additional therapy may comprise tarsorrhaphy, protective lenses, autologous serum, amniotic membrane transplantation or application, therapeutic contact lenses or topical insulin.

[0064] The additional therapy may comprise an anti-inflammatory, e.g., tacrolimus. Methods of administering tacrolimus, e.g., topically to the eye, are known in the art (see, e.g., Daeschler et al., “Sustained Release of Tacrolimus Froma Topical DrugDelivery System Promotes Corneal Reinnervation” Transl Vis Sci Technol.2022;11(8):20; Daeschler SC, So KJW, Feinberg K, Manoraj M, Cheung J, Zhang J, Mirmoeini K, Santerre JP, Gordon T, Borschel GH (2025) A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair. Neural Regen Res 20(1):291-304; and Daeschler, S.C.; Feinberg, K.; Harhaus, L.; Kneser, U.; Gordon, T.; Borschel, G.H. Advancing Nerve Regeneration: Translational Perspectives of Tacrolimus (FK506). Int. J. Mol. Sci. 2023, 24, 12771, each of which are incorporated by reference herein). The anti- inflammatory may be administered prior to TrkA agonist, after TrkA agonist, concurrently with TrkAagonist. The anti-inflammatory may be administered prior to corneal neurotization, after corneal neurotization, or both prior to or after corneal neurotization.

[0065] Administration, and grammatical variations thereof, may comprise administration by any appropriate route, e.g., topically to the eye. illustrative routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, intrathecal, intracerebral, or intrarectal routes. The particular dose and administration route can be determined by a physician.

[0066] The disclosed formulations / compositions may be administered by any means known to those skilled in the art, including, but not limited to, oral, topical, intranasal, intraperitoneal, parenteral, intravenous, intramuscular, subcutaneous, intrathecal, transcutaneous, nasopharyngeal, intra-lesional, intradermal, or transmucosal absorption. Thus, the compositions may be formulated as an ingestible, injectable, topical, ophthalmic topical, suppository formulation, or in a punctal plug or slow release insert or silicone ring placed in the inferior and / or superior cul-de-sac. The compositions may also be delivered within a liposomal or time-release vehicle. Administration of the compositions to a subject in accordance with the invention may exhibit beneficial effects in a dose-dependent manner. Thus, within broad limits, administration of larger quantities of the compositions is expected to achieve increased beneficial biological effects than administration of a smaller amount. Moreover, efficacy is also contemplated at dosages below the level at which toxicity is seen.

[0067] The specific dosage administered in any given case will be adjusted in accordance with the composition or compositions being administered, the disease to be treated or inhibited, the condition of the subject, and other relevant medical factors that may modify the activity of the compositions or the response of the subject, as is well known by those skilled in the art. For example, the specific dose for a particular subject depends on age, body weight, general state of health, diet, the timing and mode of administration, the rate of excretion, medicaments used in combination, and the severity of the particular disorder to which the therapy is applied. Dosages for a given patient can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the compositions described herein and of a known agent, such as by means of an appropriate conventional pharmacological protocol.

[0068] The maximal dosage for a subject is the highest dosage that does not cause undesirable or intolerable side effects. The number of variables in regard to an individual treatment regimen is large, and a considerable range of doses is expected. The route of administration will also impact thedosage requirements. It is anticipated that dosages of the compositions will improve the condition being treated by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more as compared to no treatment.

[0069] Ophthalmic formulations may also include an extended-release vehicle. And an extended-release vehicle may be a biocompatible polymer, dissolved in the carrier or by itself impregnated with the Trka agonist to hold the agonists and slowly release the drug to the subject, preferably for an extended- release period, e.g., one day, two days, three days, four days, five days, six days, seven days, or more. The biocompatible polymer may be biodegradable or non- biodegradable, depending on desired use and application schedule. Examplary biocompatible polymers that may be used formulations as an extended-release vehicle include but are not limited to poly-2- hydroxycthylmethacrylate (p-HEMA hydrogels), poly(lactic-co-glycolic) acid (PLGA), polycaprolactone (PCL), hydroxypropyl cellulose, Anecortave acetate (AnA), gelatin, and / or collagen. The inclusion of an extended-release vehicle may, in some cases, allow for less frequent application while still providing effective dosing of the Trka agonists.

[0070] The term '‘pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that which is acceptable for use in a subject, including a human subject.

[0071] The terms “pharmaceutically acceptable carrier,” or “excipient” as used herein, mean a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The pharmaceutical compositions may be formulated for administration by, for example, solid dosing, oral, a topical formulation, e.g., topical ophthalmic, injection, inhalation (either through the mouth or the nose), implants, oral, buccal, parenteral, or rectal administration. Techniques and formulations and acceptable pharmaceutically acceptable carriers may generally be found in "Remington's Pharmaceutical Sciences", (Meade Publishing Co., Easton, Pa.). Therapeutic compositions typically are sterile and stable under the conditions of manufacture and storage.

[0072] Suitable pharmaceutically acceptable carriers include, but are not limited to, diluents, preservatives, solubilizers, emulsifiers, liposomes, nanoparticles and adjuvants. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, com starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0073] Additionally, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, media, suspensions, and emulsions. Examples of nonaqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include isotonic solutions, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media.

[0074] In some embodiments, the compositions, such as a pharmaceutical compositions, are formulated for local delivery, for example topical delivery. Suitable additional components for local or topical delivery’ are known in the art and include creams, gels, and controlled release drug delivery’ materials (for example, but not limited to, e.g., PCNU, PGLA, etc.).

[0075] Compositions of the present disclosure may include liquids, lyophilized, or otherwise dried formulations and may include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e. g., Tween 20, Tween 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g.. ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol, complexation with metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid, polygly colic acid, hydrogels, etc., or onto liposomes, microemulsions, micelles, milamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, andrate of in vivo clearance. Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).

[0076] The compositions can be sterilized by conventional, well-known sterilization techniques. The compositions may contain pharmaceutically acceptable additional substances as required to approximate physiological conditions such as a pH adjusting and buffering agent, toxicity adjusting agents, such as, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like. Additional definitions

[0077] The disclosed subject matter may be further described using definitions and terminology as follows. The definitions and terminology used herein are for the purpose of describing particular embodiments only and are not intended to be limiting.

[0078] As used in this specification and the claims, the singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise. For example, the term “a substituent” should be interpreted to mean “one or more substituents,” unless the context clearly dictates otherwise.

[0079] As used herein, “about”, “approximately,” “substantially,” and “significantly” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” and “approximately” will mean up to plus or minus 10% of the particular term and “substantially” and “significantly” will mean more than plus or minus 10% of the particular term.

[0080] As used herein, the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of” should be interpreted as being “closed” transitional terms that do not permit the inclusion of additional components other than the components recited in the claims. The term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.

[0081] The phrase such as should be interpreted as for example, including. Moreover, the use of any and all exemplary language, including but not limited to “such as”, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

[0082] Furthermore, in those instances where a convention analogous to “at least one of A, B and C, etc.” is used, in general such a construction is intended in the sense of one having ordinary skill in the art would understand the convention (e.g., “a system having at least one of A, B and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description or figures, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or ‘B or “A and B.”

[0083] All language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can subsequently be broken down into ranges and subranges. A range includes each individual member. Thus, for example, a group having 1-3 members refers to groups having 1, 2, or 3 members. Similarly, a group having 6 members refers to groups having 1, 2, 3, 4, or 6 members, and so forth.

[0084] The modal verb “may” refers to the preferred use or selection of one or more options or choices among the several described embodiments or features contained within the same. Where no options or choices are disclosed regarding a particular embodiment or feature contained in the same, the modal verb “may” refers to an affirmative act regarding how to make or use and aspect of a described embodiment or feature contained in the same, or a definitive decision to use a specific skill regarding a described embodiment or feature contained in the same. In this latter context, the modal verb “may” has the same meaning and connotation as the auxiliary verb “can.” EXAMPLES

[0085] The following Examples are illustrative and should not be interpreted to limit the scope of the claimed subject matter.Example 1 – Specific activation of TrkA is sufficient to induce corneal wound healing

[0086] Following denervation, the corneal epithelium loses its regenerative capacity. The inventors’ experimental results indicate that corneas de-epithelialized five days after denervation exhibit impaired wound healing, accompanied by scarring and opacification24. To probe the involvement of NGF signaling in the denervation-induced loss of regenerative activity, the inventors performed a single stereotactic electrocautery of the ophthalmomaxillary branch of the trigeminal nerve68. On day five after denervation, the corneal epithelium was removed with an Amoils brush. The inventors topically applied either NGF (0.5mg / ml), or the selective TrkA agonist MIM-D3 (14.5 mg / ml, administered as 10 microliter drops), immediately following denervation, and every 24 hours during the course of the experiment. Corneal wound healing in the treated groups was compared with the vehicle-only treated group daily by fluorescein staining. The preliminary observations (n=2) demonstrate that NGF treatment inhibited the rate of corneal healing, leading to more severe scarring and opacification, comparable to denervated vehicle-treated corneas (demonstrated in FIG. 4 and WO2025 / 091016). Further supporting the inventors’ hypothesis, the results demonstrate that topical MIM-D3 accelerates recovery of denervated wounded corneas, recapitulating the healing of normally innervated corneas. Moreover, corneal opacification was almost completely prevented by MIM-D3 (FIG.4C), compared to innervated controls. This was unexpected in view of the fact that recent results (WO2025 / 091016) have shown that NGF plus a p75 inhibitor failed to improve corneal opacification to levels comparable to innervated corneas.

[0087] Furthermore, the prevention of corneal opacification by MIM-D3 indicates that MIM- D3 can be used in preventing the progression of NK from early stages to more severe stages. In certain cases, in patients in need thereof, such prevention may take the form of a maintenance therapy.

[0088] The inventors repeated the healing assay of denervated de-epithelialized corneas as in FIG.4, with the difference that, instead of starting the treatment immediately after denervation, the inventors commenced treatment with topical daily MIM-D3 (at the clinical daily dose of 50mg / 1ml69,70) on the day of de-epithelialization (i.e. five days after denervation) and during the next five days (FIG.5E-J and FIG.6). Corneal healing was compared to treatment with rhNGF (at a clinical daily dose of 0.5mg / ml71) or vehicle-only. While rhNGF failed to induce healing and caused severe corneal scarring (FIG.5E, F, J, K), MIM-D3 induced rapid wound healing and epithelial recovery in 48 hours post-de-epithelialization that was associated with a barely noticeable corneal opacity (FIG. 5E,F,K; n=4). In other words corneal clarity was improved to the levels of innervated corneas.Moreover, when rats accidently opened the tarsorrhaphy and scratched the healed MIM-D3 treated cornea, the ongoing treatment restored healing of the recurred wound (FIG. 5F,G,H,I), although in this case a local scar was formed (FIG.5G). These results demonstrate that TrkA specific agonists are an effective topical treatment for NK. Example 2 – Corneal neurotization and TrkA agonist administration

[0089] Corneal neurotization: Corneal neurotization, which involves the transfer of a healthy sensory donor nerve to the anesthetic cornea, is a surgical procedure that has been available as a possible treatment of NK for a number of years (Woo et al. American J Ophth 2022;241:179-189; Gross et al. Plastic and reconstructive surgery 2024, 154:795e-797e, which is incorporated by reference herein). The procedure may be achieved by a direct nerve transfer or an interpositional nerve graft for axons to cross from the donor sensory nerve into the cornea. Despite the usefulness of the procedure, the probability that the patient remains epithelial breakdown-free is still relatively modest. Therefore, methods for treating NK comprising surgical corneal neurotization and administration of a selective TrkA agonist are provided herein. In view of the experimental results provided herein, the combination of neurotization and TrkA agonism is expected to promote a faster and more complete recovery of the epithelium. In a prefered embodiment the TrkA agonist is tavilermide (MIM-D3). The administration of the TrkA agonist can be performed as described above. The administration of the TrkA agonist may be before the surgery, during surgery, immediately after surgery or over a period of time after the surgery or a combination of two or more of these administration protocols. Typically, with neurotization, it takes the transplanted nerve 3-6 months to slowly reinnervate the cornea. Therefore, in one embodiment, the administration of the selective TrkA agonist such as tavilermide can be administered during this window of time to support limbal stem cell activity, promote epithelial cell integrity, and promote nerve regeneration into the cornea. The results discussed above indicates that TrkA agonists, such as Tavilermide, promote a more rapid and more complete corneal recovery. Example 3 - The Effect of Tavilermide (MIM-D3) Topical on Corneal Epithelial Healing in Rodent Model of Neurotrophic Keratitis (NK)

[0090] Hypothesis: Unlike NGF that activates both trophic receptors TrkA and p75NTR, selective activation of TrkA in the corneal epithelial cells by tavilermide stimulate epithelial renewal, thereby, induces healing and prevent opacification of NK cornea.

[0091] Aim: Examine the effect of topical tavilermide on epithelial healing of experimentally denervated deepithelialized NK cornea in rats.

[0092] Experimental Procedures and Results: With the goal of developing an effective treatment for NK, the inventors performed the healing assay of denervated de-epithelialized corneas in rats. Briefly, the inventors performed corneal denervation in rats by single stereotactic electrocautery of the ophthalmomaxillary branch of the trigeminal nerve. Tarsorrhaphy was performed following denervation to protect the cornea from self-injury. Corneal denervation was validated by absence of blink reflex and pupillary dilation. By five days after denervation the denervated cornea was characterized by reduced clarity (Fig 5D). On day five after denervation, the corneal epithelium was removed with an Amoils brush. The inventors commenced treatment with topical daily tavilermide (at the clinical daily dose of 50mg / ml) on the day of de-epithelialization (i.e. five days after denervation) and during the next five days (Fig 5C). Corneal healing was compared to treatment with rhNGF (at a clinical daily dose of 0.5 mg / ml) or vehicle-only, by fluorescein staining. Corneal denervation was validated retroactively by immunostaining of the post-experimentally harvested corneas for bIII tubulin. Corneas of the right eye of some of the experimental animals were used as a reference for a normal corneal innervation (Fig 5A,B).

[0093] A rapid epithelial healing was observed in normally innervated deepithelialized corneas within 48 hours after deepithelialization (Fig 5E,J). This healing was followed by recovery of corneal clarity that was recorded at day 5 (D5) after deepithelization (Fig 5F,K). While rhNGF failed to induce healing and caused severe corneal scarring (Fig 5E,F,J,K), tavilermide induced rapid wound healing and epithelial recovery as early as 24 hours post-de-epithelialization that was associated with recovery of corneal clarity (Fig 5G,J,K). Moreover, when rats accidentally opened the tarsorrhaphy and scratched the healed tavilermide treated cornea, the ongoing treatment restored healing of the recurred wound (Fig 5H,I), although in this case a local scar was formed (Fig 5I). Note, in the rhNGF treated rat #4, partial corneal denervation was suspected due to residual blink reflex and validated by immunostaining for bIII tubulin. In this rat nearly complete corneal healing was observed. See also FIG.7, Table 1 for animal study subject details.

[0094] Conclusion: unlike NGF, tavilermide stimulated epithelial renewal and supported clarity of, otherwise, non-healing completely denervated cornea, suggesting tavilermide as a potent topical treatment of NK.

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Am J Ophthalmol Case Rep 26, 101488 (2022). doi.org:10.1016 / j.ajoc.2022.101488 Additional references [1] The Molecular Basis of Neurotrophic Keratopathy: Diagnostic and Therapeutic Implications. A Review. Ruiz-Lozano RE, Hernandez-Camarena JC, Loya-Garcia D, Merayo-Lloves J, Rodriguez-Garcia A. The Ocular Surface.2021;19:224-240. doi:10.1016 / j.jtos.2020.09.007. [2] Neurotrophic Keratopathy. Dua HS, Said DG, Messmer EM, et al. Progress in Retinal and Eye Research.2018;66:107-131. doi:10.1016 / j.preteyeres.2018.04.003. [3] Neurotrophic Keratitis: Inflammatory Pathogenesis and Novel Therapies. Wajnsztajn D, Faraj LA, Sanchez-Tabernero S, Solomon A. Current Opinion in Allergy and Clinical Immunology.2023;23(6):520-528. doi:10.1097 / ACI.0000000000000942. [4] TRK Receptors: Roles in Neuronal Signal Transduction. Huang EJ, Reichardt LF. Annual Review of Biochemistry.2003;72:609-42. doi:10.1146 / annurev.biochem.72.121801.161629. [5] A, B, C's of TRK Receptors and Their Ligands in Ocular Repair. Gupta A, Galletti JG, Yu Z, Burgess K, de Paiva CS. International Journal of Molecular Sciences. 2022;23(22):14069. doi:10.3390 / ijms232214069. [6] Nerve Growth Factor and Tissue Repair Remodeling: trkA(NGFR) and P75(NTR), Two Receptors One Fate. Micera A, Lambiase A, Stampachiacchiere B, et al. Cytokine & Growth Factor Reviews.2007 Jun-Aug;18(3-4):245-56. doi:10.1016 / j.cytogfr.2007.04.004.[7] Disentangling the Signaling Complexity of Nerve Growth Factor Receptors by CRISPR / Cas9. Testa G, Mainardi M, Vannini E, et al. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2022;36(11):e22498. doi:10.1096 / fj.202101760RR. [8] Dynamic Nature of the P75 Neurotrophin Receptor in Response to Injury and Disease. Meeker R, Williams K. Journal of Neuroimmune Pharmacology : The Official Journal of the Society on NeuroImmune Pharmacology.2014;9(5):615- 28. doi:10.1007 / s11481-014-9566-9. [9] Nerve Growth Factor Promotes Corneal Epithelial Migration by Enhancing Expression of Matrix Metalloprotease-9. Blanco-Mezquita T, Martinez-Garcia C, Proença R, et al. Investigative Ophthalmology & Visual Science. 2013;54(6):3880-90. doi:10.1167 / iovs.12-10816.

[0010] Nerve Growth Factor Effect on Human Primary Fibroblastic-Keratocytes: Possible Mechanism During Corneal Healing. Micera A, Lambiase A, Puxeddu I, et al. Experimental Eye Research.2006;83(4):747-57. doi:10.1016 / j.exer.2006.03.010.

[0011] The Role of NGF Signaling in Human Limbal Epithelium Expanded by Amniotic Membrane Culture. Touhami A, Grueterich M, Tseng SC. Investigative Ophthalmology & Visual Science.2002;43(4):987-94.

[0012] Patterned Expression of Neurotrophic Factors and Receptors in Human Limbal and Corneal Regions. Qi H, Chuang EY, Yoon KC, et al. Molecular Vision.2007;13:1934-41.

[0013] Nerve Growth Factor and Its Receptor TrkA Serve as Potential Markers for Human Corneal Epithelial Progenitor Cells. Qi H, Li DQ, Shine HD, et al. Experimental Eye Research.2008;86(1):34-40. doi:10.1016 / j.exer.2007.09.003.

[0014] Nerve Growth Factor Promotes Corneal Healing: Structural, Biochemical, and Molecular Analyses of Rat and Human Corneas. Lambiase A, Manni L, Bonini S, et al. Investigative Ophthalmology & Visual Science.2000;41(5):1063-9.

[0015] Capsaicin-Induced Corneal Sensory Denervation and Healing Impairment Are Reversed by NGF Treatment. Lambiase A, Aloe L, Mantelli F, et al. Investigative Ophthalmology & Visual Science.2012;53(13):8280-7. doi:10.1167 / iovs.12- 10593.

[0016] The Role of Nerve Growth Factor in Maintaining Proliferative Capacity, Colony- Forming Efficiency, and the Limbal Stem Cell Phenotype. Kolli S, Bojic S, Ghareeb AE, et al. Stem Cells (Dayton, Ohio).2019;37(1):139-149. doi:10.1002 / stem.2921.

[0017] Dependence of Corneal Stem / Progenitor Cells on Ocular Surface Innervation. Ueno H, Ferrari G, Hattori T, et al. Investigative Ophthalmology & Visual Science. 2012;53(2):867-72. doi:10.1167 / iovs.11-8438.

[0018] The Role of Sensory Innervation in Homeostatic and Injury-Induced Corneal Epithelial Renewal. Feinberg K, Tajdaran K, Mirmoeini K, et al. International Journal ofMolecular Sciences.2023;24(16):12615. doi:10.3390 / ijms241612615.

[0019] Nerve Growth Factor and Proprotein Convertases Furin and PC7 in Transected Sciatic Nerves and in Nerve Segments Cultured in Conditioned Media: Their Presence in Schwann Cells, Macrophages, and Smooth Muscle Cells. Marcinkiewicz M, Marcinkiewicz J, Chen A, et al.The Journal of Comparative Neurology.1999;403(4):471-85.doi:10.1002 / (sici)1096- 9861(19990125)403:4<471::aid- cne4>3.0.co;2-s.

[0020] Schwann Cells Are Key Regulators of Corneal Epithelial Renewal. Mirmoeini K, Tajdaran K, Zhang J, et al. Investigative Ophthalmology & Visual Science. 2023;64(4):7. doi:10.1167 / iovs.64.4.7.

[0021] Cenegermin: A Review in Neurotrophic Keratitis. Deeks ED, Lamb YN. Drugs.2020;80(5):489-494. doi:10.1007 / s40265-020-01289-w.

[0022] Tear Proteomics Reveals the Molecular Basis of the Efficacy of Human Recombinant Nerve Growth Factor Treatment for Neurotrophic Keratopathy. Pieragostino D, Lanzini M, Cicalini I, et al. Scientific Reports.2022;12(1):1229. doi:10.1038 / s41598-022-05229-4.

[0023] A Designed Peptidomimetic Agonistic Ligand of TrkA Nerve Growth Factor Receptors. Maliartchouk S, Feng Y, Ivanisevic L, et al. Molecular Pharmacology. 2000;57(2):385-91.

[0024] Safety and Efficacy of MIM-D3 Ophthalmic Solutions in a Randomized, Placebo- Controlled Phase 2 Clinical Trial in Patients With Dry Eye. Meerovitch K, Torkildsen G, Lonsdale J, et al. Clinical Ophthalmology (Auckland, N.Z.). 2013;7:1275-85. doi:10.2147 / OPTH.S44688.

[0096] In the foregoing description, it will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention. Thus, it should be understood that although the present invention has been illustrated by specific embodiments and optional features, modification and / or variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

[0097] Citations to a number of patent and non-patent references may be made herein. The cited references are incorporated by reference herein in their entireties. In the event that there is an inconsistency between a definition of a term in the specification as compared to a definition of the term in a cited reference, the term should be interpreted based on the definition in the specification.

Claims

1. CLAIMS 1. A method of treating a corneal disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a TrkA agonist to the subject to treat the corneal disease or disorder in the subject.

2. The method of claim 1, wherein the corneal disease or disorder comprises neurotrophic keratitis (NK).

3. The method of claim 1, wherein the TrkA agonist comprises MIM-D3 (tavilermide), Udonitrectag lysine salt, E2511, ACD856, ENT-A013, or A1.

4. The method of claim 1 or 2, wherein the TrkA agonist comprises MIM-D3 (tavilermide).

5. The method of claim 1, wherein the method reduces corneal opacity in the subject.

6. The method of claim 1, wherein administering comprises topical administration to an affected eye of the subject.

7. The method of claim 1, wherein the TrkA agonist is administered in combination with an additional therapy, optionally, wherein the additional therapy is corneal neurotization or tacrolimus.

8. The method of claim 1 or 2, wherein the subject has experienced a corneal abrasion or surgical corneal epithelial debridement.

9. The method of claim 8, wherein the subject has experienced a partial or a full denervation of at least one eye.

10. The method of claim 9, wherein the TrkA agonist is administered at least 1 day following the denervation.

11. The method of claim 10, wherein the TrkA agonist is administered at least 5 days following the denervation.

12. The method of claim 1, wherein a therapeutically effective amount comprises about 0.145 mg MIM-D3 to about 3.5 mg MIM-D3 administered about once per day, about twice per day, about three times per day, about four times per day, about every other day, about every third day, about every fourth day, about every fifth day, about every sixth day, or about once per week.

13. A method of reducing the opacity of a cornea in a subject following a corneal injury, the method comprising administering a therapeutically effective amount of a TrkA agonist to the subject to reduce the opacity of the cornea in the subject following a corneal injury.

14. The method of claim 13, wherein the subject is suffering from NK.

15. The method of claim 13, wherein the TrkA agonist comprises MIM-D3, Udonitrectag lysine salt, E2511, ACD856, ENT-A013, or A1.

16. The method of claim 15, wherein the TrkA agonist is MIM-D3 (tavilermide).

17. The method of claim 13, wherein administering comprises topical administration to an affected eye of the subject.

18. The method of claim 13, wherein the TrkA agonist is administered in combination with additional therapy, optionally, wherein the additional therapy comprises corneal neurotization or tacrolimus.

19. The method of claim 13 or 14, wherein the subject has experienced a corneal abrasion or surgical corneal epithelial debridement.

20. The method of claim 19, wherein the subject has experienced a partial or a full denervation of at least one eye.

21. The method of claim 20, wherein the TrkA agonist is administered at least 1 day following the denervation.

22. The method of claim 21, wherein the TrkA agonist is administered at least 5 days following the denervation.

23. The method of claim 13, wherein a therapeutically effective amount comprises about 0.145 mg to about 3.5 mg MIM-D3, administered about once per day, about twice per day, about three times per day, about four times per day, about every other day, about every third day, about every fourth day, about every fifth day, about every sixth day, or about once per week.

24. A method comprising performing a corneal neurotization on a subject and administering a therapeutically effective amount of a TrkA agonist to the subject.

25. The method of claim 24, wherein the TrkA agonist is administered to the subject for at least 1 day, at least 2 days, at least 3 days, at least 4 days, or at least 5 days after the corneal neurotization is performed.

26. The method of claim 24, wherein the TrkA agonist is administered to the subject for at least 1 day, at least 2 days, at least 3 days, at least 4 days, or at least 5 days before the corneal neurotization is performed.

27. The method of claim 24, wherein the TrkA agonist is MIM-D3.

28. The method of claim 24, wherein the TrkA agonist is administered once per day, twice per day, or three times per day for at least 5 days following neurotization.

29. A TrkA agonist for use in a method of treating a corneal disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of the TrkA agonist to the subject to treat the corneal disease or disorder in the subject.

30. The TrkA agonist for use of claim 29, wherein the corneal disease or disorder comprises neurotrophic keratitis (NK).

31. The TrkA agonist for use of claim 29, wherein the TrkA agonist comprises MIM-D3, Udonitrectag lysine salt, E2511, ACD856, ENT-A013, or A1.

32. The TrkA agonist for use of claim 29 or 30, wherein the TrkA agonist comprises MIM-D3 (tavilermide).

33. The TrkA agonist for use of claim 29, wherein the method reduces corneal opacity in the subject.

34. The TrkA agonist for use of claim 29, wherein administering comprises topical administration to an affected eye of the subject.

35. The TrkA agonist for use of claim 29, wherein the TrkA agonist is administered in combination with an additional therapy, optionally, wherein the additional therapy is corneal neurotization or tacrolimus.

36. The TrkA agonist for use of claim 29 or 30, wherein the subject has experienced a corneal abrasion or surgical corneal epithelial debridement.

37. The TrkA agonist for use of claim 36, wherein the subject has experienced a partial or a full denervation of at least one eye.

38. The TrkA agonist for use of claim 37, wherein the TrkA agonist is administered at least 1 day following the denervation.

39. The TrkA agonist for use of claim 38, wherein the TrkA agonist is administered at least 5 days following the denervation.

40. The TrkA agonist for use of claim 29, wherein a therapeutically effective amount comprises about 0.145 mg to about 3.5 mg MIM-D3 administered about once per day, about twice per day, about three times per day, about four times per day, about every other day, about every third day, about every fourth day, about every fifth day, about every sixth day, or about once per week.

41. A TrkA agonist for use in reducing the opacity of a cornea in a subject following a corneal injury, the method comprising administering a therapeutically effective amount of the TrkA agonist to the subject to reduce the opacity of the cornea in the subject following a corneal injury.

42. The TrkA agonist for use of claim 41, wherein the subject is suffering from NK.

43. The TrkA agonist for use of claim 41, wherein the TrkA agonist comprises MIM-D3, Udonitrectag lysine salt, E2511, ACD856, ENT-A013, or A1.

44. The TrkA agonist for use of claim 43, wherein the TrkA agonist is MIM-D3 (tavilermide).

45. The TrkA agonist for use of claim 41, wherein administering comprises topical administration to an affected eye of the subject.

46. The TrkA agonist for use of claim 41, wherein the TrkA agonist is administered in combination with additional therapy, optionally, wherein the additional therapy comprises corneal neurotization or tacrolimus.

47. The TrkA agonist for use of claim 41 or 42, wherein the subject has experienced a corneal abrasion or surgical corneal epithelial debridement.

48. The TrkA agonist for use of claim 47, wherein the subject has experienced a partial or a full denervation of at least one eye.

49. The TrkA agonist for use of claim 48, wherein the TrkA agonist is administered at least 1 day following the denervation.

50. The TrkA agonist for use of claim 49, wherein the TrkA agonist is administered at least 5 days following the denervation.

51. The TrkA agonist for use of claim 41, wherein a therapeutically effective amount comprises about 0.145 mg to about 3.5 mg MIM-D3, administered about once per day, about twice per day, about three times per day, about four times per day, about every other day, about every third day, about every fourth day, about every fifth day, about every sixth day, or about once per week.

52. A method of preventing neurotrophic keratitis (NK) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a TrkA agonist to the subject to prevent NK in the subject.

53. The method of claim 52, wherein the TrkA agonist comprises MIM-D3.

54. The method of claim 52, wherein the subject has experienced a partial or a full denervation of at least one eye.

55. The method of claim 54, wherein the TrkA agonist is administered at least 1 day following the denervation.

56. The method of claim 54, wherein the TrkA agonist is administered at least 5 days following the denervation.

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