WO2025256594A1

WO2025256594A1 - Methods and compositions for treating refractive errors

Info

Publication number: WO2025256594A1
Application number: PCT/CN2025/100691
Authority: WO
Inventors: Yan Yin Tse; Jiajun Wang; Bing ZUO; Mezbah Uddin; Chuen LAM
Original assignee: Centre For Eye And Vision Research Ltd; Hong Kong Polytechnic University HKPU
Current assignee: Centre For Eye And Vision Research Ltd; Hong Kong Polytechnic University HKPU
Priority date: 2024-06-12
Filing date: 2025-06-12
Publication date: 2025-12-18
Anticipated expiration: 2026-12-12

Abstract

A method for treating myopia is provided. Specifically, the method includes administering a mitogen-activated protein kinase (MAPK) signaling pathway inhibitor to a subject in need thereof. The inhibitor targets one or more kinases selected from MEK1, MEK2, ERK1, and ERK2, thereby modulating MAPK pathway activity to control ocular growth and progression of myopia.

Description

METHODS AND COMPOSITIONS FOR TREATING REFRACTIVE ERRORS

Inventors: Yan Yin TSE; Jiajun WANG; Bing ZUO; Mezbah UDDIN; and Chuen LAM
Cross-Reference to Related Applications:

The present application claims priority from U.S. Provisional Utility Patent application number 63/659, 307 filed June 12, 2024, and the disclosure of which is incorporated herein by reference in its entirety.

Field of the Invention:

The present invention generally relates to the field of ophthalmology, pharmacology, molecular medicine, and particularly to pharmaceutical compositions and therapeutic methods for the treatment or modulation of myopia using inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway.

Background of the Invention:

Myopia is one of the most common ocular disorders worldwide, characterized by excessive axial elongation of the eye, leading to blurred distance vision. The global prevalence of myopia is currently estimated at approximately 30%and is projected to rise dramatically to 50%by the year 2050, representing a growing public health concern. In particular, high myopia-commonly defined as a refractive error of -6.00 diopters or worse-is associated with an elevated risk of vision-threatening complications, including myopic maculopathy, retinal detachment, glaucoma, and choroidal neovascularization. As a result, early intervention and effective management of myopia progression, especially in pediatric populations, are critical to reducing the lifetime risk of severe ocular pathology and blindness.

To date, the major therapeutic approaches for controlling the progression of myopia fall into two broad categories: (i) optical interventions and (ii) pharmaceutical treatments. Optical methods include specially designed spectacle lenses, such as defocus-incorporated multiple segments (DIMS) lenses, and various contact lens modalities, including orthokeratology and multifocal soft lenses. Pharmaceutical treatment is currently limited to atropine eye drops, which have demonstrated dose-dependent efficacy in slowing axial elongation in children. In China, low-dose atropine (typically ranging from 0.01%to 0.05%) accounts for an estimated 40–50%of the pharmaceutical myopia management market and is widely recommended by ophthalmologists as a first-line therapy.

However, despite its clinical utility, atropine use is hindered by a number of limitations. These include ocular side effects such as photophobia, blurred near vision, and allergic conjunctivitis, as well as potential systemic adverse reactions. Furthermore, the precise pharmacological mechanism by which atropine inhibits myopia progression remains poorly understood. Given its known toxicity at higher doses, regulatory authorities such as the China National Medical Products Administration (cFDA) have been cautious in approving its broader clinical use. Currently, only the lowest concentrations are permitted for prescription, and even these are subject to stringent regulatory oversight.

In light of these concerns, there is an urgent and unmet need for the development of alternative pharmaceutical agents for myopia control that offer comparable or superior efficacy, with improved safety profiles and fewer side effects. As such, the present invention addresses this need.

Summary of the Invention:

It is an objective of the present invention to provide the compositions, methods, or uses, to address the aforementioned shortcomings in the current state of the art.

In accordance with a first aspect of the present invention, a method of treating myopia is introduced. Specifically, the method includes the step of administering a mitogen-activated protein kinase (MAPK) signaling pathway inhibitor to a subject in need thereof.

In accordance with one embodiment, the MAPK signaling pathway inhibitor inhibits at least one kinase selected from the group consisting of MEK1, MEK2, ERK1, and ERK2.

In accordance with another embodiment, the MAPK signaling pathway inhibitor includes at least one of binimetinib or vandetanib.

In accordance with yet another embodiment, the MAPK signaling pathway inhibitor includes a combination of binimetinib and vandetanib.

In accordance with yet another embodiment, the MAPK pathway inhibitor reduces vitreous chamber depth and axial length growth.

In accordance with yet another embodiment, the MAPK pathway inhibitor is administered by intravitreal injection at a dose ranging from 0.3 nmol to 300 nmol.

In accordance with a second aspect of the present invention, a pharmaceutical composition for the treatment of myopia is provided. Particularly, the pharmaceutical composition includes a MAPK signaling pathway inhibitor and a pharmaceutically acceptable additive.

In accordance with one embodiment, the MAPK signaling pathway inhibitor is configured to downregulate or inhibit the expression or activity of at least one of MEK1/2 proteins or ERK1/2 proteins in retinal or scleral tissues.

In accordance with another embodiment, the pharmaceutically acceptable additive includes one or more of an excipient, a stabilizer, a carrier, a diluent, or a solubilizer.

In accordance with yet another embodiment, the MAPK signaling pathway inhibitor includes one or more of binimetinib and vandetanib.

In accordance with yet another embodiment, the composition is formulated in administration form for delivery to a posterior segment of an eye of the subject via a transcorneal, transscleral, intraocular implant, or systemic administration route.

In accordance with yet another embodiment, the administration form is an immediate-release form.

In accordance with yet another embodiment, the administration form is a controlled-release form.

In accordance with yet another embodiment, the pharmaceutical composition is delivered through an intravitreal injection, a subretinal injection, or a suprachoroidal injection.

In accordance with yet another embodiment, the administration form is an injection form, an eye drop form, an eye ointment form, a hydrogel form, an ultrasonic ocular drug delivery form, a drug-loaded contact lenses form, a drug-eluting implant form, a nanoparticle-mediated delivery, an intravitreal gene therapy form, or an intravitreal microneedle form.

In accordance with a third aspect of the present invention, a usage of the aforementioned pharmaceutical composition for reducing axial elongation or choroidal thinning in a subject with myopia is provided.

Brief Description of the Drawings:

Embodiments of the invention are described in more details hereinafter with reference to the drawings, in which:

FIGs. 1A-1D depict the intraocular differences (IOD) in treated eye minus untreated eye after 7 days of treatment with binimetinib (0.3, 3, 30, and 300 nmol) on FDM in chicks, in which FIG. 1A illustrates the myopic refractive error, FIG. 1B shows the vitreous chamber depth (VCD) , FIG. 1C demonstrates the axial length (AL) and, FIG. 1D shows the choroidal thickness (ChT) ;

FIGs. 2A-2D depict the IOD in treated eye minus untreated eye after 7 days of treatment with binimetinib (0.3, 3, 30 and 300 nmol) on LIM in chicks, in which FIG. 2A shows the myopic refractive error, FIG. 2B illustrates the VCD, FIG. 2C exhibits the AL, and FIG. 2D shows the ChT;

FIGs. 3A-3D depict the IOD in treated eye minus untreated eye after 7 days of treatment with vandetanib (0.4, 2, 10 and 50 nmol) on FDM in chicks, in which FIG. 3A shows the myopic refractive error, FIG. 3B demonstrates the VCD, FIG. 3C illustrates the AL and, FIG. 3D shows the ChT; and

FIGs. 4A-4D depict the intraocular differences (IOD) in treated eye minus untreated eye after 7 days of treatment with vandetanib (0.4, 2, 10 and 50 nmol) on LIM in chicks, in which FIG. 4A illustrates the myopic refractive error, FIG. 4B shows the VCD, FIG. 4C depicts the AL, and FIG. 4D shows the ChT.

Detailed Description:

In the following description, compositions, methods and/or uses of treating refractive disorders and the likes are set forth as preferred examples. It will be apparent to those skilled in the art that modifications, including additions and/or substitutions may be made without departing from the scope and spirit of the invention. Specific details may be omitted so as not to obscure the invention; however, the disclosure is written to enable one skilled in the art to practice the teachings herein without undue experimentation.

The regulation of ocular growth is believed to function as a homeostatic process governed by a dynamic balance between “Growth” and “Stop” signals, both optically and biochemically mediated. “Growth” signals promote axial length (AL) elongation, whereas “Stop” signals inhibit this process. In experimental animal models, myopia can be induced by placing a negative lens in front of the eye, which displaces the image focus behind the retina. This condition, referred to as hyperopic defocus, serves as an optical “Growth” signal and initiates a downstream cascade of biochemical signaling that increases the rate of AL elongation. Conversely, when the negative lens is removed during a recovery phase, the image is refocused in front of the retina-known as myopic defocus-thereby acting as an optical “Stop” signal. This reversal activates a corresponding cascade of biochemical “Stop” signals that slow or reverse the myopic progression. It is generally accepted that these biochemical cascades originate in the retina and terminate in the sclera. Despite decades of research, the precise molecular and biochemical mechanisms underlying myopia remain poorly defined. At present, atropine is the only clinically approved pharmaceutical agent for myopia control, but its side effects, including photophobia and blurred near vision, make it poorly tolerated in pediatric populations.

The early growth response 1 (EGR1) gene has been previously implicated in regulating ocular axial growth. In gene knockout studies using murine models, EGR1-null (EGR1 -/-) mice exhibit significantly greater axial elongation and increased refractive error compared to heterozygous (EGR1 +/-) and wild-type (EGR1 +/+) mice. These findings suggest that EGR1 plays a protective role in early retinal development and in mitigating the progression of myopia. Beyond its role in ocular development, EGR1 has been characterized in other biological contexts as both an oncogene and a tumor suppressor, depending on the disease model. EGR1 expression is primarily regulated by the Ras/Raf-MEK (mitogen-activated protein kinase kinase) -ERK (extracellular signal-regulated kinase) axis of the MAPK pathway, but it is also influenced by parallel signaling branches involving receptor tyrosine kinases such as c-MET (hepatocyte growth factor receptor) , EGFR (epidermal growth factor receptor) , and FGFR (fibroblast growth factor receptor) . Some downstream effectors of EGR1 have been associated with retinal neuronal development, particularly dopaminergic and nitric oxide-releasing cell subtypes, which may contribute to myopia pathogenesis as demonstrated in central nervous system models in mice.

The present invention introduces that pathological overactivation of the MAPK signaling pathway may result in the downregulation (hypo-expression) of EGR1 in the retina, thereby contributing to myopia development. While EGR1 itself is a zinc finger transcription factor and is not easily targeted by small-molecule drugs due to the lack of conventional ligand-binding domains, its upstream regulatory components within the MAPK pathway are more amenable to pharmacological intervention. Recent advances in cancer research have identified numerous small-molecule inhibitors that target various MAPK pathway components, including MEK, ERK, EGFR, and c-MET. These developments provide promising pharmacotherapeutic avenues for modulating EGR1 activity indirectly and thus offer a new strategy for the treatment or prevention of myopia.

As used herein, the term “MAPK signaling pathway inhibitor” refers to any chemical or biological agent that interferes with, suppresses, or blocks one or more components of the MAPK signaling cascade. This includes, but is not limited to, inhibitors that act directly on key kinases such as RAF, MEK1, MEK2, ERK1, and ERK2, or indirectly through upstream or downstream effectors involved in the activation or propagation of MAPK pathway signaling. The inhibitor may function by reducing phosphorylation activity, blocking protein-protein interactions, or downregulating gene or protein expression associated with MAPK activation. Such inhibitors may be small molecules, peptides, antibodies, or other therapeutic agents formulated for ocular or systemic administration.

As used herein, the term “Binimetinib” refers to a selective, reversible, small-molecule inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1 and MEK2) , which are components of the MAPK/ERK signaling pathway. Binimetinib (chemical name: N- [3- [3-cyano-4- (difluoromethoxy) phenyl] -1H-pyrazol-5-yl] -4-fluoro-2- (trifluoromethyl) benzamide) functions by preventing the phosphorylation and activation of ERK1/2, thereby inhibiting downstream cell proliferation signals.

As used herein, the term “Vandetanib” refers to an oral small-molecule tyrosine kinase inhibitor that targets multiple receptor tyrosine kinases, including VEGFR (vascular endothelial growth factor receptor) , EGFR (epidermal growth factor receptor) , and RET (rearranged during transfection) . Vandetanib (chemical name: N- (4-bromo-2-fluorophenyl) -6-methoxy-7- [ (1-methylpiperidin-4-yl) methoxy] quinazolin-4-amine) exerts indirect inhibitory effects on the MAPK/ERK signaling cascade by disrupting upstream receptor-mediated activation.

In accordance with a first aspect of the present invention, a method for the treatment of myopia through the targeted inhibition of components within the MAPK signaling pathway is provided. This method involves administering a MAPK pathway inhibitor to a subject who is in need of therapeutic intervention for progressive myopia.

The MAPK signaling pathway inhibitor functions to inhibit one or more kinases selected from MEK1, MEK2, ERK1, and ERK2. Inhibition of these kinases disrupts the transmission of growth-promoting biochemical signals in ocular tissues, particularly within the retina and sclera, thereby modulating abnormal eye growth and preventing the progression of myopia. The inhibition of these specific proteins has been shown to interfere with the signaling mechanisms responsible for axial elongation and pathological ocular remodeling, processes which underlie myopic progression.

In some embodiments, the MAPK signaling pathway inhibitor includes either binimetinib or vandetanib. Binimetinib is a selective inhibitor of MEK1 and MEK2 and operates by preventing the phosphorylation and activation of ERK1/2. Vandetanib, on the other hand, acts upstream by targeting receptor tyrosine kinases such as VEGFR, EGFR, and RET, which activate MAPK signaling. Both compounds, although traditionally used in oncology, are here repurposed and demonstrated to modulate myopia-related signaling pathways effectively.

In some embodiments, the MAPK signaling pathway inhibitor includes a combination of binimetinib and vandetanib.

The administration of these inhibitors results in a marked reduction in vitreous chamber depth and axial length growth. These parameters are commonly used in ophthalmology to assess the severity and progression of myopia. The data indicate that both binimetinib and vandetanib exert dose-dependent inhibition on these structural changes, supporting their utility in slowing or halting myopic progression.

The preferred route of administration is via intravitreal injection, which ensures direct delivery of the inhibitor to the ocular tissues and minimizes systemic exposure. The dosage is optimized within the range of approximately 0.3 nmol to 300 nmol per eye per administration, based on preclinical pharmacologic studies. This dosage range has been demonstrated to achieve therapeutic efficacy while avoiding significant ocular toxicity.

Overall, the method provides a novel, mechanism-based pharmacologic approach to myopia management by intervening in a specific intracellular signaling cascade implicated in abnormal eye growth, offering an alternative to traditional treatments such as atropine eye drops.

In accordance with a second aspect of the present invention, a pharmaceutical composition for the treatment of myopia is introduced. The composition includes at least one MAPK signaling pathway inhibitor in combination with a pharmaceutically acceptable additive. The MAPK pathway inhibitor functions by targeting key enzymes involved in the MAPK signaling cascade, which has been implicated in the pathological elongation of the eyeball associated with myopic progression. Specifically, the inhibitor is configured to downregulate or inhibit the expression and/or enzymatic activity of at least one of MEK1/2 proteins or ERK1/2 proteins, particularly within retinal and scleral tissues, which are believed to mediate structural remodeling during myopic development.

The MAPK signaling pathway inhibitor used in the composition may be one or more of binimetinib or vandetanib.

To ensure biocompatibility, stability, and effective delivery, the pharmaceutical composition includes one or more pharmaceutically acceptable additives. These may include excipients to ensure isotonicity or pH balance; stabilizers to prolong shelf life; carriers to support uniform distribution of the active compound; diluents to adjust drug concentration; and solubilizers to improve drug dissolution and bioavailability.

The formulation of the pharmaceutical composition is designed for delivery to the posterior segment of the eye, which may be achieved through transcorneal, transscleral, intraocular implant, or systemic administration route. Various administration forms are contemplated to accommodate patient-specific needs and clinical conditions. These include immediate-release forms for rapid therapeutic effect or controlled-release forms for sustained drug delivery over time.

The delivery of the composition may be achieved through multiple ophthalmic administration routes. These include, but are not limited to, intravitreal injection, subretinal injection, and suprachoroidal injection, all of which provide direct access to posterior ocular tissues. Additionally, the pharmaceutical composition may be formulated into diverse dosage forms such as injections, eye drops, eye ointments, hydrogels, ultrasonic ocular drug delivery systems, drug-loaded contact lenses, drug-eluting implants, nanoparticle-mediated carriers, gene therapy constructs, or intravitreal microneedles. These varied delivery formats enhance therapeutic efficacy, optimize bioavailability, and improve patient compliance.

Altogether, the present pharmaceutical composition offers a novel and versatile approach for inhibiting the progression of myopia by directly targeting the MAPK signaling cascade, a critical pathway in ocular growth regulation. The flexibility in formulation and administration routes further supports its clinical applicability across a wide range of patient populations and stages of myopic disease.

In accordance with a third aspect of the present invention, a usage of the aforementioned pharmaceutical composition for the treatment of myopia, specifically for reducing axial elongation and choroidal thinning in a subject in need thereof, is provided. Axial elongation of the eye is one of the principal anatomical changes associated with the progression of myopia, often leading to structural remodeling of the posterior segment, including thinning of the choroid, which can further contribute to vision-threatening complications such as myopic maculopathy or retinal detachment.

EXAMPLES

Example 1. Pharmacologic modulation of ocular growth via MEK1/2 inhibition in animal models of myopia

To investigate the efficacy of pharmacological agents in modulating ocular growth associated with myopia, a series of in vivo experiments are conducted using White Leghorn chicks (Gallus gallus) as the animal model. All procedures adhere to the institutional and ARVO guidelines for animal research, and are approved by the relevant animal ethics committee at the Hong Kong Polytechnic University.

The chicks, hatched from specific pathogen-free (SPF) eggs, are housed under controlled conditions with a 12-hour light/dark cycle and ambient luminance maintained at 300 lux. The experiments commence on postnatal day 7 (PN7) and continued through day 21 (PN21) . Form-deprivation myopia (FDM) is induced in the right eyes of selected chicks using diffuser lenses, while lens-induced myopia (LIM) is produced using -10D single-vision lenses. The left eyes remain untreated as internal controls.

The animal experiment procedures are approved by the animal sciences care committee of the department of health and Hong Kong Polytechnic University. These procedures comply with the government of the Hong Kong Special Administrative Region and adhere to the Association for Research in Vision and Ophthalmology (ARVO) guideline for the use of experimental animals in vision and ophthalmology research. The White Leghorn chicks (Gallus gallus) used in the study are hatched from specific pathogen-free eggs (SPF, Jinan, China) . The house is maintained at room temperature at 25℃ and used standard stainless-steel cages. The central ambient luminance over the cages is maintained at around 300 lux. The experimental period starts from postnatal 7 days (PN 7) to 21 days (PN 21) with available food and water provided daily under the 12h: 12h light/dark cycle (lights on in the chicken room at 7 AM and turn-off at 7 PM) . Experimental chicks are monitored twice a day, once by the researcher to check the lens attachment or deliver the drug and another time by the technician responsible for cleaning the room, cages and supplying food or water if necessary.

In brief, a round-shaped Velcro ring is attached with diffuser lenses over the right eye of a single chick. In experiment I, 113 chicks are divided into eleven groups. Binimetinib FDM treated groups receive tested doses of 0.3 nmol (n=10) , 3 nmol (n=10) , 30 nmol (n=13) and 300 nmol (n=10) , control group received (10%DMSO) + (90%PBS) (n=10) and FDM with vehicle treatment group (n=10) . Similarly, binimetinib LIM treated groups receive tested doses of 0.3 nmol (n=10) , 3 nmol (n=10) , 30 nmol (n=13) and 300 nmol (n=10) , control group received (10%DMSO) + (90%PBS) (n=10) . In experiments II, 104 chicks are divided into ten groups. Vandetanib FDM treated groups receive tested doses of 0.4 nmol (n=9) , 2 nmol (n=10) , 10 nmol (n=17) and 50 nmol (n=10) , control group received (10%DMSO) + (90%PBS) (n=10) . For vandetanib LIM treated groups receive tested doses of 0.4 nmol (n=8) , 2 nmol (n=10) , 10 nmol (n=10) and 50 nmol (n=10) , control group received (10%DMSO) + (90%PBS) (n=10) .

For pharmacologic testing, two MAPK pathway inhibitors are evaluated: binimetinib, a selective MEK1/2 inhibitor, and vandetanib, a multi-kinase inhibitor targeting VEGFR, EGFR, and RET. Both agents are known to interfere with signaling pathways implicated in cellular proliferation and ocular elongation. For instance, binimetinib is a reversible and selective inhibitor of MEK1/2, which can significantly decrease the activity of the MAPK pathway. Vandetanib is a kinase inhibitor that targets multiple pathways including the mitogen-activated protein kinase pathway. Vandetanib inhibits the kinases that play critical roles in the MAPK pathway which is involved in cell proliferation, differentiation and survival. Vandetanib can disrupt the signaling pathways that lead to abnormal growth and angiogenesis making it effective in treating certain types of cancer. Its action on the MAPK pathway helps to prevent the cascade of signaling that can lead to uncontrolled cell growth.

Drug formulations are freshly prepared prior to intravitreal administration by dissolving the compounds in a vehicle comprising 10%DMSO and 90%PBS. All injections are performed under isoflurane anesthesia in a clean and standardized environment to ensure consistent delivery and minimize variability.

Intravitreal injections (10 μL) are administered every other day into the dorsal quadrant of the right eye using a 30-gauge needle. Doses for binimetinib ranged from 0.3 to 300 nmol and for vandetanib from 0.4 to 50 nmol. Each treatment group included appropriate vehicle controls. The injection sites are rotated to avoid tissue damage or backflow. Briefly, the intravitreal injections are performed every alternative day at the same time each day (10: 00 am -12: 00 pm) to control the effect of circadian rhythm. Chicks are anaesthetized with 0.5%isoflurane in 50%oxygen (O₂) and 50%nitrous oxide (N₂O) . 70%ethanol is used to clean the surface of the injected eye and lid retractor for disinfection. For the injection, 10 μl of the solution is injected into the dorsal quadrant of the eye using a 30-gauge needle attached to a 25 μl Hamilton Gastight Syringe. The needle is inserted in the chick’s eye approximately 3 to 4 mm deep, then the needle is held for three to five seconds and slowly removed to prevent the backflow. On day 7, all lenses are removed, and the eyes are allowed to recover from experimentally induced myopia.

Throughout the treatment period, biometric and refractive measurements are recorded. These include axial length (AL) , vitreous chamber depth (VCD) , anterior chamber depth (ACD) , and choroidal thickness (ChT) , obtained via high-frequency A-scan ultrasonography and custom imaging software. Refractive errors are measured with streak retinoscopy following cycloplegia with 1%cyclopentolate. Intraocular pressure (IOP) is measured using a Tono-Pen. Statistical analysis is conducted using GraphPad Prism v8 software, and results are expressed as the intraocular difference (IOD) between treated and untreated eyes, with comparisons made via ANOVA and post hoc tests where applicable.

Effect of binimetinib on form-deprivation myopia

After 7 days of treatment, results show that the treatment effect is dose-dependent with the doses of binimetinib. All higher doses of tested drugs (3, 30 and 300 nmol) significantly inhibit the induced myopic refractive error. The intraocular difference (IOD, treated eye minus untreated eye) in refractive errors (Diopters, mean ± SD) at day 7, compared to the control group are -11.15 (DMSO + PBS) , -11.10 ± 2.14D (0.3 nmol) , -5.25 ± 3.77D (3 nmol) , -3.08 ± 2.38D (30 nmol) and -3.66 ± 2.35D (300 nmol) respectively (FIG. 1A) . However, higher doses of binimetinib (3, 30 and 300 nmol) markedly reduce the elongation of the vitreous chamber depth (VCD) compared with the control group (IOD of VCD: 0.77 ± 0.13 mm vs 3 nmol: 0.22 ± 0.18 mm, p=0.001; 30 nmol: 0.30 ± 0.19 mm p=0.0001; and 300 nmol: 0.32 ± 0.17 mm, p=0.0001 (FIG. 1B) . Similarly, higher doses of binimetinib (3, 30 and 300 nmol) significantly inhibit the elongation of axial length compared to the control group is (IOD of AL: 0.83 ± 0.17 mm vs 3 nmol: 0.34 ±0.23 mm, p=0.001; 30 nmol: 0.29 ± 0.21 mm p=0.0001; and 300 nmol: 0.33 ± 0.16 mm, p=0.0001 (FIG. 1C) . Interestingly, higher doses of binimetinib (3, 30 and 300 nmol) significantly increase choroidal thickness after 7 days of treatment compared to the control group, whereas a dose of 0.3 nmol has no effect on choroidal thickness (FIG. 1D) .

Effect of binimetinib on lens-induced myopia

After 7 days of treatment results indicates that the treatment effect is in a dose-dependent manner with doses of binimetinib on lens-induced myopia model. All higher doses of tested drugs (3, 30 and 300 nmol) significantly inhibit the induced myopic refractive error. The IOD (treated eye minus untreated eye) in refractive errors (Diopters, mean ± SD) at day 7, compared to the control group: -10.74 ± 2.08D (DMSO + PBS) vs -10.30 ± 1.47D (0.3 nmol) , -5.07 ± 2.72D (3 nmol) , -4.75 ± 1.43D (30 nmol) , and -3.98 ± 2.29D (300 nmol) respectively (FIG. 2A) . However, all high doses of binimetinib (3, 30 and 300 nmol) markedly shorter vitreous chamber depth elongation compared with the control group (IOD of VCD: 0.62 ± 0.18 mm vs 3 nmol: 0.24 ± 0.15 mm, p=0.001; 30 nmol: 0.29 ± 0.11 mm p=0.0001; and 300 nmol: 0.32 ± 0.16 mm, p=0.0001 (FIG. 2B) . Although, all high doses of binimetinib (3, 30 and 300 nmol) significantly reduce the elongation of axial length compared to the control group (IOD of AL: 0.78 ± 0.16 mm vs 3 nmol: 0.32 ± 0.15 mm, p=0.001; 30 nmol: 0.35 ± 0.08 mm p=0.0001; and 300 nmol: 0.32 ± 0.17 mm, p=0.0001 (FIG. 2C) . In contrast, all high doses of binimetinib (3, 30 and 300 nmol) markedly increased choroidal thickness after 7 days treatment compared to control (DMSO + PBS) group, (IOD of ChT: -32.60 ± 9.68 μm vs 3 nmol: -11.83 ± 0.6.92 μm, p=0.001; 30 nmol: -16.23 ± 7.65 μm p=0.0001; and 300 nmol: -9.80 ±6.35 μm, p=0.0001, respectively, whereas lower dose of binimetinib (0.3 nmol) has no effect on choroidal thickness (FIG. 2D) .

Effect of vandetanib on form-deprivation myopia

After 7 days of treatment, results show that the treatment effect is dose-dependent with the doses of vandetanib on form-deprivation myopia model. All higher doses of tested drugs (2, 10 and 50 nmol) significantly inhibit the induced myopic refractive error. The IOD (treated eye minus untreated eye) in refractive errors (Diopters, mean ± SD) at day 7, compared to the control group are -10.12 ±3.24D (DMSO + PBS) , -9.51 ± 3.20D (0.4 nmol) , -7.65 ± 1.62D (2 nmol) , -6.42 ±3.09D (10 nmol) and -2.67 ± 2.20D (50 nmol) respectively (FIG. 3A) . However, higher doses of vandetanib (2, 10 and 50 nmol) markedly reduce the elongation of the VCD compared with the control group (IOD of VCD: 0.60 ± 0.14 mm vs 2 nmol: 0.34 ± 0.12 mm, p=0.001; 10 nmol: 0.35 ± 0.16 mm p=0.0001; and 50 nmol: 0.16 ±0.21 mm, p=0.0001 (FIG. 3B) . Similarly, higher doses of vandetanib (2, 10 and 50 nmol) significantly inhibit the elongation of axial length compared to the control group is (IOD of AL: 0.71 ± 0.24 mm vs 2 nmol: 0.37 ± 0.17 mm, p=0.001; 10 nmol: 0.40 ± 0.20 mm p=0.001; and 50 nmol: 0.14 ± 0.23 mm, p=0.0001 (FIG. 3C) . Interestingly, all tested doses of vandetanib (0.4 2, 10 and 50 nmol) significantly increase choroidal thickness after 7 days of treatment compared to the control group (FIG. 3D) .

Effect of vandetanib on lens-induced myopia

After 7 days of treatment results indicate that the treatment effect is in a dose-dependent manner with doses of vandetanib on lens-induced myopia model. All higher doses of tested drugs (2, 10 and 50 nmol) significantly inhibit the induced myopic refractive error. The IOD (treated eye minus untreated eye) in refractive errors (Diopters, mean ± SD) at day 7, compared to the control group are -10.43 ±1.71D (DMSO + PBS) , -8.26 ± 2.69D (0.4 nmol) , -4.22 ± 2.49D (2 nmol) , -4.92 ±2.09D (10 nmol) and -3.15 ± 2.03D (50 nmol) respectively (FIG. 4A) . However, only higher doses of vandetanib (2, 10 and 50 nmol) markedly reduce the elongation of the vitreous chamber depth (VCD) compared with the control group (IOD of VCD: 0.51 ± 0.14 mm vs 2 nmol: 0.21 ± 0.15 mm, p=0.001; 10 nmol: 0.29 ± 0.12 mm p=0.01; and 50 nmol: 0.25 ± 0.17 mm, p=0.001 (FIG. 4B) . Although, all higher doses of vandetanib (2, 10 and 50 nmol) significantly inhibit the elongation of axial length compared to the control group is (IOD of AL: 0.61 ± 0.17 mm vs 2 nmol: 0.28 ±0.12 mm, p=0.001; 10 nmol: 0.31 ± 0.15 mm p=0.01; and 50 nmol: 0.26 ± 0.17 mm, p=0.001 (FIG. 4C) . In contrast, all doses of vandetanib (0.4, 2, 10 and 50 nmol) markedly increase choroidal thickness after 7 days treatment compared to control (DMSO + PBS) group, (IOD of ChT: -34.13 ± 8.83 μm vs 0.4 nmol: -22.25 ± 5.34 μm, p=0.01; 2 nmol: -22.07 ± 4.43 μm, p=0.01; 10 nmol: -19.33 ± 6.05 μm p=0.001; and 50 nmol: -5.20 ± 8.77 μm, p=0.0001, respectively (FIG. 4D) .

These results collectively demonstrate that pharmacologic inhibition of the MAPK pathway via MEK1/2 or multi-kinase targeting can significantly reduce myopia progression in chick models. Both binimetinib and vandetanib showed dose-dependent efficacy in reducing axial lengthening, vitreous chamber elongation, and refractive error, while promoting choroidal thickening. These findings support the therapeutic potential of MAPK pathway inhibitors as promising candidates for pharmaceutical management of myopia, offering a possible alternative to atropine with fewer systemic side effects.

As used herein, terms "approximately" , "basically" , "substantially" , and "about" are used for describing and explaining a small variation. When being used in combination with an event or circumstance, the term may refer to a case in which the event or circumstance occurs precisely, and a case in which the event or circumstance occurs approximately. As used herein with respect to a given value or range, the term "about" generally means in the range of ±10%, ±5%, ±1%, or ±0.5%of the given value or range. The range may be indicated herein as from one endpoint to another endpoint or between two endpoints. Unless otherwise specified, all the ranges disclosed in the present disclosure include endpoints. When reference is made to "substantially" the same numerical value or characteristic, the term may refer to a value within ±10%, ±5%, ±1%, or ±0.5%of the average of the values.

The foregoing description of the present invention has been provided for the purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations will be apparent to the practitioner skilled in the art.

The embodiments were chosen and described in order to best explain the principles of the invention and its practical application, thereby enabling others skilled in the art to understand the invention for various embodiments and with various modifications that are suited to the particular use contemplated.

Claims

A method of treating myopia, comprising:

administering a mitogen-activated protein kinase (MAPK) signaling pathway inhibitor to a subject in need thereof;

wherein the MAPK signaling pathway inhibitor inhibits at least one kinase selected from the group consisting of MEK1, MEK2, ERK1, and ERK2.
The method of claim 1, wherein the MAPK signaling pathway inhibitor comprises one or more of binimetinib and vandetanib.
The method of claim 1, wherein the MAPK pathway inhibitor reduces vitreous chamber depth and axial length growth.
The method of claim 1, wherein the MAPK pathway inhibitor is administered by intravitreal injection at a dose ranging from 0.3 nmol to 300 nmol.
A pharmaceutical composition for use in treating myopia, comprising:

a MAPK signaling pathway inhibitor; and

a pharmaceutically acceptable additive;

wherein the MAPK signaling pathway inhibitor is configured to downregulate or inhibit the expression or activity of at least one of MEK1/2 proteins or ERK1/2 proteins in retinal or scleral tissues.
The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable additive comprises one or more of an excipient, a stabilizer, a carrier, a diluent, or a solubilizer.
The pharmaceutical composition of claim 5, wherein the MAPK signaling pathway inhibitor comprises one or more of binimetinib and vandetanib.
The pharmaceutical composition of claim 5, wherein the composition is formulated in administration form for delivery to a posterior segment of an eye of the subject via a transcorneal, transscleral, intraocular implant, or systemic administration route.
The pharmaceutical composition of claim 8, wherein the administration form is an immediate-release form.
The pharmaceutical composition of claim 8, wherein the administration form is a controlled-release form.
The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is delivered through an intravitreal injection, a subretinal injection, or a suprachoroidal injection.
The pharmaceutical composition of claim 8, the administration form is an injection form, an eye drop form, an eye ointment form, a hydrogel form, an ultrasonic ocular drug delivery form, a drug-loaded contact lenses form, a drug-eluting implant form, a nanoparticle-mediated delivery, an intravitreal gene therapy form, or an intravitreal microneedle form.
A use of the pharmaceutical composition of claim 5 for reducing axial elongation or choroidal thinning in a subject with myopia.