CN116348103A

CN116348103A - Methods and compositions for preventing and treating myopia using Histone Deacetylase (HDAC) inhibitors, trichostatin A and derivatives thereof

Info

Publication number: CN116348103A
Application number: CN202180058290.3A
Authority: CN
Inventors: A·V·特卡琴科; T·V·特卡琴科
Original assignee: Columbia University in the City of New York
Current assignee: Columbia University in the City of New York
Priority date: 2020-06-11
Filing date: 2021-06-09
Publication date: 2023-06-27
Also published as: CA3182426A1; KR20230051153A; WO2021252628A1; EP4164606A1; IL298982A; JP2023530677A

Abstract

The present disclosure relates to methods and compositions for preventing and/or treating ocular disorders. In particular, the present disclosure relates to the prevention and/or treatment of myopia by systemic or topical administration of trichostatin a or a derivative thereof as a Histone Deacetylase (HDAC) inhibitor.

Description

Methods and compositions for preventing and treating myopia using Histone Deacetylase (HDAC) inhibitors, trichostatin A and derivatives thereof

Cross Reference to Related Applications

The present application claims priority from U.S. patent application Ser. No. 63/037,901, filed on even date 11 at 6/2020, which is hereby incorporated by reference in its entirety.

Technical Field

The present disclosure relates to methods and compositions for preventing and/or treating ocular disorders. In particular, the present disclosure relates to the prevention and/or treatment of myopia by systemic or topical administration of trichostatin a and its derivatives as Histone Deacetylase (HDAC) inhibitors.

Background

Myopia (myopic eye) is the most common ocular condition in the world. Over the last 40 years, the prevalence of myopia in the united states has increased from 25% to 48%. ^1,2 In parts of asia, more than 80% of the population is affected by myopia. ³ Global myopia prevalence is expected to increase from 25% in 2020 to 50% in 2050. ⁴ Myopia results in a loss of 2500 billions of dollars in global productivity each year.

Myopia often results in serious pathological complications such as chorioretinal atrophy, retinal cleavage, retinal holes, retinal detachment, and myopic macular degeneration, which often lead to blindness. ^5,6 It is also a major risk factor for many other serious ocular diseases such as cataracts and glaucoma, which also often lead to vision disorders and loss of vision. ^7,8 Myopia is rapidly becoming one of the leading causes of vision loss due to the increasing prevalence, and the world health organization lists myopia as one of five major priority health conditions. ^5,9

The progression of myopia is governed by environmental and genetic factors. ¹⁰ Population studies reveal that the major environmental factors responsible for myopia in humans are near-distance eye use and reading, ^11-13 this is associated with hyperopic defocus created by accommodation hysteresis, i.e., insufficient accommodation response to near objects when the subject performs near eye tasks. ^14,15 The optical blur produced by hyperopic defocus is considered a signal that drives the eye overgrowth and leads to myopia. ^16,17 For example, analysis of the incidence of myopia for regular kosher students (who read most of the day) and for popular kosher students (who read less time) found that the incidence and extent of myopia for regular students was much higher than for popular students, ¹⁸ this reveals that reading is a factor in myopia. In addition, there are several epidemiological studies showing that myopia is more common in urban areas, in professionals, educated patients, computer users, college students, and is associated with improved intelligence. ^19-23 Myopia in individuals who perform more ocular tasks (e.g., microscopy workers) may also increase. ²⁴ The correlation between optical defocus and myopia is supported by a number of animal studies that have found that degeneration of visual input using diffusers or negative lenses can lead to overgrowth of eyes and myopia in a variety of species such as fish, chickens, tree shrews, monkeys, guinea pigs and mice. ²⁵

Although the increase in myopia prevalence over the last decades has been mainly due to the rapid increase in near-distance eyes for young children, ²⁶ it is estimated that genetic factors contribute between 60% and 80% to myopia progression. ²⁷ When both parents suffer from near vision, the incidence of myopia increases. ²⁰ Numerous studies have shown that parental refractive error is the most important predictor of myopia progression. ^28,29 Powerful support for the role of genetic factors in myopia progression is also derived from comparing synova ³⁰ And double egg twins. ^31,32 Myopia is a complex genetic disease, controlled by hundreds of genes; similar to height and weight. ^27,33 Genetic studies have shown that over 900 genes are involved in the development of myopia in humans. ^27,33

Thus, both environmental and genetic factors have been shown to promote the progression of myopia. ¹⁰ Furthermore, a recent study demonstrated the existence of genes that could regulate the effects of myopic environmental factors on refractive eye development. ³⁴ Gene expression profiling studies further support gene-environment interactions in the progression of myopia, which found that progression of myopia was accompanied by large-scale changes in gene expression in the eye, revealed that near-distance ocular activation of molecular signaling pathways in the eye that stimulated overgrowth of the eye, resulting in progression of myopia. ^33,35-37 Several studies have shown that the eye reacts to local changes in optical defocus and local changes in growth rate, thus revealing that there areInformation about optical defocus is summarized across the retinal surface and the integrated signal modulates eye growth. ^38,39 It is important that, even if the optic nerve is cut, the eye is able to react to myopic optical defocus, ³⁹ this suggests that the signaling cascade regulating the progression of the refractive eye is located in the eye itself and does not require feedback from the brain.

Myopia appears to progress fastest during the period of susceptibility between 6-16 years of age, and then begins to slow down. ^40,41 In the first few generations, it was thought that myopia progression ended around 20 years of age. However, the situation has changed as more students enter the study room and then do work that takes 8 hours to continue with computer work. ⁴² This hypothesis was recently studied in a university graduate cohort with an average age of 35 years. ⁴³ As a result, myopia progression was found to occur in the pre-computer queue for approximately 10% of the time. Those subjects who did not spend time before the computer did not progress much.

Currently approved myopia treatment options are limited to optical correction using spectacles or contact lenses. Optical correction using single vision correction lenses is the most widely used treatment option for myopia, which does not prevent myopia progression nor the blinding pathological complications associated with the disease. ^44,45 Several optical-based experimental clinical interventions for slowing myopia progression, such as spectacles with bifocal, multifocal, and cornea-shaping (Ortho-K) contact lenses, have shown promise; however, the efficacy of these treatment options is low. ⁴⁶

The glasses with bifocal lenses are the first glasses to control myopia progression. Multi-center COMET studies aimed at determining if bifocal lenses can slow the progression of myopia compared to single vision lens lenses, and the results indicate that bifocal lenses slow the progression of myopia by 20% in the first year; however, this effect was significantly reduced in years 2-4. ⁴⁷

Two independent meta-analyses analyzed the ability of the cornea shaping lens to slow down myopia progression, ^48、49 and it was found that myopia progression could be reduced by about 45%; however, the method is thatIn contrast, one study found that considerable rebound effects occurred when the cornea shaping lens was deactivated. ⁵⁰

Recently, there has been increasing interest in using soft multifocal contact lenses to replicate the optical properties of cornea shaping lenses. ^51-53 A meta-analysis comprising 587 subjects from 8 studies found that concentric rings and distance-centered multifocal contact lenses slowed near vision progression by 30-38% within 24 months. ⁵⁴

The myopia control pharmacological options currently available are essentially limited to two drugs, atropine and 7-methylxanthine, which have significant side effects and/or relatively low efficacy.

Atropine is a non-selective muscarinic antagonist, an alkaloid produced by belladonna (Atropa belladonna) and has traditionally been used in ophthalmic practice as a mydriatic and ciliary muscle-paralytic drug. Several clinical trials have evaluated the effect of different concentrations of atropine on myopia progression in children and their long-term effect on visual function in children. The first trial, atropine treatment of myopia 1 (ATOM 1), revealed that 1% of atropine eye drops delayed myopia progression by about 76% over a 2 year treatment period. ⁵⁵ However, follow-up studies found that discontinuation of treatment resulted in a strong rebound effect, resulting in a 300% increase in the rate of myopia progression over placebo in the first 12 months after atropine withdrawal, which abrogated about 60% of the 2 year treatment effect. ⁵⁶ In addition, 1% atropine causes uncomfortable side effects such as photophobia, reduced accommodative amplitude and blurred vision. Follow-up test ATOM2 evaluates the effects of 0.5%, 0.1%, and 0.01% atropine on myopia progression in children, and found that 0.5% atropine inhibited myopia progression by 75%, while 0.1% and 0.01% atropine delayed progression by 68% and 59%, respectively. ⁵⁷ Stopping treatment resulted in a 218% increase in rebound rate in the group treated with 0.5% atropine and 170% increase in the group treated with 0.1% atropine over placebo during the first 12 months after stopping administration of the drug. ⁵⁸ However, in the group receiving 0.01% atropine treatment, the rate of progression was reduced by about 30%. ⁵⁸ Recent 5 years follow-up studies confirm these findings, the 5 yearsFollow-up studies indicate that higher initial atropine doses predispose children to greater myopia progression after cessation of treatment and reveal that 0.01% atropine provides optimal long-term results with approximately 30% inhibition. ⁵⁹ A recent trial, a low concentration atropine (LAMP) study for myopia control, further perfected these findings, revealing that low doses of atropine have a dose-dependent inhibition of myopia progression ⁶⁰ . This study found that 0.01% atropine delayed 27% of myopia progression during 1 year, while 0.025% and 0.05% atropine reached 43% and 67%, respectively. However, a recent study found that the use of atropine in young primates had a long-term adverse effect on the development and orthographic visualization of ocular components, which questioned the utility of atropine as an anti-myopia drug. ⁶¹

7-methylxanthine (7-MX) is a non-selective adenosine receptor antagonist, a natural metabolite of caffeine and theobromine, both of which are produced by a variety of plants and are also the major components of cocoa, coffee and tea. 7-MX is probably the first sign of a potential drug for myopia control from the observation that 7-MX causes scleral thickening and an increase in scleral collagen fiber diameter, ⁶² i.e., it causes the sclera to undergo an opposite change from that observed in a myopic eye. A small follow-up clinical trial analyzed the effect of daily oral administration of 400mg (-15 mg/kg) of 7-MX on myopia progression in children and indicated that 7-MX could potentially suppress myopia progression in subjects with slow myopia progression by about 22% without affecting myopia progression in subjects with high progression rates. ⁶³ In guinea pigs, a 300mg/kg dose of 7-MX proved to suppress myopia by 49%. ⁶⁴ Likewise, a dose of 30mg/kg of 7-MX reduced the induced myopia in rabbits by about 67%. ⁶⁵ Recent data from a monkey study also revealed that 7-MX can suppress primate myopia, but the effect is largely dependent on the genetic background of the particular subject. ⁶⁶ Thus, preliminary data indicate that 7-MX has therapeutic potential for myopia control in subjects with slow myopia progression, but effective dose and efficacy problems remain in humansAnd (5) clarifying. The safety profile and long-term impact of daily oral administration of 7-MX by children is currently unknown.

Several other compounds have also been suggested to suppress myopia to varying degrees. The muscarinic receptor antagonists pirenzepine and hizocine have been shown to inhibit the development of experimental myopia in tree shrew, rhesus monkey and chicken. ^67,68 Although pirenzepine was found to suppress progression of myopia in children by 40%, clinical trials were eventually stopped due to serious side effects. ⁶⁹ Several GABA _B And GABA _C Receptor antagonists such as (1, 2,5, 6-tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA), CGP46381 and (3-aminocyclopentyl) butylphosphinic acid (3-acppa) have been shown to suppress myopia progression in chickens and guinea pigs. ^70-72 Further, alpha adrenergic agonists, such as clonidine and guanfacine, have been shown to inhibit experimentally induced myopia in chickens, ⁷³ while brimonidine suppresses chicken ⁷³ And guinea pig myopia. ⁷⁴ In addition, apomorphine is a dopamine receptor agonist that has been found to inhibit myopia progression in several animal models, such as chickens, mice and non-human primates, ^75,76 and the ocular hypotensive drug latanoprost was found to reduce the progression of guinea pig myopia. ⁷⁷ Finally, recent drug screening in a mouse model of myopia identified crocetin as a potential anti-myopia agent, a natural carotenoid found in crocus sativus and gardenia (Gardenia jasminoides) fruits. ⁷⁸

In recent years, the prevalence of myopia has grown exponentially throughout the world, and the proportion of epidemics has been reached in many countries. It is expected that the prevalence of near vision will increase to 50% of the world population by 2050, and the world will soon face public health crisis with vision loss, as 8% low to moderate myopia and 29% high myopia will develop myopic macular degeneration and blindness. ⁷⁹ The currently available optical-based treatment options for myopia are inefficient and can only slow down the progression of myopia but not stop it. The pharmacological options currently available have low efficacy and/or serious side effects. Clearly, there is an urgent need in the medical community to develop one such device for near-end useDepending on the product being controlled, the product can achieve a much greater efficacy than currently available products and can be safely used for children.

Disclosure of Invention

The present disclosure provides a method of preventing and/or treating myopia in a subject in need thereof by using an oral composition, an extended drug release formulation or composition, an extended drug contact delivery lens (extended drug delivery by contact lenses), or an eye drop comprising a drug compound or agent identified using a pharmacogenomic pipeline (pharmacogenomic pipeline) for anti-myopia drug development to inhibit the potential ocular signaling pathway of myopia progression.

Accordingly, one embodiment is a method of preventing and/or treating myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an active pharmaceutical compound identified using a pharmacogenomic pipeline for anti-myopia drug development.

In one embodiment, the active pharmaceutical compound is a Histone Deacetylase (HDAC) inhibitor trichostatin a having the structure:

or a derivative thereof.

In some embodiments, the present disclosure provides methods of preventing and/or treating myopia by administering to a subject during the susceptible period of myopia progression a therapeutically effective amount of trichostatin a or a derivative thereof in the form of an oral composition, an extended drug release formulation or composition, an extended drug contact delivery lens, or eye drops.

In some embodiments, the present disclosure provides methods of preventing and/or treating myopia by administering repeated doses of therapeutically effective amounts of trichostatin a or derivatives thereof in the form of an oral composition, an extended drug release formulation or composition, an extended drug contact delivery lens, or eye drops to a subject during the susceptible period of myopia progression.

In a further embodiment, the active pharmaceutical compound is an HDAC inhibitor.

In some embodiments, HDAC inhibitors include, but are not limited to, vorinostat (vorinostat), belinostat (belinostat), panobinostat (panobinostat), entinostat (entinostat), and mocetiostat (mocetinostat), and derivatives thereof.

Thus, in a further embodiment, the present disclosure provides a method of preventing and/or treating myopia by administering to a subject during the susceptible period of myopia progression a therapeutically effective amount of an HDAC inhibitor in the form of an oral composition, an extended drug release formulation or composition, an extended drug contact delivery lens, or eye drops.

In some embodiments, the present disclosure provides methods of preventing and/or treating myopia by administering repeated doses of a therapeutically effective amount of an HDAC inhibitor in the form of an oral composition, an extended drug release formulation or composition, an extended drug contact delivery lens, or eye drops to a subject during the susceptible period of myopia progression.

In some embodiments, the composition is administered to the subject once daily. In some embodiments, the composition is administered once a week. In some embodiments, the composition is administered twice a week. In some embodiments, the composition is administered three times per week. In some embodiments, the composition is administered to the subject continuously or intermittently for about 5 years to about 10 years.

In some embodiments, the subject is a young adult, i.e., under 30 years of age. In some embodiments, the subject is a child, i.e., under 18 years of age. In some embodiments, the subject is about 4 years old to about 30 years old. In some embodiments, the subject is about 6 to about 20 years old. In some embodiments, the subject is about 8 years old to about 15 years old. In some embodiments, the subject is about 10 years to about 12 years old.

In some embodiments, the subject has myopia. In some embodiments, the subject is at risk of developing myopia. In some embodiments, the subject is susceptible to myopia.

In some embodiments, the subject is monitored for myopia inhibition, and the therapeutically effective amount and/or frequency of administration of the pharmaceutical compound is adjusted according to the extent of inhibition. Inhibition of myopia may be monitored using methods known in the art.

A further embodiment of the present disclosure is a kit comprising compositions and agents for practicing the disclosed methods.

Drawings

For the purpose of illustrating the invention, there is depicted in the drawings certain embodiments of the invention. The invention is not limited to the precise arrangements and instrumentalities of the embodiments depicted in the drawings, however.

Figure 1. Experimentally induced myopia in mice is characterized by human myopia. Figure 1A shows a mouse with-25D lens to induce myopia. Fig. 1B is a graph showing statistically significant myopic refractive shift observed in the eye of a mouse treated with a-25D lens for 21 days. Fig. 1C shows that lens-induced myopia in mice is due to statistically significant increases in vitreous cavity depth, as is human myopia. Fig. 1D shows a power simulation demonstrating the relationship between statistical power and number of animals used to induce myopia experiments. ACD, anterior chamber depth; CRC, corneal radius of curvature; LT, lens thickness; VCD, vitreous cavity depth; OD, right (myopic) eye; OS, left (control) eye. Error bars, sd.p, significance values.

Figure 2 shows that systemic administration of 1mg/kg trichostatin a suppresses myopia progression in mice with experimentally induced myopia by more than 100%.

Detailed Description

Definition of the definition

The following definitions and explanations are intended and intended to be controlling in any construction unless explicitly and clearly modified in the following examples or when the application of meaning renders any construction nonsensical or substantially nonsensical. In cases where the construction of the terms makes it nonsensical or substantially nonsensical, the definition should be taken from the Webster's Dictionary or a Dictionary known to those skilled in the art, such as the oxford biochemical and molecular biological Dictionary (Oxford Dictionary of Biochemistry and Molecular Biology) or similar Dictionary.

The contents of any patent, patent application, and reference cited throughout this patent specification are hereby incorporated by reference in their entirety.

As used herein and unless otherwise indicated, the term "a" means "one", "at least one" or "one or more". As used herein, singular terms shall include the plural and plural terms shall include the singular unless the context requires otherwise.

The term "myopia" or "myopic" refers to an ocular condition in which the posterior segment of the eye is too large for the optical power of the eye and the focal point is located in front of the retina; thus, blurred distance vision is produced.

The term "hyperopia" or "hyperopia" refers to an eye condition in which the posterior segment of the eye is too small for the optical power of the eye and the focal point is located behind the retina; thus, blurred near vision is produced.

The term "negative lens" means a lens that moves the focal point of the eye toward the back of the eye, thus causing the eye to become presbyopic.

The term "genetic network" means an interconnected network of genes that regulate physiological or biological processes.

The term "differential expression" means a change in the level of gene expression induced by environmental factors, genetic background changes, or other internal or external aggressions or effects.

The term "experimentally induced myopia" is used herein to describe myopia induced in animal models by experimental procedures, such as applying negative lenses to the eyes.

The term "whole genome gene expression profiling" refers to a method of analyzing differential gene expression at the whole genome level, thus providing information about the expression of all genes encoded by the genome.

The term "gene-based whole genome association study" refers to a genetic study that analyzes the statistical association between genetic variations in the genome and disease at levels where a particular gene involved in the disease process was previously found by other experimental methods, such as whole genome gene expression profiling.

The term "positive optical defocus" refers to a condition in which the focal point of the eye is in front of the retina.

The term "negative optical defocus" refers to a condition in which the focal point of the eye is located behind the retina.

The term "derivative" refers to a structural analogue of a compound derived from the compound by a chemical reaction. A structural analog is a compound that has a structure similar to that of another compound, but differs from the other compound in some components. It may differ in one or more atoms, functional groups or substructures that are substituted with other atoms, groups or substructures. Structural analogs may also differ from another compound in one or more atoms, functional groups, or substructures that are added to or subtracted from another compound. At least in theory, one skilled in the art can envision the formation of structural analogs from other compounds.

The term "subject" as used in this application means a human subject. In some embodiments of the invention, a "subject" has myopia, is at risk of having myopia, or is susceptible to myopia.

The term "treatment" or the like refers to a means to slow, alleviate, ameliorate or mitigate at least one of the symptoms of a disease or reverse the disease after the onset of the disease.

The term "prevention" or the like refers to taking action prior to the onset of an apparent disease to prevent the progression of the disease or to minimize the extent of the disease or to slow the progression of the disease.

The term "in need thereof" refers to a subject known to have or suspected of having myopia.

The subject in need of treatment will be one who has already had the disease or condition. The subject in need of prevention will be a subject with a risk factor for the disease or condition.

The term "agent" as used herein means a substance that produces or is capable of producing an effect and will include, but is not limited to, chemicals, pharmaceuticals, biological agents, small organic molecules, antibodies, nucleic acids, peptides, and proteins.

The phrase "therapeutically effective amount" is used herein to mean an amount sufficient to result in an improvement in a clinically significant condition in a subject, or to delay or minimize or alleviate one or more symptoms associated with the disease, or to produce a desired beneficial physiological change in a subject.

Identification of anti-myopia drugs using pharmacogenomic tubing

Shown herein are results of using pharmacogenomic tubing developed by the inventors to identify pharmaceutical compounds capable of inhibiting myopia progression. ⁸⁰ Systematic genetic methods are used to identify potential genes, genetic networks, and signaling pathways for refractive eye progression and myopia progression. Systematic genetic approaches include the use of whole genome gene expression profiling to identify genes differentially expressed in the eyes of animals with experimentally induced myopia, and gene-based whole genome association studies to identify genes associated with human myopia. One study by the inventors found that the potential signaling pathways of the eye's response to positive optical defocus (which inhibits myopia) and negative optical defocus (which promotes myopia progression) propagate via two largely distinct signaling cascades, as described in U.S. provisional application No. 62/730,301.

The inventors extend this observation to several vertebrate species and demonstrate that the potential signaling cascade for myopia progression is highly evolutionarily conserved among vertebrate species, including humans. The inventors then used their description in Tkatchenko et al 2019, ⁸¹ the vast myopia-associated gene data sets (which include more than 3,500 genes) and computational tools reconstruct genetic networks that control myopia progression and identify pharmaceutical compounds that can suppress signaling pathways that promote myopia progression and stimulate pathways that inhibit myopia progression.

138 drug compounds with anti-myopia potential were identified altogether. Using gene pathways and z-scores, these drug compounds are assigned to the top 10, top 20, top 40, top 80 and low priority classes based on their predicted myopia-suppressing potential and known or predicted side effects. These drug compounds were then tested on a myopic mouse model (example 1).

Methods and compositions for preventing and/or treating myopia using Histone Deacetylase (HDAC) inhibitors trichostatin a and derivatives thereof

The present disclosure provides, in some aspects, methods of preventing and/or treating myopia comprising administering to a subject in need thereof a therapeutically effective amount of trichostatin a or a derivative thereof.

In certain embodiments, the trichostatin a or derivative is administered systemically. In certain embodiments, the trichostatin a or derivative is administered orally. In certain embodiments, the trichostatin a or derivative is administered topically. In some embodiments, trichostatin a or a derivative is administered directly to the eye or into the eye. In some embodiments, the trichostatin a or derivative is administered via injection. In other embodiments, the trichostatin a or derivative is administered as an extended drug release formulation or composition, an extended drug contact delivery lens, or an eye drop.

In certain embodiments, trichostatin a is directly used as an active ingredient in a medicament. In other embodiments, trichostatin a may be chemically modified to increase its efficacy, reduce side effects, increase penetration through ocular tissues, increase stability, or increase bioavailability.

In certain embodiments, trichostatin a (or a derivative thereof) is the sole component of the medicament. In other embodiments, the methods and compositions described herein involve the use of pharmaceutical formulations comprising trichostatin a (or a derivative thereof).

The term "pharmaceutical formulation" refers to a preparation comprising trichostatin a (or a derivative thereof) and additional ingredients (such as other drugs capable of inhibiting myopia) or excipients (vehicles, additives, preservatives, buffers) that can be reasonably administered to a subject to improve the efficacy of or increase the stability of one or more active ingredients. The formulation is stable if one or more of the active ingredients substantially retains their physical and/or chemical and/or biological properties at room temperature (15-30 ℃) for at least one week, or at 2-8 ℃ for 3 months to 1 year.

Trichostatin a (or a derivative thereof) is considered to retain its physical properties in a pharmaceutical formulation if it meets the specifications for defined degradation and/or aggregation and/or precipitation upon visual inspection of color and/or clarity or as measured by light scattering or other suitable art-recognized methods.

An active ingredient is considered to retain its chemical stability in a pharmaceutical formulation if the trichostatin a (or derivative thereof) content is within about 90% of the amount at which the pharmaceutical formulation is prepared. Some types of chemical degradation include oxidation and hydrolysis, which can be assessed, for example, by LC-MS/MS based methods.

An active ingredient is considered to retain its biostability in a pharmaceutical formulation if, at a given time, trichostatin a (or a derivative thereof) is within about 90% of the bioactivity exhibited when the pharmaceutical formulation is prepared as determined, for example, by in vivo testing.

In the context of the present disclosure, a therapeutically effective dose of trichostatin a (or a derivative thereof) is an amount sufficient to at least partially prevent and/or treat myopia. A therapeutically effective dose is sufficient if it can even produce an incremental change in the symptoms or conditions associated with the disease. The therapeutically effective dose need not completely cure the disease or completely eliminate symptoms. Preferably, a therapeutically effective dose may significantly slow the progression of myopia in a subject suffering from myopia. The dosage and frequency of drug administration effective for this use will depend on factors such as the severity of the disease (i.e., low-progression myopia or high-progression myopia), the type of myopia (i.e., symptomatic myopia or normal myopia), the age of the subject, the weight of the subject, and the route of administration. The dosage and frequency of drug administration can be adjusted using prior art techniques well understood and commonly used in optometry and ophthalmic practice.

The trichostatin a described herein may be co-administered with other agents, including additional agents for preventing and/or treating myopia. Co-administration of the agents may be by any administration described herein. Furthermore, the additional agent may be in the same composition as trichostatin a. The additional agent may be in a different composition than trichostatin a. The administration of more than one composition may be simultaneous, concurrent or sequential.

The present disclosure also provides, in some aspects, a method of preventing and/or treating myopia comprising administering to a subject in need thereof a therapeutically effective amount of an HDAC inhibitor.

In some embodiments, HDAC inhibitors include, but are not limited to, vorinostat, belinostat, panobinostat, entinostat, and mocetinostat (mocetinostat), and derivatives thereof.

In certain embodiments, the HDAC inhibitor is administered systemically. In certain embodiments, the HDAC inhibitor is administered orally. In certain embodiments, the HDAC inhibitor is administered topically. In some embodiments, the HDAC inhibitor is administered directly to the eye or into the eye. In some embodiments, the HDAC inhibitor is administered via injection. In other embodiments, the HDAC inhibitor is administered as an extended drug release formulation or composition, an extended drug contact delivery lens, or eye drops.

In a further embodiment, the HDAC inhibitor is directly used as an active ingredient in a medicament. In other embodiments, the HDAC inhibitor may be chemically modified to increase its efficacy, reduce side effects, increase penetration through ocular tissues, increase stability, or increase bioavailability.

In certain embodiments, the HDAC inhibitor is the sole component of the drug. In other embodiments, the methods and compositions described herein comprise the use of pharmaceutical formulations comprising HDAC inhibitors.

The term "pharmaceutical formulation" refers to a preparation comprising an HDAC inhibitor and additional ingredients (such as other myopia-inhibiting drugs) or excipients (vehicles, additives, preservatives, buffers) that may be reasonably administered to a subject to improve the efficacy of or increase the stability of one or more active ingredients. The formulation is stable if one or more of the active ingredients substantially retains their physical and/or chemical and/or biological properties at room temperature (15-30 ℃) for at least one week, or at 2-8 ℃ for 3 months to 1 year.

An HDAC inhibitor is considered to retain its physical properties in a pharmaceutical formulation if it meets the specifications for prescribed degradation and/or aggregation and/or precipitation upon visual inspection of color and/or clarity or as measured by light scattering or other suitable art-recognized methods.

An active ingredient is considered to retain its chemical stability in a pharmaceutical formulation if the HDAC inhibitor content is within about 90% of the amount at which the pharmaceutical formulation is prepared. Some types of chemical degradation include oxidation and hydrolysis, which can be assessed, for example, by LC-MS/MS based methods.

An active ingredient is considered to retain its biostability in a pharmaceutical formulation if at a given time the HDAC inhibitor is within about 90% of the bioactivity exhibited when the pharmaceutical formulation is prepared as determined, for example, by in vivo testing.

In the context of the present disclosure, a therapeutically effective dose of an HDAC inhibitor is an amount sufficient to at least partially prevent and/or treat myopia. A therapeutically effective dose is sufficient if it can even produce an incremental change in the symptoms or conditions associated with the disease. The therapeutically effective dose need not completely cure the disease or completely eliminate symptoms. Preferably, a therapeutically effective dose may significantly slow the progression of myopia in a subject suffering from myopia. The dosage and frequency of drug administration effective for this use will depend on factors such as the severity of the disease (i.e., low-progression myopia or high-progression myopia), the type of myopia (i.e., symptomatic myopia or normal myopia), the age of the subject, the weight of the subject, and the route of administration. The dosage and frequency of drug administration can be adjusted using prior art techniques well understood and commonly used in optometry and ophthalmic practice.

The HDAC inhibitors described herein may be co-administered with other agents, including additional agents for preventing and/or treating myopia. Co-administration of the agents may be by any administration described herein. Furthermore, the additional agent may be in the same composition as the HDAC inhibitor. The additional agent may be in a different composition than the HDAC inhibitor. The administration of more than one composition may be simultaneous, concurrent or sequential.

The oral compositions of the medicament may be in the form of capsules, tablets, powders, granules, solutions, syrups, suspensions (in non-aqueous or aqueous liquids) or emulsions. The tablet or hard gelatin capsule may comprise lactose, starch or derivatives thereof, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, stearic acid or salts thereof. Soft gelatin capsules may comprise vegetable oils, waxes, fats, semi-solid or liquid polyols. Solutions and syrups may comprise water, polyols and sugars. Active agents intended for oral administration may be coated with or admixed with a substance that delays disintegration and/or absorption of the active agent in the gastrointestinal tract. Thus, sustained release can be achieved over many hours and, if necessary, the active agent can be protected from degradation in the stomach. Pharmaceutical compositions for oral administration may be formulated to facilitate release of the active agent at a particular gastrointestinal location due to particular pH or enzymatic conditions.

It will be appreciated that in addition to the ingredients specifically mentioned above, the composition may also contain other conventional agents of the type considered in the art for the formulation in question, such as those suitable for oral administration may contain flavouring agents.

The extended drug release formulation or composition may be in the form of a nanosponge, patch, gel, or other device capable of gradually releasing the drug over an extended period of time, which is injected into or applied to the anterior or posterior segment of the eye.

The extended drug contact delivery lens may be in the form of a piano contact lens, a single vision correcting contact lens, or a multifocal contact lens, wherein the inner surface of the lens is coated with the drug, or the entire volume of the lens is loaded with the drug.

Eye drops may be in the form of conventional eye drops well known and commonly used by those skilled in the art, or in the form of microdose delivery devices that deliver tightly controlled amounts of drug to the eye.

In some embodiments, the composition is applied more than once.

Treatment using the methods and compositions of the present invention may be continued as desired.

In one embodiment, the efficacy of the treatment on subjects with myopia is assessed every 3-6 months, and the dose and/or frequency of administration of the drug is adjusted according to the extent of myopia suppression. Once the subject does not show any further myopia progression, the treatment is stopped, which can be assessed by temporarily stopping the treatment and measuring the change in refractive error over 1-6 months using prior art techniques well known in optometry and ophthalmic practice.

In some embodiments, the subject is a child, i.e., under 18 years of age. In some embodiments, the subject is a young adult, i.e., under 30 years of age. In some embodiments, the subject is about 4 years old to about 30 years old. In some embodiments, the subject is about 6 to about 20 years old. In some embodiments, the subject is about 8 years old to about 15 years old. In some embodiments, the subject is about 10 years to about 12 years old.

Risk factors for myopia include, but are not limited to, one or more of the parents having myopia.

Medicament box

Also within the scope of the present disclosure are kits for practicing the disclosed methods.

In some embodiments, the kit may include instructions for use in any of the methods described herein. The included instructions may include a description of administration of the agent to the subject to achieve the desired activity in the subject. The kit may also include a description of selecting a subject suitable for treatment based on identifying whether the subject is in need of treatment.

Instructions relating to the use of the medicaments described herein generally include information about the dosage, dosing regimen, and route of administration of the intended treatment. The container may be a unit dose, a bulk package (e.g., a multi-dose package), or a subunit dose. The instructions provided in the kits of the present disclosure are typically written instructions on a label or package insert. The label or package insert indicates that the pharmaceutical composition is for treating a disease or disorder in a subject, delaying the onset of a disease or disorder in a subject, and/or alleviating a disease or disorder in a subject.

The kits provided herein are in suitable packaging. Suitable packages include, but are not limited to, vials, bottles, jars, flexible packages, and the like.

The kit may optionally provide additional components, such as buffers and interpretation information. Typically, a kit includes a container and a label or one or more package inserts on or associated with the container. In some embodiments, the present disclosure provides an article of manufacture comprising the contents of the above-described kit.

Examples

The following examples are included to demonstrate preferred embodiments of the invention. Those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1 myopia induction in mammals Using negative spectacle lenses

Myopia was induced in 24-day-old C57BL/6J (B6) mice by placing a-25 diopter (D) lens in a plastic 3D print frame over the right eye. The contralateral eye served as a control. Mice were kept with lenses for 3 weeks. After 3 weeks, the lenses were removed and the refractive errors of the lens treated eyes and the contralateral control eyes were compared. Lens treatment produced myopia (mean refractive error = -14.6 ± 0.3D) in the lens treated eyes relative to the control eye (mean refractive error = +0.6 ± 0.6D) (fig. 1); the interocular differences in refractive error (-15.2±0.7d) were very pronounced (P < 0.0001). High resolution MRI shows enlargement of the eye and vitreous cavity of the treated eye. The diameter of the lens-treated eyes was 65.+ -.8 μm larger than the average of the control eyes (P <0.0001; FIG. 1C), and the vitreous cavity depth of the lens-treated eyes was 61.+ -.4 μm longer than the control eyes (P <0.0001; FIG. 1D). No significant interocular differences were observed in anterior chamber depth, corneal radius of curvature and lens thickness (fig. 1D), indicating that the induced changes in the mouse eye treated with negative lenses are largely limited to the posterior segment of the eye, similar to human myopia. Statistical power analysis showed that at a sample size of 22 mice, a difference in refractive error between eyes as small as 0.5 diopters could be identified with 90% statistical power.

Example 2. Trichostatin A suppresses myopia in subjects with lens-induced myopia

Trichostatin a was identified as one of the first 10 candidate drugs using the drug genome pipeline for the development of anti-myopia drugs. Systemic oral administration of trichostatin a was found to inhibit myopia by more than 100% (fig. 2).

The experimental group of B6 mice had a-25D lens above the right eye when raised, was raised for 3 weeks on a diet supplemented with 1mg/kg trichostatin a, while the control group of B6 mice had a-25D lens above the right eye, raised on a conventional drug-free diet. After 3 weeks of lens treatment, the interocular difference of refractive errors between the lens treated eyes and the control eyes was 0.48±1.46D for trichostatin a treated animals, whereas in the control group, -10.47±3.02D, p=4.43×10 ^-10 . See fig. 2.

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Claims

1. A method of preventing or treating myopia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising trichostatin a or a derivative thereof.

2. The method of claim 1, wherein the subject is about 4 years to about 30 years old.

3. The method of claim 1, wherein the subject is about 6 to about 20 years old.

4. The method of claim 1, comprising administering the composition to the subject once a day.

5. The method of claim 1, comprising administering the composition to the subject about once, twice, or three times per week.

6. The method of claim 1, comprising continuously or intermittently administering the composition to the subject for about 5 years to about 10 years.

7. The method of claim 1, wherein myopia suppression of the subject is monitored and the therapeutically effective amount or frequency of administration is adjusted according to the extent of suppression.

8. The method of claim 1, wherein the composition is administered orally, via eye drops, via injection, via a patch, or by a contact lens.

9. The method of claim 1, wherein the composition is in an extended release form.

10. The method of claim 8, wherein the contact lens is selected from the group consisting of a plano-optic contact lens, a single vision contact lens, and a multifocal contact lens.

11. The method of claim 8, wherein the composition is loaded onto the inner surface of the lens or the entire volume of the contact lens.

12. The method of claim 1, wherein the composition is in an extended drug release formulation or composition.

13. The method of claim 12, wherein the extended-drug-release formulation or composition is selected from the group consisting of a nanosponge, a patch, and a gel.

14. The method of claim 1, wherein the composition further comprises an excipient or additional agent that inhibits, prevents, or treats myopia.

15. The method of claim 1, wherein the trichostatin a or derivative thereof is modified to increase its efficacy, penetration through ocular tissue, stability and/or bioavailability, and/or to reduce side effects.