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WO2025043297A1 - Méthode de traitement de la myopie - Google Patents

Méthode de traitement de la myopie Download PDF

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Publication number
WO2025043297A1
WO2025043297A1 PCT/AU2024/050931 AU2024050931W WO2025043297A1 WO 2025043297 A1 WO2025043297 A1 WO 2025043297A1 AU 2024050931 W AU2024050931 W AU 2024050931W WO 2025043297 A1 WO2025043297 A1 WO 2025043297A1
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myopia
agent
mfa
acid
connexin
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Sally MCFADDEN
William Myles
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the invention relates to methods of treating or preventing myopia by administering an agent that uncouples a retinal cell network, for example a connexin inhibitor such as Mefenamic acid.
  • an agent that uncouples a retinal cell network for example a connexin inhibitor such as Mefenamic acid.
  • Myopia or 'short-sightedness' is a visual impairment where distant objects appear blurred and hence unclear. It is a significant public health problem with 50% of the world population expected to be myopic by 2050 and up to 1 billion people expected to develop high myopia. High myopia (more than -5D) causes low vision and results in ocular pathologies in 70% of patients including detached retina, lacquer cracks and staphyloma which in one-third of patients can lead to profound blindness including from myopic macular degeneration.
  • Myopia arises when light entering the eye come to focus in front of the retina instead of directly on it. This is due to elongation of the eyeball resulting in blurred vision. Myopia commonly develops from childhood, become progressively worse through adolescence so that correction lenses of increasing negative power are needed over time, and can progress to high myopia. Myopia and myopic progression are associated with a higher risk of myopic retinal degeneration, glaucoma, and retinal detachment. Thus there is a need to slow myopia development. There is also a need to stop the eye progressing from myopia to high myopia. Although standard single vision spectacle and contact lenses correct a myopic refractive error, they do not treat the underlying growth response of the eye. Novel multifocal spectacle and contact lens designs and corneal reshaping contact lenses have assisted with slowing myopia development, but none stop progression.
  • Atropine a muscarinic antagonist
  • a 1% eye drop This is known to strongly slow myopia development and while 1% atropine shows excellent efficacy, this concentration is associated with undesirable side effects such as blurred vision and cycloplegia, and when 1% atropine is discontinued rebound occurs.
  • 1% atropine shows excellent efficacy, this concentration is associated with undesirable side effects such as blurred vision and cycloplegia, and when 1% atropine is discontinued rebound occurs.
  • much lower concentrations have been proposed as an alternative.
  • efficacy tends to reduce with lower concentrations.
  • Gap junctions are composed of two hemiconnexons that dock together across adjoining cell membranes. Each hemiconnexon protein consists of six connexins arranged in a hexagonal pattern which spans the cell membrane. Each of the five subfamilies of connexins (a, p, y, 5 and E) mostly only interact with members of their own subfamily. Connexins (Cx) are therefore the constituent gap junction channel proteins and are ubiquitously expressed throughout body tissues with over 20 different types in humans.
  • the inventors demonstrate that coupling between retinal networks is sensitive to the sign of imposed defocus, and that interfering with this coupling can be used to treat or prevent myopia.
  • a method of treating or preventing myopia in a subject comprising administering to the subject a therapeutically effective amount of an agent that uncouples a retinal cell network.
  • the agent may be a gap junction inhibitor, such as a non-specific inhibitor of retinal gap junctions.
  • the gap junction inhibitor may block channels comprised of connexin and/or pannexin proteins.
  • the gap junction inhibitor may be a connexin inhibitor of one or more of 0x36, 0x43, 0x45, 0x50, 0x57, or 0x60, or any combination thereof.
  • the retinal cell network comprises a Horizontal cell and/or an amacrine cell.
  • the Horizontal cell may be an A-Type Horizontal cell
  • the amacrine cell may be a neuronal nitric oxide synthase (nNOS) amacrine cell.
  • the agent is a periodic exposure of an eye to short periods of darkness.
  • the agent is one or more of Mefenamic acid (MFA), flufenamic acid, meclofenamic acid, tolfenamic acid, orthoaminobenzoic acid, palmitoleic acid, Carbenoxolone (CBX), C8H17OH, tonabersat, Cx43 oligonucleotide (5-GTA-ATTGCG- GCA-GGA-GGAATT- GTT-TCT-GTC-3'),or a peptide selected from the group consisting of YPXGAG, a-Connexin carboxyl terminal RQPKIWFPNRRKPWKK - RPRPDDLEI, VDCFLSRPTEKT, YGRKKRRQRRRKQIEIKKFK, and LCLRPVGG -KQIEIKKFK.
  • MFA Mefenamic acid
  • flufenamic acid flufenamic acid
  • meclofenamic acid meclofenamic acid
  • the agent is Mefenamic acid (MFA), for example in a sustained release formulation or depot.
  • MFA Mefenamic acid
  • the treatment may comprise reversing established myopia.
  • the agent may be administered intraocularly or topically.
  • the intraocular administration may comprise intravitreal, retinal, conjunctival, subconjunctival, or scleral injection preferably the agent is administered intravitreal ly.
  • the topical administration may comprise eye drops, eye wash solution, ointment, gel, suspension, emulsion, or via a contact lens.
  • the myopia may be axial myopia, refractive myopia, myopic astigmatism, simple myopia, early- or late-onset myopia, progressive myopia, degenerative myopia or pathological myopia.
  • an agent that uncouples a retinal cell network in the manufacture of a medicament for treating or preventing myopia may be a gap junction inhibitor.
  • the agent may be one or more of Mefenamic acid (MFA), flufenamic acid, meclofenamic acid, tolfenamic acid, orthoaminobenzoic acid, palmitoleic acid, Carbenoxolone (CBX), C8H17OH, tonabersat, Cx43 oligonucleotide (5 -GTA- ATTGCG- GCA-GGA-GGAATT- GTT-TCT-GTC-3'), or a peptide selected from the group consisting of YPXGAG, a-Connexin carboxyl terminal RQPKIWFPNRRKPWKK - RPRPDDLEI, VDCFLSRPTEKT, YGRKKRRQRRRKQIEIKKFK, and LCLRP
  • the agent is Mefenamic acid (MFA), for example in a sustained release formulation or depot.
  • MFA Mefenamic acid
  • the agent is a gap junction inhibitor that blocks channels comprising connexin and/or pannexin proteins.
  • the connexin may be Cx36, Cx43, Cx45, Cx50, Cx57, or Cx60, or any combination thereof.
  • mefenamic acid for use in the treatment or prevention of myopia, preferably wherein the MFA blocks channels comprising connexin and/or pannexin proteins.
  • the connexin may be Cx36, Cx43, Cx45, Cx50, Cx57, or Cx60, or any combination thereof.
  • the MFA may be in a sustained release formulation or depot.
  • myopia encompasses all forms of myopia, including but not limited to, axial myopia, refractive myopia, myopic astigmatism and simple myopia.
  • Myopia may be classified by a number of different criteria, such as cause, degree, age of onset, and clinical appearance.
  • myopia may be induced myopia, such as lens- or instrument-induced myopia, form deprivation myopia, index myopia, simple myopia, early or late-onset myopia, progressive myopia, degenerative myopia, pathological myopia or pseudomyopia.
  • the myopia may be, for example, low, medium or high myopia.
  • the myopia may be, for example, congenital myopia, childhoodonset myopia or adult-onset myopia.
  • a reference to 'an agent that inhibits retinal gap junctions and/or uncouples retinal cell networks' can refer, in one embodiment, to an agent that inhibits retinal gap junctions only and, in another embodiment, to an agent that uncouples retinal cell networks only and in yet another embodiment, to an agent that inhibits retinal gap junctions and uncouples retinal cell networks.
  • an antagonist is used interchangeably with the term “antagonist” and refers to any agent such as a compound or molecule which results in a decrease in the magnitude of a biological activity of a protein.
  • the presence of an antagonist or inhibitor blocks or dampens, i.e., results in complete or partial inhibition, of a biological activity of a protein.
  • an antagonist or inhibitor may be referred to as a modulator.
  • an agent that inhibits retinal gap junctions or retinal hemi-channels may refer to a compound or molecule that inhibits an activity or function of a gap junction protein, for example, an activity or function of one or more connexins, in whole or in part.
  • the term 'gap junction inhibitor' relates to an inhibitor that interferes with connexin or pannexin proteins that constitute a gap junction so as to close, block, inhibit or partially close, block, or inhibit the ability of the hemichannel or the gap junction to pass signals across the cell membrane.
  • Pannexin proteins may include but is not limited to Pannexinl (Panxl), Pannexin2 (Panx2) and Pannexin3 (Panx3).
  • a and “an” are used to refer to one or more than one (i.e., at least one) of the grammatical object of the article.
  • an element means one element, or more than one element.
  • the term "about” means that reference to a figure or value is not to be taken as an absolute figure or value, but includes margins of variation above or below the figure or value in line with what a skilled person would understand according to the art, including within typical margins of error or instrument limitation.
  • use of the term “about” is understood to refer to a range or approximation that a person or skilled in the art would consider to be equivalent to a recited value in the context of achieving the same function or result.
  • treating means: (1) preventing or delaying one or more symptoms of myopia from developing in a subject that may be predisposed to myopia but does not yet experience or display symptoms of myopia, (2) inhibiting myopia, i.e., arresting or reducing the development or progression of myopia or at least one or more symptoms thereof, or (3) relieving myopia, i.e., causing regression or reversing myopia or at least one of its symptoms.
  • the benefit to a subject to be treated is either statistically significant or at least perceptible to the patient and/or to the physician.
  • Effective amount refers to an amount of an agent or compound (e.g., MFA or another retinal gap junction inhibitor) sufficient to produce a desired therapeutic or pharmacological effect in the subject being treated.
  • agent or compound e.g., MFA or another retinal gap junction inhibitor
  • the terms are synonymous and are intended to qualify the amount of each agent that will achieve the goal of improvement in disease severity and/or the frequency of incidence over treatment of each agent by itself while preferably avoiding or minimizing adverse side effects, including side effects typically associated with other therapies.
  • the “effective amount” or “therapeutically effective amount” will vary depending on the agent or compound, the disease severity, and the age, weight, physical condition and responsiveness of the individual to be treated.
  • a "pharmaceutical carrier, diluent or excipient” includes, but is not limited to, any physiological buffered (i.e. , about pH 7.0 to 7.4) medium comprising a suitable water- soluble organic carrier, conventional solvents, dispersion media, gels, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.
  • Subject refers to any animal including mammals (e.g., primates, mice, rabbits, guinea pigs, dogs, cats, sheep, pigs, cattle, horses and human) and is used interchangeably with the term "patient”.
  • mammals e.g., primates, mice, rabbits, guinea pigs, dogs, cats, sheep, pigs, cattle, horses and human
  • administering includes contacting, applying, delivering, or providing an agent or compound of the invention to a subject by any appropriate means.
  • Figure 1 is a comparison of the effect of low and high dose atropine on myopia development in young guinea pigs where atropine was administered as a daily eye drop in one eye concurrently with myopia induction in the same eye using form deprivation (FD) for two weeks. The difference between the untreated and treated eye in their spherical equivalent (SE) refractive error is shown. Open circles show the data for individual animals. Low dose (0.15%) atropine had reduced efficacy in inhibiting myopia compared to high dose (1%) atropine.
  • FD form deprivation
  • FIG. 2 is a schematic drawing showing example intracellular pathways that can close or block Cx36 and Cx45 connexin mediated gap junctions in retinal amacrine cells.
  • Nitric Oxide (NO) can block 0x45 hemichannels via a cGMP-dependent kinase mechanism (protein kinase G (PKG)).
  • Dopamine D1 receptor-driven uncoupling results from protein kinase A (PKA) activation of protein phosphatase 2A (PP2A) and subsequent dephosphorylation of 0x36.
  • PKA protein kinase A
  • P2A protein phosphatase 2A
  • Figure 3 shows the effect of interrupting monocular negative lens wear (-6D) with regular daily exposure periods to different lighting conditions in young guinea pigs, a., b.
  • Experiment 1a During 2 x 1 hr daily periods, a negative lens was either left in place (-6D) or removed and animals were exposed to darkness (Dark), white light (03), cool white (06) or lime light, c., d.
  • Experiment 1b During a single 1 hr daily period, the negative lens was either left in place (-6D) or removed and animals were exposed to white light (White), darkness (Dark), or the -6D lens was substituted with an opaque black diffuser, a., c.
  • Figure 4 shows bidirectional change in Horizontal cell (HC)-HC coupling in the guinea pig superior retina, a., b. Show example sections of stained a-type horizontal cells (aHC) in control guinea pig retina loaded with neurobiotin dye demonstrating greater dye spread (meaning greater cell coupling) in the superior retina (b) compared to the inferior retina (a), c. The images in a. and b. were enlarged from c. which shows the entire guinea pig retina cut-loaded with neurobiotin dye along the superior, temporal and inferior retinal axes and counter labelled with streptavidin (488). d.
  • each bar on the left of each pair of bars is the LE control
  • the right-hand bars of each pair are the RE Lens-wear myopia ( Figures 4f, g and i) or the RE Form deprivation myopia (FD) ( Figure 4h).
  • the solid line in each is the LE control eyes.
  • the dashed line is for the RE lens-wearing eyes and in Figure 4h the dashed line is for the RE form-deprivation eyes.
  • Figure 5 shows differences in coupling between neuronal nitric oxide synthase (nNOS) amacrine cells (mediated by Cx45 and Cx36 connexins) in the guinea pig superior retina, a. difference between the two eyes (RE - LE) in displaced nNOS amacrine cell coupling in form-deprivation myopia compared to animals undergoing -6D lens-induced myopia with intermittent periods of free viewing in lime light or darkness.
  • nNOS neuronal nitric oxide synthase
  • FIG. 6 demonstrates the effects of Mefenamic acid (MFA) in guinea pigs: a. MFA uncouples A-Type Horizontal cells in a dose dependent manner in vitro with MFA dissolved in the bath solution; b. In-vivo intravitreal injection of MFA (concentration in vitreous was 250pm) reduces coupling within 1 hr and the effects persist for at least another 2 hours; c.
  • MFA Mefenamic acid
  • the methods provided herein are based on the finding that strongly coupled specific cell networks characterise a myopic retina and a rapidly growing eye, while uncoupling in these specific networks is indicative of a significant reduction in accelerated eye elongation or growth.
  • the inventors have found that interfering with retinal cell network coupling (mediated by gap junctions) can be used to treat or prevent myopia.
  • Non-limiting examples of connexin inhibitors include Mefenamic acid (MFA) and other fenamates such as flufenamic acid, meclofenamic acid, and tolfenamic acid which are derivatives of orthoaminobenzoic acid, palmitoleic acid, Carbenoxolone (CBX) and other synthetic glycyrrhetinic acid derivatives, long carbon chain n-alkanols such as heptanol and octanols (C8H17OH),Tonabersat (XiflamTM), Cx43 oligonucleotide (Nexagon®) (5 -GTA- ATTGCG- GCA-GGA-GGAATT- GTT-TCT-GTC-3'), Rotigaptide (YPXGAG), a-Connexin carboxyl terminal peptide (ACT1) (RQPKIWFPNRRKPWKK - RPRPDDLEI),
  • Cx Connexins
  • the most common connexin is 0x36, which supports gap junctions between photoreceptors, and specific types of bipolar cells, amacrine cells, and retinal ganglion cells.
  • All amacrine cells integrate scotopic signals from the rod pathway with on-bipolar cells via gap junctions composed of 0x36 connexins in homologous gap junctions but with 0x36/0x45 connexins in heterologous gap junctions (Veruki and Hartveit, 2009, Meclofenamic acid blocks electrical synapses of retinal All amacrine and on-cone bipolar cells. (J Neurophysiol, 101(5), 2339-47).
  • the compounds and pharmaceutical compositions of the invention may be formulated for oral, injectable, parenteral, subcutaneous, intravenous, topical, intravitreal, or intramuscular delivery.
  • Non-limiting examples of particular formulation types include tablets, capsules, caplets, powders, granules, injectables, ampoules, vials, ready-to-use solutions or suspensions, lyophilized materials, creams, lotions, ointments, drops, suppositories and implants.
  • Solid formulations such as the tablets or capsules may contain any number of suitable pharmaceutically acceptable excipients or carriers described above.
  • the compounds of the invention may also be formulated for sustained delivery.
  • Liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example, sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example, sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan
  • ophthalmically acceptable formulations may be lyophilizable.
  • Lyophilizable formulations can be reconstituted into solutions, suspensions, emulsions, or any other suitable form for administration or use. Lyophilizable formulations are typically first prepared as liquids, then frozen and lyophilized. The total liquid volume before lyophilization can be less, equal to, or more than, the final reconstituted volume of the lyophilized formulation.
  • the lyophilization process is well known to those of ordinary skill In the art, and typically Includes sublimation of water from a frozen formulation under controlled conditions. Lyophilized formulations typically can be stored at a wide range of temperatures. For example, lyophilized formulations may be stored below 25°C, for example, refrigerated at 2-8°C, or at room temperature (e.g., approximately 25°C).
  • the composition is administered using an ocular implant, for example, a biodegradable implant such as those made from, for example, polylactic acid (PLA), polyglycolic acid, poly(lactide-co-glycolide) (PLGA), cross-linked gelatin derivatives, hypromellose, polyesters and/or polycaprolactones; or a non-biodegradable implant such as those made from, for example, polyvinyl alcohol, ethylene vinyl acetate, silicon and/or polysulfone capillary fiber.
  • a biodegradable implant such as those made from, for example, polylactic acid (PLA), polyglycolic acid, poly(lactide-co-glycolide) (PLGA), cross-linked gelatin derivatives, hypromellose, polyesters and/or polycaprolactones
  • a non-biodegradable implant such as those made from, for example, polyvinyl alcohol, ethylene vinyl acetate, silicon and/or polysulfone capillary fiber.
  • the composition of the invention is formulated in a sustained release formulation or depot.
  • sustained release formulations or depots include a microsphere; matrix; emulsion; lipid-based; polymer-based; nanomicelle; micelle; nanovesicle such as a liposome, noisome, transfersome, discome, pharmacosome, emulsome or spanlastic, especially a liposome; microparticle; nanoparticle such as a nanocapsule or nanosphere composed of e.g. lipids, proteins, natural or synthetic polymers such as albumin, sodium alginate, chitosan, PLGA, PLA and/or polycaprolactone; or in situ gel such as an in situ hydrogel drug delivery system.
  • the pharmaceutical compositions may contain an active ingredient in the range of about 0.001 mM (1 pM) to about 1 mM (1000pM), from about 0.01 mM to about 0.5 mM, or from about 0.15 mM to about 0.25 mM.
  • MFA may be administered in an amount of about 0.001 mM, 0.01 mM, 0.05 mM, 0.1 mM, 0.15 mM, 0.2 mM, 0.25 mM, 0.3 mM, 0.35 mM, 0.4 mM, 0.45 mM, 0.5 mM, 0.55 mM, 0.6 mM, 0.65 mM, 0.7 mM, 0.75 mM, 0.8 mM, 0.85 mM, 0.9 mM, 0.95 mM or 1 mM, which is preferably administered by intravitreal, conjunctival or scleral injection to the subject in need thereof.
  • the daily dose will typically be administered in one or multiple, e.g., two, three or four, doses per day.
  • the agent that uncouples a retinal cell network for example a connexin inhibitor such as Mefenamic acid may be formulated or administered in combination with one or more other therapeutic agents.
  • the agent may be included in combination treatment regimens with surgery and/or other known treatments or therapeutic agents, and/or adjuvant or prophylactic agents.
  • the agent is a prodrug or a potential prodrug and the like.
  • the agent that uncouples a retinal cell network as described herein may be administered in combination with a growth factor inhibitor.
  • growth factor inhibitors include, but are not limited to, a vascular endothelial growth factor (VEGF) inhibitor, such as ranibizumab, aflibercept, bevacizumab, pegaptanib, conbercept, abicipar pegol (MP0112) and MP0250; a platelet derived growth factor (PDGF) inhibitor, such as E10030 (anti-PDGF PEGylated aptamer), trapidil and pegpleranib; and pharmaceutically acceptable salts and combinations thereof.
  • VEGF vascular endothelial growth factor
  • PDGF platelet derived growth factor
  • the one or more pharmaceutically active agent is a VEGF inhibitor selected from the group consisting of ranibizumab, aflibercept, bevacizumab, pegaptanib, conbercept and pharmaceutically acceptable salts and combinations thereof.
  • the agent that uncouples a retinal cell network as described herein may be administered in combination with agents that increase the levels of neuronal nitric oxide synthase, such as L-arginine.
  • gap junction inhibitor such as MFA injected intravitreally into the eye not only slows myopia development but reverses the direction of eye growth indicating that inhibitors of gap junctions such as MFA can slow, prevent, or reverse myopia.
  • a method of treating or preventing myopia by administering to a subject in need thereof an effective amount of an agent that inhibits retinal gap junctions and/or uncouples retinal cell networks.
  • the agent is a non-specific inhibitor of gap junctions such as MFA.
  • the agent is an inhibitor of one or more connexins. For example, 0x36, 0x43, 0x45, 0x50, 0x57, or 0x60, or any combination thereof.
  • the myopia may be induced myopia, such as lens- or instrument-induced myopia, form deprivation myopia, index myopia, simple myopia, early or late-onset myopia, progressive myopia, degenerative myopia, pathological myopia or pseudomyopia.
  • the myopia may be, for example, low, medium or high myopia.
  • the myopia may be, for example, congenital myopia, childhood-onset myopia or adult-onset myopia.
  • Administration may be, for example, once per day, twice per day or multiple times per day.
  • an agent that inhibits retinal gap junctions and/or uncouples retinal cell networks may be administered by implantation.
  • the agent may be conjugated to, or coated on, the surface of a contact lens or the contact lens may be impregnated with the agent.
  • the agent may be administered by injection directly into a specific tissue or region of the eye, such as into the conjunctiva or sclera.
  • the agent may be administered by, for example, intravitreal, conjunctival or scleral injection, or an intraocular implant or other slow-release delivery method.
  • the agent may be administered topically such as in eye drops, an eye wash solution, an ointment or gel.
  • the agent is administered in an eye drop formulation, via a contact lens, or via injection (e.g., intravitreal injection).
  • the agent of the invention can be formulated for intraocular injection, topical administration to the eye, or oral administration.
  • Agents may be administered in the form of pharmaceutical compositions where the compositions may comprise one or more pharmaceutically acceptable carriers, excipients or diluents.
  • the compositions may be administered as injectable solutions or in a form or vehicle suitable for topical administration (such as eye drops, eye wash, ointment, gel or contact lenses). Examples
  • Tri-coloured domestic guinea pig pups (Cavia porcellus) were reared in opaque boxes with wire lids (590 x 410 x 210mm) illuminated by overhead light emitting diodes diffused through a 3mm thick Perspex screen positioned 200 mm above the lid. Lights operated on a 12-hour light-dark cycle and food and water was provided ad libitum.
  • Guinea pigs were divided into one of four groups.
  • Groups 2-4 were treated the same as in Group 1, but the lens was removed each day for a single 1 hr period to interrupt myopia development.
  • Data corresponding to Experiment 1b is represented in Figure 3c. and d.
  • Guinea pigs were divided into one of four groups.
  • a -6D negative lens (Gelflex, Perth WA, base curve 8.5mm, diameter 14 mm) or white diffuser molded from Perspex was mounted onto a Velcro® backing and attached to matching Velcro® arcs glued above and below the eye as previously described (Howlett and McFadden, 2009, Spectacle lens compensation in the pigmented guinea pig. Vision Research 49, 219-227). After one week, a thin white elasticized hood (made from latex) was worn over the diffuser of form-deprived animals.
  • a custom infrared keratometer was used to measure cornea power as previously described. Refractive error was measured using a Nidek autorefractor (AR-20Nidek; Gamagori, Aichi) following cycloplegia, induced using 1% cyclopentolate hydrochloride eye drops (MinimsTM, Bausche and Lomb) applied to each eye for three mins. On axis ocular biometry was measured using high-frequency (20MHz) A-scan ultrasonography under gaseous isoflurane (5% in 1.5L/min O2 until induction of anesthesia then reduced to 3% in 1.5L/min O2).
  • Euthanasia was performed under far-red LED light following one hour of dark adaptation. Briefly, animals were deeply anaesthetized using gaseous isoflurane (5% in 1.5 L/min O2) and euthanized via intracardial injection of Lethabarb (160mg/kg, Pentobarbitone Sodium).
  • Cut loading was performed as previously detailed (Myles and McFadden, 2022, Analytical methods for assessing retinal cell coupling using cut-loading. PLoS One 17). Briefly, eyes were enucleated in Ames solution (Sigma-Aldrich) at room temperature (21 °C). The cornea and limbus were removed followed by the crystalline lens and vitreous. Eye cups were transferred to a well plate containing 10mL of Ames solution (36°C) bubbled with carbonox (95% 02/5% CO2). The retina was separated from the underlying choroid using a blunt dental spatula and photoreceptor was mounted down onto 0.22pm pore size Millipore membrane filter paper (Merck & Co.).
  • Tissues were acclimatized for 15 mins in darkness in the Ames solution and then briefly removed from solution and cut along the superior and inferior axes with a size 11 scalpel blade dipped in 3% biotin derivative, N-(2-aminoethyl) biotinamide hydrochloride (NeurobiotinTM Tracer, Vector Laboratories) diluted in Ames solution.
  • the tissue was returned to the Ames solution for 25 mins before being removed from the bath solution and fixed in 4% paraformaldehyde (4% wt/v, diluted in 0.1 M phosphate buffer) at room-temperature (for 30 mins).
  • Retinas were washed in 1 x PBS (for 30 mins) and reacted with Alexa-Fluor 488 conjugated streptavidin (ThermoFisher
  • Coupling strength of aHC networks was assessed as described previously (Myles and McFadden, 2022, Analytical methods for assessing retinal cell coupling using cutloading. PLoS One 17). Briefly, the mean fluorescence (C) of each aHC soma and the perpendicular distance (x) to the cut were measured using the oval tool in Fiji. The x- distance was divided by the mean distance from aHC soma-soma to determine distance (n), or the number of cell-separations from the cut. This series was fitted with the following differential equation series: etc.
  • kj is a rate constant describing dye transfer between coupled cells within a network (cells 2 /s)
  • k s is sequestration or loss of dye as it passes through the tissue (cells 2 /s)
  • V is the relative volume of the cell (equal to 1 as all HC are assumed to have equal volume).
  • MFA retinal gap junctions Mefenamic acid

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Abstract

L'invention concerne des méthodes de traitement ou de prévention de la myopie chez un sujet par l'administration au sujet d'une quantité thérapeutiquement efficace d'un agent tel que l'acide méfénamique qui découple un réseau de cellules rétiniennes.
PCT/AU2024/050931 2023-08-31 2024-08-30 Méthode de traitement de la myopie Pending WO2025043297A1 (fr)

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Citations (4)

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EP0709099A2 (fr) * 1994-09-28 1996-05-01 Senju Pharmaceutical Co., Ltd. Suspension aqueuse nasale comprenant cyclodextrine
WO2001095913A1 (fr) * 2000-06-13 2001-12-20 Synphora Ab Procedes et compositions destines a la prevention de la myopie
WO2016029191A2 (fr) * 2014-08-22 2016-02-25 Auckland Uniservices Limited Modulateurs de canaux
EP3750540A1 (fr) * 2015-12-17 2020-12-16 Link Genomics, Inc. Suppresseur de néovascularisation choroïdienne ou suppresseur de formation de drusen

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Publication number Priority date Publication date Assignee Title
EP0709099A2 (fr) * 1994-09-28 1996-05-01 Senju Pharmaceutical Co., Ltd. Suspension aqueuse nasale comprenant cyclodextrine
WO2001095913A1 (fr) * 2000-06-13 2001-12-20 Synphora Ab Procedes et compositions destines a la prevention de la myopie
WO2016029191A2 (fr) * 2014-08-22 2016-02-25 Auckland Uniservices Limited Modulateurs de canaux
EP3750540A1 (fr) * 2015-12-17 2020-12-16 Link Genomics, Inc. Suppresseur de néovascularisation choroïdienne ou suppresseur de formation de drusen

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Title
HARKS ERIK G.A., DE ROOS ALBERT D.G., PETERS PETER H.J., DE HAAN LAURA, BROUWER ABRAHAM, YPEY DIRK, VAN ZOELEN EVERARDUS J.J., THE: "Fenamates: A Novel Class of Reversible Gap Junction Blockers", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, ELSEVIER INC, UNITED STATES, vol. 298, no. 3, United States, pages 1033 - 1041, XP009561852, ISSN: 0022-3565, Retrieved from the Internet <URL:https://jpet.aspetjournals.org/content/298/3/1033> DOI: 10.1016/S0022-3565(24)29472-6 *
JHAWAT VIKAS, GUPTA SUMEET, SAINI VIPIN: "Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid", DRUG DELIVERY, ACADEMIC PRESS, ORLANDO, FL., US, vol. 23, no. 9, 21 November 2016 (2016-11-21), US , pages 3573 - 3581, XP093292990, ISSN: 1071-7544, DOI: 10.1080/10717544.2016.1212439 *
MANJARREZ-MARMOLEJO, J.: "Gap junction blockers: an overview of their effects on induced seizures in animal models", CURRENT NEUROPHARMACOLOGY, vol. 14, no. 7, 2016, pages 759 - 771, XP055634571, DOI: 10.2174/1570159X14666160603115942 *
MICHELLE TEVES; QING SHI; WILLIAM K STELL; DEREK ENG: "The role of cell - cell coupling in myopia development and light adaptation", INVESTIGATIVE OPTHALMOLOGY & VISUAL SCIENCE, ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY, US, vol. 55, no. 13, 1 April 2014 (2014-04-01), US , pages 3036, XP009561820, ISSN: 1552-5783 *
ZHU XIAOYING, MCFADDEN SALLY A.: "Chick Eyes Can Recover from Lens Compensation without Visual Cues", OPTOMETRY AND VISION SCIENCE, vol. 97, no. 8, 1 August 2020 (2020-08-01), pages 606 - 615, XP093292987, ISSN: 1040-5488, DOI: 10.1097/OPX.0000000000001542 *

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