Prevention and treatment of conditions using ethyl pyruvate

Abstract

Disclosed is a method of treating or preventing a condition in a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a derivative or analog thereof, or a pharmaceutical composition thereof. Methods of treating or preventing a condition in a subject are described, comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a derivative or analog thereof, or a pharmaceutical composition thereof, and one or more other therapeutic agents.

Description

[0001] Cross-reference to related applications This application claims priority to U.S. Provisional Application No. 63 / 453,419, filed March 20, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] By incorporating via reference Any patents, patent publications, journal publications or other documents cited in this article are expressly incorporated herein in their entirety by reference.

[0003] Statement regarding federally funded research or development This invention was made with government funding granted by USAF / AFOSR under license numbers FA9550-20-1-0233 and FA9550-22-1-0226. The government holds certain rights to this invention.

[0004] field This application generally relates to the prevention and treatment of conditions using ethyl pyruvate and combinations of ethyl pyruvate with one or more other therapeutic agents.

[0005] background Metabolic intermediates such as sodium pyruvate, calcium pyruvate, and nicotinamide have therapeutic potential for certain diseases or conditions. For example, in some preclinical animal models, these compounds have been shown to effectively treat glaucoma by lowering intraocular pressure (“IOP”) through metabolic regulation and / or providing neuroprotection. See, for example, WO 2017 / 070647 A1; Jeffrey M. Harder et al., Disturbed Glucose and Pyruvate Metabolism in Glaucoma with Neuroprotection by Pyruvate or Rapamycin, 117 Proc. Nat'l Acad. Sci. 33619 (2020); Pete A. Williams et al., Vitamin B3 Modulates Mitochondrial Vulnerability and Prevents Glaucoma in Aged Mice, 355 Science 756 (2017).

[0006] However, there are currently no direct neuroprotective therapies approved for glaucoma. Moreover, new therapies would be beneficial in preventing tissue damage associated with ocular fluid drainage and / or reducing IOP. Current treatments are often patient-specific and transient, requiring surgical intervention, which can itself fail over time. There are currently no treatments to prevent developmental malformations with certain functional, cosmetic, and / or psychological implications. Moreover, molecules such as sodium pyruvate suffer from physiological properties and suboptimal efficacy issues. Thus, there is a need for improved therapies and treatment strategies that not only address the aforementioned ocular conditions, but also enable the use of metabolic intermediates for other types of diseases or conditions.

[0007] SUMMARY In one aspect, described is a method of treating or preventing a condition in a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate, or a derivative or analog thereof, or a pharmaceutical composition thereof; wherein the condition is selected from the group consisting of an ocular disease or disorder, a neurodegenerative disease or disorder, a vascular disease or disorder, a metabolic disease or disorder, an inflammatory disease or disorder, a disease or disorder involving abnormal cell death or oxidation, a disease or disorder associated with one or more Lmxlb mutations, and combinations thereof.

[0008] In another aspect, described is a method of reducing or preventing an increase in intraocular pressure, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate, or a derivative or analog thereof, or a pharmaceutical composition thereof.

[0009] In another aspect, described is a method of reducing or preventing damage or dysfunction of ocular tissue in a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate, or a derivative or analog thereof, or a pharmaceutical composition thereof. In certain instances, the subject is a pregnant female and the ethyl pyruvate is administered during prenatal care to prevent the fetus from developing a dysfunction / disorder. Treatment of the child can continue after birth by direct administration to the child or through the mother via breast milk or a combination thereof.

[0010] In another aspect, described is a method of reducing or preventing damage or dysfunction of ocular tissue associated with ocular fluid drainage in a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate, or a derivative or analog thereof, or a pharmaceutical composition thereof.

[0011] In another aspect, described is a method of reducing or preventing a developmental malformation, a disease-related malformation, or a dysfunction of the eye in a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate, or a derivative or analog thereof, or a pharmaceutical composition thereof.

[0012] In any of the embodiments described herein, the method further comprises administering to the subject one or more additional therapeutic agents, or one or more pharmaceutical compositions thereof.

[0013] In any of the embodiments described herein, the one or more additional therapeutic agents are selected from the group consisting of: an antioxidant, an anti-inflammatory agent, an agent that modulates metabolism, an agent that modulates the integrated stress response, an agent that modulates the unfolded protein response, an agent that modulates autophagic forms, an agent that modulates expression or activity of genes that control or mediate antioxidant or other protective responses, an anti-cell death agent, an anti-aging agent, an agent that modulates mitochondria or mitochondrial autophagy, an anti-aging agent, an agent that modulates intraocular pressure, a resilience-enhancing agent, an anti-fibrotic agent, an agent that prevents epithelial or endothelial mesenchymal transition, a neuroprotective agent, a gene therapy agent, and combinations thereof.

[0014] Any of the embodiments disclosed herein can be suitably combined with any other embodiment disclosed herein. Combinations of any of the embodiments disclosed herein with any other embodiment disclosed herein are expressly contemplated. In particular, the selection of one or more embodiments of a substituent can be suitably combined with the selection of one or more particular embodiments of any other substituent. Such combinations can be made in any one or more of the embodiments of the application described herein, or in any of the formulae described herein. BRIEF DESCRIPTION OF DRAWINGS

[0015] The present application is illustrated by reference to the following figures, which are for illustrative purposes only and are not intended to be limiting. In the drawings: Figure 1 It is shown that, according to one or more embodiments, ethyl pyruvate prevents high IOP.

[0016] Figure 2 It is shown that, according to one or more embodiments, ethyl pyruvate, alone or in combination with nicotinamide, reduces IOP elevation.

[0017] Figure 3 It is shown that, according to one or more embodiments, ethyl pyruvate, in combination with other therapeutic agents, provides enhanced protection from disease.

[0018] Figure 4 It is shown that, according to one or more embodiments, ethyl pyruvate rescues ocular dysplasia.

[0019] Figure 5 It is shown that, according to one or more embodiments, ethyl pyruvate prevents anterior chamber depth increase and reduces anterior chamber deepening.

[0020] Figure 6 It is shown that, according to one or more embodiments, ethyl pyruvate, in combination with other therapeutic agents, provides enhanced protection from disease.

[0021] Figure 7 It is shown that sodium pyruvate does not affect IOP elevation or dysplasia.

[0022] Figure 8 It is shown that according to one or more embodiments, ethyl pyruvate alone, nicotinamide alone, and ethyl pyruvate in combination with nicotinamide prevent glaucomatous optic nerve damage.

[0023] FIGS. 9A and 9C are 3D fluorescent images of the trabecular meshwork and Schlemm’s canal tissue volume, respectively. FIGS. 9B and 9D are box plots of the corresponding data showing that according to one or more embodiments, the combination of ethyl pyruvate and nicotinamide rescues developmental abnormalities in ocular drainage tissues.

[0024] Figure 10 It is shown that treatment with ethyl pyruvate (2000 mg / kg / day) and nicotinamide (NAM, 550 mg / kg / day) greatly prevents cell death in mice carrying a model of early-onset Lmxlb developmental glaucoma.

[0025] DETAILED DESCRIPTION The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The use of the term “at least one” can mean “one” but it is also consistent with the meaning of “one or more.”

[0026] As used herein, the term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the upper and lower limits a full range higher and lower, respectively. In general, the term “about” is used herein to modify a value by up to 20% higher and 20% lower than the stated value.

[0027] “Effective amount,” “sufficient amount,” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect a beneficial or desired result, including clinical results. Thus, an effective amount can be sufficient, for example, to reduce or alleviate the severity and / or duration of a painful or debilitating condition or one or more symptoms thereof, prevent the development of a condition associated with a painful or debilitating condition, prevent the recurrence, development, or onset of one or more symptoms associated with a painful or debilitating condition, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another treatment. An effective amount also includes an amount of a compound that avoids or significantly reduces adverse side effects.

[0028] According to one aspect, the present application relates to a method of treating or preventing a condition in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of ethyl pyruvate, or a derivative or analog thereof, or a pharmaceutical composition thereof. According to some aspects, the condition is selected from the group consisting of an ocular disease or disorder, a neurodegenerative disease or disorder, a vascular disease or disorder, a metabolic disease or disorder, an inflammatory disease or disorder, a disease or disorder involving abnormal cell death or oxidation, a disease or disorder associated with one or more Lmxlb mutations, and combinations thereof.

[0029] As used herein, the term "glaucoma" refers to an eye disease that results in damage to the retina and optic nerve and visual dysfunction or decreased vision. Glaucoma occurs more often in older adults. The vision loss caused by glaucoma is permanent and cannot be reversed. Glaucoma is usually associated with elevated intraocular pressure, but glaucoma also includes normal tension glaucoma (NTG), which is a form of primary open angle glaucoma (POAG). Glaucoma can also be a result of traumatic nerve damage.

[0030] As used herein, the term "normal intraocular pressure" (normal IOP) in a human refers to an IOP value of 10 mmHg to 21 mmHg in a human subject. However, certain individuals can develop optic nerve damage even with normal IOP, which is referred to as normal tension glaucoma.

[0031] As used herein, the term "high intraocular pressure" (high IOP) in a human refers to an IOP value greater than 21 mmHg (or 2.8 kPa) in a human subject. High IOP is known to be a risk factor for glaucoma. However, certain individuals can have high IOP for many years and never develop glaucoma or optic nerve damage.

[0032] As used herein, the term "preventing" or "prevention" in relation to, for example, general neuronal damage or neuronal death or specifically intraocular pressure refers to the ability of the compounds or agents of the present application to provide neuroprotection, preferably prior to the occurrence of such damage, death or disease, or to prevent the occurrence of high intraocular pressure in a subject. Thus, prevention of high intraocular pressure includes avoiding the development of high intraocular pressure, reducing the risk or likelihood of high intraocular pressure eventually occurring, delaying the onset or progression of high intraocular pressure, or if high intraocular pressure does eventually occur, reducing the severity of neuronal damage / neuronal death / loss of range.

[0033] As used herein and as is well understood in the art, “treatment” refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.

[0034] In some embodiments, the condition is an ocular disease or disorder. In some embodiments, the ocular disease or disorder comprises elevated intraocular pressure, one or more changes in structure or function of one or more ocular tissues, abnormal cell death, or a combination thereof. In some embodiments, the one or more changes in structure or function of one or more ocular tissues comprises malformation or dysfunction of ocular drainage structures, one or more developmental abnormalities, neural or non-neural cell degeneration, dysfunction, or death, or a combination thereof. In some embodiments, the one or more changes in structure or function of one or more ocular tissues results from environmental exposure, disease, aging, metabolic abnormality, mitochondrial abnormality, genetic variation or epigenetic difference, or a combination thereof. In some embodiments, the one or more developmental abnormalities comprises a change in anterior chamber depth, pupil abnormality, iridocorneal adhesion, trabecular meshwork, Schlemm’s canal, cornea, or a combination thereof. In some embodiments, the neural or non-neural cell degeneration or dysfunction comprises neural degeneration and / or neural dysfunction of retinal ganglion cells in the subject. In some embodiments, the malformation or dysfunction of ocular drainage tissues comprises Schlemm’s canal, trabecular meshwork, or a combination thereof.

[0035] In some embodiments, the ocular disease or disorder is a neurodegenerative disease or disorder. In some embodiments, the ocular disease or disorder is glaucoma.

[0036] In some embodiments, the condition is a neurodegenerative disease that does not directly affect the ocular system. In some embodiments, the condition comprises late-onset neurodegeneration. In some embodiments, the condition is Alzheimer’s disease or Parkinson’s disease.

[0037] In some embodiments, the disease or disorder associated with one or more Lmx1b mutations is a disease or disorder of the brain or kidney. In some embodiments, one or more Lmx1b variants cause cellular stress, developmental abnormalities, cell death, and / or IOP elevation, which in turn can lead to other diseases or conditions. In some embodiments, Lmx1b mutations lead to developmental defects, organ diseases (e.g., kidney disease), ocular diseases (e.g., glaucoma), and / or neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease). In some embodiments, Lmx1b-associated diseases or conditions manifest at different ages.

[0038] In some embodiments, the condition is age-related macular degeneration. In some embodiments, the condition is traumatic glaucoma.

[0039] In some embodiments, the condition includes retinal pigment epithelium.

[0040] In some embodiments, the method further comprises administering to the subject one or more additional therapeutic agents, or one or more pharmaceutical compositions thereof. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: an antioxidant, an anti-inflammatory agent, an agent that modulates metabolism, an agent that modulates the integrated stress response, an agent that modulates the unfolded protein response, an agent that modulates multiple forms of autophagy, an agent that modulates expression or activity of genes that control or mediate antioxidant or other protective responses, an anti-aging agent, an agent that modulates mitochondria or mitochondrial autophagy, an anti-aging agent, an agent that modulates intraocular pressure, a resilience-enhancing agent, an anti-fibrotic agent, an agent that prevents epithelial- or endothelial-mesenchymal transition, a neuroprotective agent, a gene therapy agent, and combinations thereof. In some embodiments, the agent modulates metabolic reprogramming or promotes metabolism. In some embodiments, the antioxidant reduces oxidative stress and enhances antioxidant control. In some embodiments, the gene therapy agent results in genome editing, genome reprogramming, epigenetic editing, epigenetic reprogramming, or combinations thereof. In some embodiments, the agent that prevents epithelial- or endothelial-mesenchymal transition is an anti-transforming growth factor beta (“TGFB”) or a ligand-trapping molecule. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: nicotinamide (NAM), nicotinamide mononucleotide, nicotinamide adenine dinucleotide, nicotinamide riboside, pyrroloquinoline quinone, N - acetylcysteine, and combinations thereof.

[0041] Examples of other agents that can be used in combination with ethyl pyruvate include, but are not limited to, saffron, berry extracts or powders, antioxidants (e.g., bilberry), flavonoids, anthocyanins, carotenoids, polyphenols, folate, xanthine, polyamines (e.g., spermidine), ginkgo (Glaucocetin), coenzyme Q10, vitamin A, vitamin B12, vitamin B50 complex, vitamin C, vitamin D, vitamin E, betaine, choline, citicoline, epigallocatechin-3-gallate (EGCG and derivatives or analogs thereof), compounds that increase the activity of Sirts, including Sirt3, lutein, xeozanthine, molecules that induce genes that protect against oxidative damage, dimethyl fumarate and other forms of fumarate, and anti-fibrotic agents (such as anti-TGFB, curcumin, blueberries, silymarin, coffee, vitamin C, vitamin E, and vitamin D, resveratrol, quercetin, and epigallocatechin-3-gallate). According to some embodiments, the other agent can be a molecule that supports metabolism, such as, but not limited to: ketones, ketone bodies - metabolites used in energy metabolism (e.g., hydroxybutyric acid, beta-hydroxybutyric acid (BHB) and salts thereof, such as acetoacetate). The methods disclosed herein can also be combined with diets that have been shown to be helpful in treating glaucoma, such as, but not limited to, ketogenic diets and low-carbohydrate diets. The methods disclosed herein can also be combined with glucagon-like peptide (GLP-1) agonists, including, but not limited to, exenatide, liraglutide, and semaglutide. Taurine and creatine can also be used in combination with the methods disclosed herein. Other examples useful herein also include molecules and gene therapies that increase or induce NMNAT2 (nicotinamide mononucleotide adenosine transferase) or other NMNAT, molecules or gene therapies that induce or otherwise increase TEK / angiopoietin system signaling, any molecule that increases NAD or insulin and its derivatives, molecules that increase Ca 2+agents, anti-inflammatory molecules, and metabolites. This also includes similar systems for ANPT / TEK, insulin, etc. Other examples that can be combined with EP therapy include any drug that lowers IOP, such as latanoprost and other prostaglandin analogs. The methods disclosed herein can also be combined with lasers and / or other glaucoma surgeries aimed at lowering IOP, various implant tubes, shunts, and stents, or long-term drug formulation and delivery devices that lower IOP. Biotin, hemp seed / powder, long-chain polyunsaturated fatty acids (PUFAS) (e.g., omega 3 fatty acids), spirulina, and green leaf powder or extract can also be combined with the ethyl pyruvate therapy disclosed herein. Derivatives and analogs of the compounds disclosed herein can also be used.

[0042] In some embodiments, one or more other therapeutic agents are administered together in a pharmaceutical composition with ethyl pyruvate. In other embodiments, one or more other therapeutic agents are administered separately from ethyl pyruvate. In yet other embodiments, the subject is already being treated with one or more other therapeutic agents when ethyl pyruvate is administered; or one or more other therapeutic agents are administered to the subject after ethyl pyruvate is administered.

[0043] In some embodiments, the ethyl pyruvate is administered in an amount sufficient to treat or prevent a condition in the subject. In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce an increase in intraocular pressure, prevent or reduce one or more changes in structure or function of one or more ocular tissues, prevent or reduce abnormal cell death, or a combination thereof. In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce malformation or dysfunction of ocular drainage structures, prevent or reduce one or more developmental abnormalities, prevent or reduce neurologic or non-neurologic cell degeneration, dysfunction, or death, or a combination thereof. In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce one or more changes in the subject resulting from environmental exposure, disease, aging, metabolic abnormality, mitochondrial abnormality, genetic mutation, or a combination thereof. In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce one or more developmental abnormalities in the subject (e.g., but not limited to, changes in anterior chamber depth, pupil abnormalities, iridocorneal adhesions, trabecular meshwork, Schlemm’s canal, cornea, or a combination thereof). In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce cell degeneration or dysfunction in the subject (e.g., but not limited to, neurologic degeneration and / or neurologic dysfunction in retinal ganglion cells of the subject). In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce changes or dysfunction of ocular drainage structures (e.g., but not limited to, Schlemm’s canal, trabecular meshwork, or a combination thereof) in the subject. In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce a neurodegenerative disease or condition in the subject, e.g., but not limited to, glaucoma or late-onset neurodegeneration (e.g., Alzheimer’s disease or Parkinson’s disease). In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce a disease or condition associated with one or more Lmxlb mutations (e.g., but not limited to, a disease or condition of the eye, brain, or kidney). In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce an aging condition in the subject (e.g., but not limited to, age-related macular degeneration). In some embodiments, the ethyl pyruvate is administered in an amount sufficient to prevent or reduce retinal pigment epithelium in the subject.

[0044] In some embodiments, the amount of ethyl pyruvate sufficient to produce the effects described in the preceding paragraph will be the same when administered alone or in combination with one or more other therapeutic agents. In some embodiments, the amount of ethyl pyruvate sufficient to produce the effects described in the preceding paragraph will be less when administered with one or more other therapeutic agents than when administered alone.

[0045] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse or rat. In some embodiments, the subject is a canine or equine. In some embodiments, the subject is a non-human primate. In some embodiments, the subject is a human.

[0046] In some embodiments, the subject has the condition. In other embodiments, the subject is at risk of developing the condition, including but not limited to a genetic risk. In other embodiments, the subject has the condition and is at risk of developing a more severe variant or complication of the condition, including but not limited to a genetic risk. In some embodiments, the subject has the condition and is at risk of developing other conditions, including but not limited to a genetic risk, which can or can not be related to the original condition.

[0047] In another aspect, a method of reducing or preventing an increase in intraocular pressure is described, the method comprising administering to a subject a therapeutically effective amount of ethyl pyruvate or a pharmaceutical composition thereof.

[0048] In another aspect, a method of reducing or preventing damage or dysfunction of an ocular tissue in a subject is described, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a pharmaceutical composition thereof.

[0049] In another aspect, a method of reducing or preventing damage or dysfunction of an ocular fluid drainage-related tissue in a subject is described, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a pharmaceutical composition thereof.

[0050] In another aspect, a method of reducing or preventing a developmental malformation or dysfunction of an eye in a subject is described, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a pharmaceutical composition thereof.

[0051] In any of the embodiments described herein, the method further comprises administering to the subject one or more additional therapeutic agents, or one or more pharmaceutical compositions thereof.

[0052] In some embodiments, ethyl pyruvate is administered in an amount sufficient to reduce or prevent an increase in intraocular pressure in the subject. In some embodiments, the subject has an increase in intraocular pressure, and administration of ethyl pyruvate reduces the intraocular pressure or prevents the intraocular pressure from increasing further. In some embodiments, the subject does not have an increase in intraocular pressure, and administration of ethyl pyruvate prevents the intraocular pressure from increasing in the subject.

[0053] In some embodiments, ethyl pyruvate is administered in an amount sufficient to prevent or reduce neurodegeneration and / or neuropathy in neural and non-neural cells of the subject. In some embodiments, the subject has neurodegeneration and / or neuropathy, and administration of ethyl pyruvate reduces the neurodegeneration and / or neuropathy or prevents further neurodegeneration and / or neuropathy. In other embodiments, the subject does not have neurodegeneration and / or neuropathy, and administration of ethyl pyruvate prevents the development of neurodegeneration and / or neuropathy. In some embodiments, the effect of ethyl pyruvate in preventing or reducing neurodegeneration and / or neuropathy is related to its activity in modulating intraocular pressure. In other embodiments, the effect of ethyl pyruvate in preventing or reducing neurodegeneration and / or neuropathy is not related to its activity in modulating intraocular pressure.

[0054] In some embodiments, ethyl pyruvate is administered in an amount sufficient to prevent or reduce changes in ocular drainage tissues of the subject. In some embodiments, the subject has changes in ocular drainage tissues, and administration of ethyl pyruvate reduces the changes or prevents further changes. In other embodiments, the subject does not have the changes, and administration of ethyl pyruvate prevents the development of the changes. In some embodiments, the effect of ethyl pyruvate in preventing or reducing changes in ocular drainage tissues of the subject is related to its activity in modulating intraocular pressure. In other embodiments, the effect of ethyl pyruvate in preventing or reducing changes in ocular drainage tissues of the subject is not related to its activity in modulating intraocular pressure.

[0055] In some embodiments, ethyl pyruvate is administered in an amount sufficient to prevent or reduce one or more functional and / or developmental changes in the eye of the subject. In some embodiments, the one or more functional and / or developmental changes are functional and / or malformations of ocular drainage tissues of the subject, including but not limited to Schlemm’s canal and the trabecular meshwork. In some embodiments, the one or more functional and / or developmental changes are anterior chamber depth, pupillary abnormalities, trabecular meshwork, Schlemm’s canal, and / or iris-corneal adhesion. In some embodiments, the subject has the functional and / or developmental changes, and administration of ethyl pyruvate reduces the developmental changes or prevents further developmental changes. In other embodiments, the subject does not have the functional and / or developmental changes, and administration of ethyl pyruvate prevents the development of the developmental changes. In some embodiments, the effect of ethyl pyruvate in preventing or reducing one or more functional and / or developmental changes in the eye of the subject is related to its activity in modulating intraocular pressure. In other embodiments, the effect of ethyl pyruvate in preventing or reducing one or more functional and / or developmental changes in the eye of the subject is not related to its activity in modulating intraocular pressure.

[0056] In some embodiments, the disease or disorder of the eye is a neurodegenerative disease. In some embodiments, the disease or disorder of the eye is glaucoma.

[0057] In some embodiments, the disease or disorder of the eye is a non-neurodegenerative disease.

[0058] In some embodiments, the disease or disorder of the eye is a senescence disease or disorder. In some embodiments, the disease or disorder of the eye is age-related macular degeneration. In some embodiments, the age-related macular degeneration includes neurodegeneration. In some embodiments, the age-related macular degeneration includes retinal pigment epithelium (“RPE”). In some embodiments, the age-related macular degeneration includes a vascular disease or condition.

[0059] In some embodiments, preventing or reducing an increase in intraocular pressure in the subject prevents or treats a disease or disorder of the eye. In some embodiments, the disease or disorder of the eye includes non-neurological cell degeneration, dysfunction, and / or death. In some embodiments, the disease or disorder of the eye includes neurological cell degeneration, dysfunction, and / or death. In some embodiments, the disease or disorder of the eye is a neurodegenerative disease. In some embodiments, the disease or disorder of the eye is glaucoma. In some embodiments, the disease or disorder of the eye is a non-neurodegenerative disease. In some embodiments, the disease or disorder of the eye is a senescence disease or disorder. In some embodiments, the disease or disorder of the eye is age-related macular degeneration. In some embodiments, the disease or disorder of the eye is glaucoma or age-related macular degeneration.

[0060] In some embodiments, preventing or reducing an increase in intraocular pressure in the subject prevents or treats neurodegeneration and / or neurological dysfunction of retinal ganglion cells in the subject, changes in the drainage tissue of the eye of the subject, and / or developmental changes in the eye of the subject.

[0061] The chemical structure of ethyl pyruvate is as follows The present disclosure also contemplates derivatives or analogs of ethyl pyruvate. Derivatives or analogs of ethyl pyruvate can include, but are not limited to, different ester chain lengths or substitutions, different substitutions on the acyl carbon, halogenated and isotopically derived analogs, and isomers, and combinations thereof; and pharmaceutically acceptable salts thereof. Derivatives or analogs of ethyl pyruvate can also include, but are not limited to, conjugates with imaging agents, macromolecules, biological macromolecules, targeting agents, and isomers and combinations thereof; and pharmaceutically acceptable salts thereof. The use of ethyl pyruvate or derivatives and analogs thereof in a pharmaceutical composition with one or more pharmaceutically acceptable excipients and / or one or more drug delivery or targeting vehicles is also contemplated.

[0062] According to some embodiments, the derivative or analog of ethyl pyruvate is selected from the group consisting of methyl pyruvate, propyl pyruvate, butyl pyruvate, pentyl pyruvate, hexyl pyruvate, octyl pyruvate, isobutyl pyruvate, isoamyl pyruvate, isoheptyl pyruvate, isooctyl pyruvate, cyclopentyl pyruvate, cyclopentylmethyl pyruvate, cyclohexyl pyruvate, cyclohexylmethyl pyruvate, butenyl pyruvate, hexenyl pyruvate, isobutenyl pyruvate, isoheptenyl pyruvate, butynyl pyruvate, hexynyl pyruvate, methoxymethyl pyruvate, ethoxymethyl pyruvate, ethoxycarbonylmethyl pyruvate, and combinations thereof.

[0063] In some embodiments, the elevated IOP is a risk factor for a disease or disorder. In some embodiments, the elevated IOP is a risk factor for a disease or disorder of the eye. In some embodiments, the elevated IOP is a risk factor for a non-neurodegenerative or neurodegenerative disease or disorder of the eye. In some embodiments, the elevated IOP is a risk factor for glaucoma. In some embodiments, the elevated IOP is a risk factor for dysfunction, malformation, and / or death of one or more cells, tissues, or structures in the eye.

[0064] In some embodiments, ethyl pyruvate protects ocular tissues from stress due to environmental, developmental, disease, and / or age (including but not limited to mitochondrial and metabolic abnormalities, mutations in Lmxlb, or mutations in other genes affecting metabolism, development, and / or glaucoma).

[0065] In some embodiments, ethyl pyruvate protects ocular drainage structures from changes and cell death due to developmental conditions, genetic and epigenetic effects, and / or environmental and / or exposure effects. In some embodiments, ethyl pyruvate protects ocular drainage structures from malformation. In some embodiments, ethyl pyruvate prevents developmental abnormalities in the eye. In some embodiments, ethyl pyruvate prevents developmental malformations that can have functional, cosmetic, and / or psychological effects on the subject.

[0066] In some embodiments, ethyl pyruvate prevents cell death and / or elevated IOP in ocular tissues. In some embodiments, such cell death and elevated IOP are not associated with glaucomatous neurodegeneration, while in other embodiments, it is associated with glaucomatous neurodegeneration. Thus, in certain embodiments, ethyl pyruvate prevents glaucoma and other ocular neurodegeneration.

[0067] In some embodiments, ethyl pyruvate protects cells from dysfunction and death. In some embodiments, these cells can be neural cells and / or neurons.

[0068] In some embodiments, ethyl pyruvate prevents brain diseases or disorders, including but not limited to late-onset neurodegeneration (e.g., Parkinson’s disease and Alzheimer’s disease).

[0069] In some embodiments, ethyl pyruvate prevents diseases or disorders associated with aging.

[0070] In some embodiments, ethyl pyruvate, alone or in combination with other therapeutic agents (e.g., nicotinamide), is an effective treatment for early-onset glaucoma with developmental abnormalities. In some embodiments, ethyl pyruvate, alone or in combination with other therapeutic agents (e.g., nicotinamide), is an effective treatment for late-onset glaucoma.

[0071] In some embodiments, the inventors surprisingly found that ethyl pyruvate protects mice with Lmx1b mutations. In some embodiments, Lmx1b mutations result in developmental defects, kidney disease, and / or glaucoma, with different ages of onset in mice and humans. Thus, in some embodiments, ethyl pyruvate treatment can prevent various Lmx1b-induced diseases.

[0072] In some embodiments, the inventors surprisingly found that ethyl pyruvate reduces IOP elevation in mouse models, including genetic models that result in cellular stress, developmental abnormalities, cell death, and / or high IOP. In some embodiments, one or more of these factors can result in glaucoma. In some embodiments, the mouse model is a Lmx1b mouse model. This is unexpected, at least because sodium pyruvate had no effect on IOP in age-onset mouse glaucoma models or early-onset Lmx1b developmental glaucoma models. For example, treatment of Lmx1b mice with about 500 mg / kg / day of sodium pyruvate had no effect on IOP at 2 months, 3 months, and 4 months post-treatment. This is unexpected, at least because in prior clinical studies, calcium pyruvate had no effect on IOP in humans.

[0073] In some embodiments, the inventors surprisingly found that ethyl pyruvate reduces the presence and severity of anterior eye structure developmental abnormalities in glaucoma mouse models. This is unexpected, at least because sodium pyruvate treatment showed no change in the severity of anterior eye developmental abnormalities. For example, treatment of Lmx1b mice with about 500 mg / kg / day of sodium pyruvate had no effect on the severity of anterior eye developmental abnormalities at 2 months, 3 months, and 4 months post-treatment.

[0074] In some embodiments, a dose of about 2000 mg / kg / day of ethyl pyruvate reduces the severity of ocular dysplasia and IOP elevation in mice. In some embodiments, ethyl pyruvate in combination with another agent capable of modulating metabolism (e.g., a metabolic enhancer) provides a higher degree of protection against ocular dysplasia severity and IOP elevation in mice compared to ethyl pyruvate alone. For example, in some embodiments, ethyl pyruvate in combination with a metabolic enhancer provides greater protection against developmental pupillary abnormalities.

[0075] In some embodiments, the inventors surprisingly found that ethyl pyruvate is more protective than sodium pyruvate. In some embodiments, the inventors surprisingly found that ethyl pyruvate is a better neuroprotective agent than sodium pyruvate.

[0076] In some embodiments, ethyl pyruvate enables the use of lower doses of other therapeutic modalities, such as, but not limited to, nicotinamide and other agents capable of modulating metabolism.

[0077] Without wishing to be bound by theory, the superior properties of ethyl pyruvate compared to existing therapies (e.g., sodium pyruvate) can be due to enhanced stability, cellular penetration properties, anti-oxidative properties, anti-inflammatory properties, anti-apoptotic properties, and / or metabolic (bioenergetic) properties of ethyl pyruvate (e.g., relative to sodium pyruvate). Likewise, without wishing to be bound by theory, the enhanced anti-inflammatory and anti-apoptotic properties of ethyl pyruvate can be due to its enhanced molecular structure, stability, and / or ability to penetrate into cells. See, e.g., Chenxi Lu et al, Ethyl Pyruvate: A Newly Discovered Compound Against Ischemia-Reperfusion Injury in Multiple Organs, 171 Pharmacological Res. 105757 (2021); Ivan Koprivica, Ethyl Pyruvate, A Versatile Protector in Inflammation and Autoimmunity, 71 Inflammation Res. 169 (2022).

[0078] Pharmaceutical compositions The present application also provides pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0079] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and the subject being treated. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as

[0080] As described above, certain embodiments of the subject agent can be provided in the form of a pharmaceutically acceptable salt. In this respect, the term "pharmaceutically acceptable salt" means a relatively non-toxic, inorganic and organic acid addition salt of a compound of the present application.

[0081] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0082] Formulations of the present application include those suitable for oral, nasal, topical (including buccal and sublingual), and / or parenteral administration. The most suitable form of administration will depend on the particular use and clinical indication. Particularly useful formulations include oral and direct ocular or topical periocular formulations. The formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of the compound, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent of the compound.

[0083] The processes of preparation of these formulations or compositions include the step of bringing into association the compounds of the present application with the carrier and, optionally, one or more accessory ingredients. In general, the processes of preparation are carried out by uniformly and intimately bringing into association the compounds of the present application with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0084] Formulations of the present application suitable for oral administration can be in the form of capsules, cachets, tablets, pills, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and the like, each containing a predetermined amount of the compounds of the present application as an active ingredient. The compounds of the present application can also be administered as a bolus, electuary or paste.

[0085] In solid dosage forms of the present application for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (8) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0086] The tablets can be prepared by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets can be prepared by using binders (e.g., gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or crosscarmellose sodium), surface-active or dispersing agents. Molded tablets can be made by molding the mixture in a suitable machine.

[0087] The tablets and other solid dosage forms of the pharmaceutical compositions of the present application can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known to those in the art of pharmaceutical formulation. They can also be formulated so as to provide a sustained, or controlled release of the active ingredient therein.

[0088] Liquid dosage forms for oral administration of the compounds disclosed herein include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and mixtures of these

[0089] Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0090] Suspensions, in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

[0091] Dosage forms for topical or transdermal administration of a compound of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any needed preservatives, buffers, or propellants which can be required.

[0092] Ointments, pastes, creams and gels can contain, in addition to an active compound of this application, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0093] Powders and sprays can contain, in addition to a compound of this application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances.

[0094] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present application to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the agent across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0095] Ophthalmic formulations, ophthalmic ointments, powders, solutions, and the like are also considered to be within the scope of the present disclosure. Implants or injections can also be used to introduce agents into the eye. Any excipient disclosed herein as suitable for use in these applications can be incorporated into the pharmaceutical formulations.

[0096] Pharmaceutical compositions of the present application suitable for parenteral administration include one or more of the compounds disclosed herein in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions just prior to use, which can contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending agents or thickening agents.

[0097] When the compounds of the present application are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0098] In some embodiments, pyruvate ethyl ester doses of about 100 mg / kg / day - 2000 mg / kg / day, more particularly about 250 mg / kg / day - 1000 mg / kg / day, reduce the severity of ocular dysplasia and IOP elevation in mice. Human equivalent doses can be calculated as described in the literature. In some embodiments, the combination of pyruvate ethyl ester and other agents capable of modulating metabolism (e.g., metabolic enhancers) provides a higher degree of prevention of the severity of ocular dysplasia and IOP elevation in mice compared to pyruvate ethyl ester alone. For example, in some embodiments, the combination of pyruvate ethyl ester and NAM provides greater prevention of developmental pupillary abnormalities. In some embodiments, doses as high as about 8000 mg / kg / day can be used in mice, for example, in the case of traumatic injury to the optic nerve, eye, or neural tissue and short-term treatment. Likewise, human equivalent doses can be calculated accordingly.

[0099] In some embodiments, the combination of pyruvate ethyl ester and NAM is particularly useful. In some embodiments, the dose of NAM is about 100 mg / kg / day - 2500 mg / kg / day, more particularly about 500 mg / kg / day - 1000 mg / kg / day. Human equivalent doses can be calculated as described in the literature. Nicotinamide riboside can also be used at similar or lower doses.

[0100] One of ordinary skill in the art can use Freireich et al., Quantitative comparison of toxicity of anticancer agents in mouse, rat, dog, monkey and man, Cancer Chemother Rep.50(4):219-244, 1966 (incorporated herein by reference) or similar methods to convert doses from one species to another to calculate species-specific equivalent doses. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human . J BasicClin Pharm. 2016;7:27-31. This results in animal equivalent doses based on mouse doses. For example, a pyruvate ethyl ester dose of 550 mg / kg / day in mice is equivalent to a dose of about 2.7 g-3 g / day in a 70 kg human. In some embodiments, treatment is ongoing until a certain target milestone is reached. In some cases, treatment is ongoing for a long period of time, e.g., weeks, months, or years, to prevent the onset of glaucoma and / or elevated IOP.

[0101] According to some embodiments, a typical administration can be once, twice, three times, or more times a day. The total daily dose can be administered in one, two, three, or more separate doses. For multiple administrations, each dose can be the same amount or a different amount. The pharmaceutical composition can be administered in the morning or in the evening. The pharmaceutical composition can be taken with or without food.

[0102] The following representative examples are intended to aid in illustrating the present application and are not intended to, nor should they be construed as, limiting the scope of the application. Indeed, various modifications of the application, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire content of this document, including the following examples and references to the scientific and patent literature cited herein. It should also be understood that the contents of these cited documents are incorporated herein by reference to aid in the illustration of the state of the art. The following examples contain important additional information, exemplification, and guidance that can be adapted to the practice of the application in its various embodiments and equivalents thereof.

[0103] Example Example 1 Pyruvate ethyl ester provides disease protection Pyruvate ethyl ester shows protective effects in mice with Lmx1b mutations, demonstrating that pyruvate ethyl ester treatment can prevent various Lmx1b-induced diseases. For example, Lmx1b is implicated in neurodegenerative conditions such as glaucoma and Parkinson’s disease. Genetic models with Lmx1b mutations can result in cellular stress, developmental abnormalities, cell death, and / or elevated IOP, which can lead to further diseases or conditions. For example, in a mouse model of glaucoma, pyruvate ethyl ester reduced IOP and rescued ocular developmental abnormalities at multiple doses and with or without co-administration of another therapeutic agent.

[0104] Ethyl pyruvate is sourced from Sigma-Aldrich. Ethyl pyruvate has been shown to be safe and well-tolerated in multiple mammalian species, including humans, mice, rats, and horses. See, e.g., Clinical Trial Identifier NCT00107666 (human heart trial, 7.5 g (90 mg / kg) of ethyl pyruvate administered intravenously every six hours for two days); Xiujing Sun et al., Ethyl Pyruvate Supplemented in Drinking Water Ameliorates Experimental Nonalcoholic Steatohepatitis, 137 Biomedical Pharmacotherapy 11392 (2021); Leilei Mao et al., Ethyl Pyruvate Improves White Matter Remodeling in Rats After Traumatic Brain Injury, 27 CNS Neuroscience & Therapeutics 113 (2021); C. C. Jacobs et al, Ethyl Pyruvate Diminishes the Inflammatory Response to Lipopolysaccharide Infusion in Horses, 45 Equine Veterinary J. 333 (2013). Mice have been dosed for at least nine months without side effects. In addition, ethyl pyruvate is an FDA-approved food additive and flavoring agent.

[0105] A dose of about 2000 mg / kg of ethyl pyruvate in mice is equivalent to about 9.8 g / day for a 60 kg human.

[0106] Figure 1 Treatment of two-month-old (assessed age) mice carrying the early-onset Lmx1b developmental glaucoma model with ethyl pyruvate (500 mg / kg / day) is shown to result in a reduction in IOP. This shows a significant difference, indicating that ethyl pyruvate prevents high IOP.

[0107] Figure 2 Treatment of mice carrying the early-onset Lmx1b developmental glaucoma model with ethyl pyruvate (2000 mg / kg / day) is shown to result in a reduction in IOP. Figure 2It was also shown that treatment with ethyl pyruvate (500 mg / kg / day) and nicotinamide (550 mg / kg / day) also prevented IOP elevation in mice carrying the early onset Lmx1 b developmental glaucoma model.

[0108] As shown in Figure 3 , the combination of ethyl pyruvate with nicotinamide and other metabolic enhancers had a higher degree of protection from the severity of IOP elevation. Figure 3 It was shown that treatment with ethyl pyruvate (2000 mg / kg / day), nicotinamide (550 mg / kg / day), and N - acetyl-L-cysteine (200 mg / kg / day) increased disease protection in mice carrying the early onset Lmx1 b developmental glaucoma model. Treatment was initiated at P2 and IOP was measured at 5 weeks of age.

[0109] As shown in Figure 4- Figure 6 , in addition to preventing or treating high IOP, treatment with ethyl pyruvate alone or in combination with metabolic enhancers in mice carrying the early onset Lmx1 b developmental glaucoma model unexpectedly rescued ocular developmental abnormalities. Figure 4 It was shown that ethyl pyruvate (2000 mg / kg / day) treatment showed a lower incidence and severity of abnormal adhesions between the iris and cornea (i.e., iris-corneal adhesions). Ethyl pyruvate treatment also showed a significant effect in preventing or reducing anterior chamber deepening as shown in Figure 5- Figure 6 . The anterior chamber of a developmental glaucoma deepens due to high IOP; therefore, this result is consistent with ethyl pyruvate preventing high IOP.

[0110] The ability of ethyl pyruvate to treat or prevent IOP elevation and ocular developmental abnormalities is surprising at least because no such effect was observed with sodium pyruvate treatment. Figure 7 It was shown that treatment with sodium pyruvate (500 mg / kg / day) had no effect on IOP elevation in mice carrying the glaucoma model after two months. IOP was also measured at three and four months and no changes were observed compared to untreated. In addition, there was no change in the severity of anterior eye developmental abnormalities in the sodium pyruvate treated mice.

[0111] Figure 8 It was shown that treatment with ethyl pyruvate (2000 mg / kg / day) in mice carrying the early onset Lmx1 b developmental glaucoma model resulted in less glaucomatous optic nerve damage (neurodegeneration) in 6 month old mice. This indicates that the protective time was extended to a time point when most of the untreated mice had severe glaucoma. Figure 8 It was further shown that treatment with nicotinamide (550 mg / kg / day) in mice with the early onset Lmx1 b developmental glaucoma model also prevented glaucomatous optic nerve damage. Figure 8Further shown, treatment of mice carrying the early-onset Lmx1 b developmental glaucoma model with ethyl pyruvate (2000 mg / kg / day) and nicotinamide (550 mg / kg / day) also prevents glaucomatous optic nerve damage. As shown in the plotted data, the combination treatment provides the greatest protection against glaucomatous optic nerve damage.

[0112] Figure 9 shows that treatment of mice carrying the early-onset Lmx1 b developmental glaucoma model with ethyl pyruvate (2000 mg / kg / day) and NAM (500 mg / kg / day) administered to the mother mouse rescues the developmental abnormalities of the ocular drainage tissue of the pups, which also receive the active substances from the mother’s milk in the first two to three weeks after birth. This is a morphogenesis correction study (morphogenesis of the drainage tissue is completed at postnatal day 21 in mice). Analysis was performed on 3- to 4-week-old mice. Treatment was performed in the drinking water starting at birth (administration to the mother before birth is also effective). Figures 9A and 9C show 3D representations of the tissue volume, TM = Trabecular meshwork and SC = Schlemm’s canal. Figures 9B and 9D are box plots of the corresponding data. (Abbreviations: UTD = untreated. Com = combination treatment).

[0113] Figure 10 Shown, treatment of mice carrying the early-onset Lmx1 b developmental glaucoma model with ethyl pyruvate (2000 mg / kg / day) and NAM (550 mg / kg / day) greatly prevents cell death. The tested mice were treated starting at postnatal day 2 and evaluated at postnatal day P10 (at this age, cell death is easily detected in this glaucoma model). Cell death was quantified as the number of TUNEL+ cells in each TM section. This was extrapolated to the entire TM volume.

[0114] While the application has been described and shown in the foregoing illustrative embodiments, it should be understood that the disclosure is by way of example only and that numerous changes in the details of the illustrated embodiments can be made without departing from the spirit and scope of the application, which is defined solely by the claims appended hereto. The features of the disclosed embodiments can be combined and / or re-arranged in various ways without departing from the scope and spirit of the application, which is defined solely by the claims appended hereto. One skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are considered to be within the scope of the following claims.

Claims

1. A method of treating or preventing a condition in a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a derivative or analog thereof or a pharmaceutical composition thereof; wherein the condition is selected from the group consisting of an ocular disease or disorder, a neurodegenerative disease or disorder, a vascular disease or disorder, a metabolic disease or disorder, an inflammatory disease or disorder, a disease or disorder involving abnormal cell death or oxidation, a disease or disorder associated with one or more Lmxlb mutations, and combinations thereof.

2. The method of claim 1, wherein the condition is an ocular disease or disorder.

3. The method of claim 1 or 2, wherein the ocular disease or disorder comprises one or more changes in structure or function of one or more ocular tissues, abnormal cell death, or a combination thereof.

4. The method of claim 3, wherein the one or more changes comprise malformation or dysfunction of ocular drainage structures, one or more developmental abnormalities, neurologic or non-neurologic cell degeneration, dysfunction, or death, or a combination thereof.

5. The method of claim 3 or 4, wherein the one or more changes arise from environmental exposure, disease, aging, metabolic abnormalities, mitochondrial abnormalities, genetic mutations, or a combination thereof.

6. The method of claim 4, wherein the one or more developmental abnormalities comprise changes in anterior chamber depth, pupil abnormalities, iridocorneal adhesions, trabecular meshwork, Schlemm’s canal, cornea, or a combination thereof.

7. The method of claim 4, wherein cell degeneration or dysfunction comprises neurodegeneration and / or neurologic dysfunction in retinal ganglion cells of the subject.

8. The method of claim 4, wherein the ocular drainage structures comprise Schlemm’s canal, trabecular meshwork, or a combination thereof.

9. The method of claim 1 or 2, wherein the ocular disease or disorder is a neurodegenerative disease or disorder.

10. The method of any one of claims 1-2 and 9, wherein the ocular disease or disorder is glaucoma or optic nerve disease.

11. The method of claim 1, wherein the condition is a neurodegenerative disease.

12. The method of claim 1 or 11, wherein the condition comprises late-onset neurodegeneration.

13. The method of any one of claims 1 and 11-12, wherein the condition is Alzheimer’s disease or Parkinson’s disease.

14. The method of claim 1, wherein the disease or disorder associated with one or more Lmxlb mutations is a disease or disorder of the brain or kidney.

15. The method of claim 1 or 2, wherein the condition is age-related macular degeneration.

16. The method of claim 1 or 2, wherein the condition comprises retinal pigment epithelium.

17. The method of any one of claims 1-16, further comprising administering to the subject one or more additional therapeutic agents or one or more pharmaceutical compositions thereof.

18. The method of claim 17, wherein the one or more additional therapeutic agents are selected from the group consisting of: an antioxidant, an anti-inflammatory agent, an agent that modulates metabolism, an agent that modulates integrated stress response, an agent that modulates unfolded protein response, an agent that modulates multiple forms of autophagy, an agent that modulates expression or activity of genes that control or mediate antioxidant responses or other protective responses, an anti-aging agent, an agent that modulates mitochondria or mitochondrial autophagy, an anti-aging agent, an agent that modulates intraocular pressure, a resilience-enhancing agent, an anti-fibrotic agent, an agent that prevents epithelial or endothelial mesenchymal transition, a neuroprotective agent, a gene therapy agent, and combinations thereof.

19. The method of claim 18, wherein the agent that modulates metabolism reprograms or promotes metabolism.

20. The method of claim 18, wherein the antioxidant reduces oxidative stress and enhances antioxidant control.

21. The method of claim 18, wherein the gene therapy agent results in genome editing, genome reprogramming, epigenetic editing, epigenetic reprogramming, or combinations thereof.

22. The method of claim 18, wherein the agent that prevents epithelial or endothelial mesenchymal transition is an anti-transforming growth factor beta (TGFB) or a ligand trapping molecule.

23. The method of claim 18, wherein the one or more additional therapeutic agents are selected from the group consisting of nicotinamide, nicotinamide mononucleotide, nicotinamide adenine dinucleotide, nicotinamide riboside, pyrroloquinoline quinone, N-acetyl cysteine, and combinations thereof.

24. The method of any one of claims 1-23, wherein the subject is a mammal.

25. A method of reducing or preventing elevated intraocular pressure, the method comprising administering to a subject a therapeutically effective amount of ethyl pyruvate or a derivative or analog thereof or a pharmaceutical composition thereof.

26. The method of claim 25, further comprising administering to the subject one or more additional therapeutic agents or one or more pharmaceutical compositions thereof.

27. The method of claim 26, wherein the one or more additional therapeutic agents are selected from the group consisting of: an antioxidant, an anti-inflammatory agent, an agent that modulates metabolism, an anti-aging agent, an agent that modulates mitochondria or mitochondrial autophagy, an anti-aging agent, an agent that modulates intraocular pressure, a resilience-enhancing agent, an anti-fibrotic agent, an agent that prevents epithelial or endothelial mesenchymal transition, a neuroprotective agent, a gene therapy agent, and combinations thereof.

28. A method of reducing or preventing ocular tissue damage or dysfunction in a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a derivative or analog thereof or a pharmaceutical composition thereof.

29. The method of claim 28, further comprising administering to the subject one or more additional therapeutic agents or one or more pharmaceutical compositions thereof.

30. The method of claim 29, wherein the one or more additional therapeutic agents are selected from the group consisting of: an antioxidant, an anti-inflammatory agent, an agent that modulates metabolism, an anti-aging agent, an agent that modulates mitochondria or mitophagy, an anti-aging agent, an agent that modulates intraocular pressure, a resilience-enhancing agent, an anti-fibrotic agent, an agent that prevents epithelial or endothelial mesenchymal transition, a neuroprotective agent, a gene therapy agent, and combinations thereof.

31. A method of reducing or preventing damage or dysfunction of a tissue associated with fluid drainage from the eye of a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a derivative or analog thereof or a pharmaceutical composition thereof.

32. The method of claim 31, further comprising administering to the subject one or more additional therapeutic agents or one or more pharmaceutical compositions thereof.

33. The method of claim 32, wherein the one or more additional therapeutic agents are selected from the group consisting of: an antioxidant, an anti-inflammatory agent, an agent that modulates metabolism, an anti-aging agent, an agent that modulates mitochondria or mitophagy, an anti-aging agent, an agent that modulates intraocular pressure, a resilience-enhancing agent, an anti-fibrotic agent, an agent that prevents epithelial or endothelial mesenchymal transition, a neuroprotective agent, a gene therapy agent, and combinations thereof.

34. A method of reducing or preventing malformation or dysfunction of an eye of a subject, the method comprising administering to the subject a therapeutically effective amount of ethyl pyruvate or a derivative or analog thereof or a pharmaceutical composition thereof.

35. The method of claim 34, further comprising administering to the subject one or more additional therapeutic agents or one or more pharmaceutical compositions thereof.

36. The method of claim 35, wherein the one or more additional therapeutic agents are selected from the group consisting of: an antioxidant, an anti-inflammatory agent, an agent that modulates metabolism, an anti-aging agent, an agent that modulates mitochondria or mitophagy, an anti-aging agent, an agent that modulates intraocular pressure, a resilience-enhancing agent, an anti-fibrotic agent, an agent that prevents epithelial or endothelial mesenchymal transition, a neuroprotective agent, a gene therapy agent, and combinations thereof.

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