Compositions and methods for treating eye conditions

Abstract

Methods for treating ophthalmic disease using compositions containing an aliphatic aldehyde adductor are described herein.

Description

COMPOSITIONS AND METHODS FOR TREATING EYE CONDITIONS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 551,982, filed on February 9, 2024. FIELD OF THE INVENTION

[0002] The present disclosure relates to aliphatic aldehyde adductors useful for treating eye conditions. BACKGROUND

[0003] Mammals have varying levels of antioxidant capabilities. Those capabilities use superoxide dismutase, catalase, and glutathione peroxidase, as well as non-enzymatic antioxidants like vitamins C and E, and glutathione to combat the effects of reactive oxygen species (ROS). Mammalian antioxidants are important because ROS are known to contribute to disease progression through cellular damage, inflammation, DNA damage, mitochondrial dysfunction and nerve damage.

[0004] Oxidative stress plays an important role in diseases of the eye. Those diseases include age- related macular degeneration, glaucoma, cataracts, diabetic retinopathy, degeneration of the retina, uveitis, and dry eye. By accelerating and increasing lipid peroxidation in the cell membrane, for example, oxidative stress results in the formation of aldehydes that are particularly toxic. One particular aldehyde, 4-hydroxy-2-nonenal (4-HNE), forms adducts with DNA or proteins, thereby disrupting many cell processes and signaling. This in turn disrupts the regulation of apoptotic signal transduction pathways within the cell, hence triggering cell death and adversely impacting eye health. As such, 4-HNE has been implicated in eye diseases such as dry eye, macular degeneration, and glaucoma.

[0005] The retina is particularly susceptible to damage due to ROS. The factors that make the retina susceptible to high ROS concentrations are high energy use by photoreceptors and nerve cells, which are also high oxygen consumers. In addition, the retina is made up of highly specialized cells that do not have substantial antioxidant capabilities. These specialized cells make up delicate structures in the eye, including the retinal pigment epithelial (RPE) cells. In many diseases of the retina, these cells experience significant oxidative stress resulting in apoptosis ofRPE cells and the photoreceptors they support. It is imperative for the success of any ophthalmic treatment to have persistence that ROS are controlled in the eye. SUMMARY OF THE INVENTION

[0006] In certain example aspects, provided is a method for treating an ophthalmic disease in a subject, the method including administering to a subject in need thereof an aliphatic aldehyde adductor. For example, the aliphatic aldehyde adductor includes any one of the compounds of Formulas I-VII as set forth herein. In certain example aspects, the aldehyde adductor is set forth as either Formula VI or Formula VII.

[0007] In certain example aspects, the ophthalmic disease that is treated includes glaucoma, macular degeneration, diabetic retinopathy, hereditary retinal degeneration, age-related macular degeneration (AMD), non-exudative age-related macular degeneration, exudative (wet) AMD, macular edema, ocular rosacea, amblyopia, cataracts, dry eye, iritis, photoreceptor degeneration, retinitis pigmentosa, Stargardt disease, Leber Congenital Amaurosis, keratoconus, retrobulbar optic neuritis, loss of conjunctival cells, loss of lacrimal gland cells, central or branch retinal artery occlusions, ocular hypertension, or ocular inflammation.

[0008] The ophthalmic disease can also be a neurodegenerative disorder of the retina and optic nerve head, uveitis, or a neurodegenerative disorder. In certain examples aspects, the neurodegenerative disorder includes atrophic macular degeneration, retinitis pigmentosa, iatrogenic retinopathy, retinal tears or holes, diabetic retinopathy, sickle cell retinopathy, retinal vein or artery occlusion, or optic neuropathy.

[0009] In certain example aspects, the aldehyde adductor targets a reactive aldehyde species. Examples of such reactive aldehyde species that can be targeted include 4-hydroxynonenal (4HNE), 4-hydroxy-2E-hexenal (4-HHE), 2-hydroperoxyeicosa-tetraenoic acid (12-HpETE), 12- hydroxyeicostetrae-noic acid (12-HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, retinaldehydes, 11-cis retinal, all trans retinal, all trans retinal dimers, all trans retinyl esters, retinol (vitamin A1), or a combinations thereof.

[0010] In certain example aspects, provided is a method for targeting a reactive aldehyde species in a subject, the method including administering to the subject one or more of the aliphatic aldehyde adductors set forth in Formulas I-VII, such as the compound of Formula VI or Formula VII. In such example aspects, the aliphatic aldehyde adductor targets, for example, 4- hydroxynonenal (4HNE), 4-hydroxy-2E-hexenal (4-HHE), 2-hydroperoxyeicosa-tetraenoic acid(12-HpETE), 12-hydroxyeicostetrae-noic acid (12-HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, retinaldehydes, 11-cis retinal, all trans retinal, all trans retinal dimers, all trans retinyl esters, retinol (vitamin A1), or a combinations thereof.

[0011] In certain example aspects, the aliphatic aldehyde adductor described herein is formulated into a pharmaceutical composition for oral, mucosal, parenteral, topical, or transdermal delivery. For example, the aldehyde adductor is formulated into an ophthalmic solution or gel. In certain example aspects, the pharmaceutical composition is a solid dosage form for oral delivery.

[0012] These and other aspects, objects, features and advantages of the example embodiments will become apparent to those having ordinary skill in the art upon consideration of the following detailed description of illustrated example embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG.1 is a graph showing ARPE-19 retinal pigment epithelial cell viability with increasing dosages of REN-101, in an unbuffered solution. Based on these data, an LC50 of 52.9 was determined. One-way ANOVA: Comparison to untreated control. N=3: Where N = 3 independent experimental repeats (different cell passage) ***P<0.001.

[0014] FIG.2 is a graph showing ARPE-19 retinal pigment epithelial cell viability with increasing dosages of REN-101, in the presence of buffer. Notably, high concentrations of buffered REN- 101 did significantly impact cell viability. One-way ANOVA: Comparison to untreated control. N=3: Where N = 3 independent experimental repeats (different cell passage) ***P<0.001.

[0015] FIG. 3 is a graph showing cell viability in ARPE-19 retinal pigment epithelial cells following treatment with either 12.2 µM 4HNE alone or with 12.2 µM 4HNE and either 10 mM glutathione (positive control), 0.5 to 2 mM ascorbic acid (AA) (positive control), or REN-101 at concentrations ranging from 10 mM to 10-6mM. As shown, treatment at each REN-101 concentration provided significantly improved percent cell viability (similar to control) verses insult with 12.2 µm 4-HNE alone. One-way ANOVA statistics on multiple comparisons between Control (N=9) and compounds (N=9) at cell passages 4-6. ***P<0.001: Comparison to 4HNE. N = technical repeats.

[0016] FIG. 4 is a graph showing cell viability in ARPE-19 retinal pigment epithelial cells following treatment with either 200 µm H2O2alone or with 200 µM H2O2and either 10 mM glutathione (positive control), 0.5 to 2 mM ascorbic acid (AA) (positive control), or REN-101 atconcentrations ranging from 10 mM to 10-6mM. As shown, treatment at each REN-101 concentration provided a significantly improved percent cell viability (similar to control) verses insult with 200 H2O2 µm alone. One-way ANOVA statistics on multiple comparisons between Control (N=9) and compounds (N=9) at cell passages 4-6. ***P<0.001: Comparison to H2O2. N = technical repeats.

[0017] FIG. 5 is a graph showing the effect of REN-101 treatment on 4HNE-induced oxidative stress in ARPE19 retinal pigment epithelial cells. ARPE19 cells were subjected to a CellRox+TManalysis following treatment with 12.2 µM 4HNE alone or 12.2 µM 4HNE with 10.0 mM glutathione (positive control), 0.5 mM ascorbic acid (AA) (positive control), or REN-101 at concentrations ranging from 10 mM to 10-6mM. As shown, REN-101 attenuates 4HNE-induced Oxidative Stress. N=4: N=1 biological repeat (3 experimental repeats); Passage 4-6; One-way ANOVA, ***P<0.001, **P<0.01, relative to 4HNE; outliers were removed using Grubbs Test.

[0018] FIG. 6 is a graph showing the effect of REN-101 treatment on H2O2-induced oxidative stress in ARPE19 retinal pigment epithelial cells. ARPE19 cells were subjected to a CellRox+TManalysis following treatment with either 200 µM H2O2 alone or with H2O2 and either 10.0 mM glutathione (positive control), 0.5 mM ascorbic acid (AA) (positive control), or REN-101 at concentrations ranging from 10 mM to 10-6mM and H2O2200 µM insult. As shown, REN-101 attenuates H2O2-induced oxidative stress. N=3: N=1 biological repeat (3 experimental repeats); Passage 4-6; One-way ANOVA, **P<0.01, *P<0.05, relative to H2O2; outliers were removed using Grubbs Test.

[0019] FIG.7 is a graph showing the effect of REN-101 treatment on H2O2-induced mitochondrial superoxide production in ARPE19 retinal pigment epithelial cells. ARPE19 cells were subjected to a MitoSOXTManalysis following treatment with 200 µM H2O2 and 10.0 mM glutathione (positive control), or REN-101 at concentrations ranging from 10 mM to 10-6mM and H2O2200 µM insult. As shown, REN-101 attenuates H2O2-induced mitochondrial superoxide production. N=3: N=1 biological repeat (3 experimental repeats); Passage 5-7; ***P<0.001, **P<0.01: Comparison to control; ###P<0.001: Comparison to H2O2.

[0020] FIG. 8 is a graph showing the preservational effect of REN-101 treatment on neuroretinal cells (rods, cones, horizontal, bipolar, amacrine and retinal ganglion cells) in the rd10 mouse model. In the total neuroretina SD-OCT, the 500 mg / kg, Ren-101 treated, rd10 mice displayed significantly reduced deterioration of the cells making up the inner and outer retina. The 500 mg / kgdose exhibited a p-value of <0.01 at 2.0 mm from the fovea and <0.05 at 1.5mm from the fovea versus vehicle. Although Ren-101 at 1000 mg / kg did not show significance, there too shows consistent improvement in neuroretinal structures over the untreated rd10 mice.

[0021] FIG.9 is a graph showing the preservational effect of REN-101 treatment on rod and cone cells in the rd10 mouse model. In the photoreceptor layer SD-OCT, the 500 and 1000 mg / kg Ren- 101 treated rd10 mice exhibited significantly reduced deterioration of rods and cones versus untreated rd10 animals. The 1000 mg / kg Ren-101 treated rd10 animals had a p-value of <0.05 at 1.5 mm and 2.0 mm from the fovea, versus vehicle. The 500mg / kg Ren-101 treated mice exhibited a p-value of 0.01 versus vehicle at all four positions from the fovea.

[0022] FIG.10 is a graph showing the preservational effect of REN-101 treatment on visual acuity on ABCA4 mice following treatment for 24 weeks. In this study, mice were treated daily with vehicle, Ren-101 30 mg / kg, Ren-101 100 mg / kg or metformin (active comparator) 500 mg / kg. The visual acuity measure of Optokinetic Tracking Response (OKT) analysis was performed at 9, 13, 17 and 24 weeks. On average, mice consistently maintained their visual function at 24 weeks with no decline from the 9-week baseline, demonstrating sustained effectiveness in preserving sight. ABCA4 mice treated with only vehicle had ~20% reduction in visual function when comparing 24 weeks to 9 weeks DETAILED DESCRIPTION

[0023] Various aspects now will be described more fully hereinafter. Such aspects may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art. Terms and Nomenclature

[0024] For convenience, certain terms employed in the specification, examples, and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0025] Where a range of values is provided, it is intended that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within thatrange. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0026] By hereby reserving the right to proviso out or exclude any individual members of any such group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, less than the full measure of this disclosure can be claimed for any reason. Further, by hereby reserving the right to proviso out or exclude any individual substituents, analogs, compounds, ligands, structures, or groups thereof, or any members of a claimed group, less than the full measure of this disclosure can be claimed for any reason.

[0027] All percentages, parts and ratios are based upon the total weight of the topical compositions and all measurements made are at about 25 ºC, unless otherwise specified.

[0028] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a “polymer” includes a single polymer as well as two or more of the same or different polymers; reference to an “excipient” includes a single excipient as well as two or more of the same or different excipients, and the like.

[0029] The word “about” when immediately preceding a numerical value means a range of plus or minus 10% of that value, e.g. “about 50” means 45 to 55, “about 25,000” means 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55,” “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein.

[0030] The terms “administer,” “administering” or “administration” as used herein refer to directly administering a compound (also referred to as an agent of interest) or pharmaceutically acceptable salt of the compound (agent of interest) or a composition to a subject.

[0031] The term “carrier” as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material involved in carrying or transporting a pharmaceutical, cosmetic or other agent across a tissue layer such as the stratum corneum or stratum spinosum.

[0032] The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0033] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound that, when administered to a subject, is capable of reducing a symptom of a disorder in a subject or enhance the texture, appearance, color, sensation, or hydration of the intended tissue treatment area. The actual amount which comprises the “effective amount” or “therapeutically effective amount” will vary depending on a number of conditions including, but not limited to, the severity of the disorder, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.

[0034] The phrase “pharmaceutically acceptable” or “cosmetically acceptable” is employed herein to refer to those agents of interest / compounds, salts, compositions, dosage forms, etc., which are- -within the scope of sound medical judgment--suitable for use in contact with the tissues of human beings and / or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some aspects, pharmaceutically acceptable means approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals (e.g. animals), and more particularly, in humans.

[0035] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form additional salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. The term “salts” also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. Non-limiting examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic,phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric and galacturonic acid.

[0036] The term “patient” and “subject” are interchangeable and may be taken to mean any living organism which may be treated with compounds of the present invention. As such, the terms “patient” and “subject” may include, but is not limited to, any non-human mammal, primate or human. In some embodiments, the “patient” or “subject” is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans. In some embodiments, the patient or subject is an adult, child or infant. In some embodiments, the patient or subject is a human.

[0037] The term “treating” is used herein, for instance, in reference to methods of treating a disorder or a systemic condition, and generally includes the administration of a compound or composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition or enhance the texture, appearance, color, sensation, or hydration of the intended tissue treatment area of the tissue surface in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject’s condition.

[0038] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to non-toxic solvent, phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The compositions also can include stabilizers and preservatives.

[0039] The term “alkyl”, by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbyl having the designated number of carbon atoms (i.e., C1- C6 means one to six carbons). Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Most preferred is (C1-C6)alkyl, more preferably (C1- C3)alkyl, particularly methyl and ethyl.

[0040] The term “alkenyl” employed alone or in combination with other terms, means, unless otherwise stated, a straight chain or branched chain hydrocarbyl having the stated number of carbon atoms, and containing one or more double bonds. Examples include ethenyl (vinyl),propenyl (allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, and 1,4-pentadienyl. A functional group representing an alkenyl is exemplified by —CH2—CH═CH2—.

[0041] The term “alkynyl” employed alone or in combination with other terms, means, unless otherwise stated, a straight chain or branched chain hydrocarbyl having the stated number of carbon atoms, and containing one or more triple bonds.

[0042] The term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. The alkyl portion of the alkoxy group can have a designated number of carbon atoms as defined for alkyl groups above. Preferred are (C1-C6)alkoxy, more preferably (C1-C3)alkoxy, particularly methoxy and ethoxy.

[0043] The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).

[0044] The term “aryl” refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring can optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl.

[0045] The term “aralkyl” group refers to an alkyl group substituted with an aryl group.

[0046] The terms “halo” or “halogen” by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Preferably, a halogen includes fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.

[0047] The term “heteroarylalkyl” group refers to an alkyl group substituted with a heteroaryl group.

[0048] The term “heterocycle” or “heterocyclyl” or “heterocyclic” by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted, mono- or multi-cyclic heterocyclic ring system which consists of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S. The heterocycle typically contains from five to ten ring atoms. The heterocyclic system may be attached to another atom, unless otherwise stated, at any heteroatom or carbon atom of the heterocyclic system which affords a structural isomer.

[0049] The term “heteroaryl” or “heteroaromatic” refers to a heterocycle having aromatic character.

[0050] The term “hydrocarbyl”, by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. C1-C6 means one to six carbons). Examples include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. The term “unsaturated hydrocarbyl” means a hydrocarbyl that contains at least one double or triple bond.

[0051] The term “haloalkyl” means an alkyl group wherein at least one hydrogen atom is replaced by a halogen atom. The term “perhaloalkyl” means a haloalkyl group wherein all the hydrogen atoms are replaced by halogen atoms. A preferred perhaloalkyl is perfluoroalkyl, particularly — (C1-C6)perfluoroalkyl; more preferred is —(C1-C3)perfluoroalkyl; most preferred is —CF3.

[0052] The term “haloalkoxy” means an alkoxy group wherein at least one hydrogen atom is replaced by a halogen atom. The term “perhaloalkoxy” means a haloalkoxy group wherein all the hydrogen atoms are replaced by halogen atoms. A preferred perhaloalkoxy is perfluoroalkoxy, particularly —(C1-C6)perfluoroalkoxy; more preferred is —(C1-C3)perfluoroalkoxy; most preferred is —OCF3.

[0053] As used herein, the term “pharmaceutically acceptable” refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and / or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.

[0054] The term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. For aryl and heteroaryl groups, the term “substituted” refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. Substituents may include, for example, one of the moieties from the group of halo, oxy, azido, nitro, cyano, alkyl, alkoxy, alkyl-thio, alkyl-thio-alkyl, alkoxyalkyl, alkylamino, trihalomethyl, hydroxyl, mercapto, hydroxy, alkylsilyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, alkenyl, alkynyl, aryl, and amino groups. Substituents comprising carbon chains preferably contain 1-6, more preferably 1-3, most preferably 1-2, carbon atoms.

[0055] It is to be understood that the disclosed methods and compositions may assume various alternative variations and step sequences, except where expressly specified to the contrary. Moreover, other than in any operating examples, or where otherwise indicated, all numbers such as those expressing values, amounts, percentages, ranges, subranges and fractions may be read as if prefaced by the word “about,” as that term is described herein, even if the term does not expressly appear. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the results desired to be obtained by the disclosed methods. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Where a closed or open-ended numerical range is described herein, all numbers, values, amounts, percentages, subranges and fractions within or encompassed by the numerical range are to be considered as being specifically included in and belonging to the original disclosure of this application as if these numbers, values, amounts, percentages, subranges and fractions had been explicitly written out in their entirety.

[0056] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard variation found in their respective testing measurements.

[0057] As used herein, unless indicated otherwise, a plural term can encompass its singular counterpart and vice versa, unless indicated otherwise. For example, although reference is made herein to “a” composition, a combination (i.e., a plurality) of these components can be used. In addition, in this application, the use of “or” means “and / or” unless specifically stated otherwise, even though “and / or” may be explicitly used in certain instances. Compositions and Formulations

[0058] Embodiments of the present invention are described below. It is, however, expressly noted that the present invention is not limited to these embodiments, but rather the intention is that modifications that are apparent to the person skilled in the art and equivalents thereof are also included.

[0059] Oxidative stress can cause reversible or irreversible changes in proteins. Reversible changes occur in cysteine residues and can be repaired by antioxidant compounds. On the otherhand, oxidative stress can directly or indirectly induce irreversible damage to the proteins by formation of reactive carbonyl groups, mainly aldehydes and ketones. Direct protein carbonylation of lysine or arginine residues occurs through a Fenton reaction of metal cations with hydrogen peroxide, forming glutamic semialdehyde. Indirect carbonylation can occur by reactive α,β-unsaturated aldehydes, which are products of oxidative modification of polyunsaturated fatty acids (PUFA).

[0060] Common reactive aldehydes include 4-hydroxyalkenals, such as 4-hydroxynonenal (4HNE) (also known -hydroxy-2E-nonenal or 4-hydroxy-2-nonenal), 4-hydroxy-2E-hexenal (4- HHE), 2-hydroperoxyeicosa-tetraenoic acid (12-HpETE), 12-hydroxyeicostetrae-noic acid (12- HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, retinaldehydes, for example, 11-cis retinal, and all trans retinal. Further included are all trans retinal dimers, all trans retinyl esters, Retinol (vitamin A1) and the like.

[0061] Reactive aldehydes react with cysteine, lysine, and histidine residues of proteins via Michael addition and Schiff base formation. The introduction of carbonyl derivatives (i.e., aldehydes and ketones) alters the conformation of the polypeptide chain, resulting in the partial or total inactivation.

[0062] Because protein carbonylation is an irreversible process, including for example the formation of covalent bonds within the protein, it is deleterious to the cells. Reactive aldehydes are associated with various cellular processes including apoptosis, cell division, inflammation, mutation, drug transport, cellular integrity, membrane potential, neurodegeneration, cell-cell interactions, immune cell activation, and innate immunity among others, and has been implicated in various pathological conditions including, for example, asthma, COPD, cancer, diabetes, ophthalmic diseases such as diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa, metabolic syndromes, renal diseases such as polycystic kidney disease, chronic kidney disease, and diabetic nephropathy, infectious diseases such as influenza, COVID-19, ventilator associated pneumonia, autoimmune diseases such as lupus, systemic lupus erythematosus, RA, atherosclerosis, cardiovascular disease, sepsis, liver diseases such as alcoholic liver disease, and non-alcoholic fatty liver disease, ageing, and neurologic diseases such as Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease, neuropathic pain, and the like.

[0063] In the eye, it has long been accepted that oxidative stress, and hence the generation of reactive aldehydes, plays an important role in many retinal degeneration conditions. Persistent oxidative stress can lead to damage to ocular tissues such as the cornea, lens and retina. In addition, inflammatory and immune responses can exacerbate the production of aldehydes. Age-related macular degeneration (AMD), for example -- the leading cause of blindness in elderly populations in the developed world -- is accompanied by degeneration of retinal pigment epithelial cells (RPE). The retinal pigment epithelium, for example, is essential for retinoid recycling and phagocytosis of photoreceptors, with increased levels of lipid peroxidation products such as 4-HNE reported in retinas, while increased level of oxidized phospholipids in photoreceptors and RPE cells is associated with aging and AMD.

[0064] Accordingly, in certain example embodiments provided are compositions and methods for treating diseases associated with the generation of reactive aldehyde compounds such as 4- hydroxynonenal (4HNE), 4-hydroxyalkenals, such as 4-hydroxy- 2E-hexenal (4-HHE), 4- hydroxy-2E-nonenal (4HNE), 2-hydroperoxyeicosa- tetraenoic acid (12-HpETE), 12- hydroxyeicostetrae-noic acid (12-HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, and the like. In certain example embodiments, provided are compositions and methods for treating diseases of the eye, including oxidative retinal diseases, such as by the administration of one or more of the compositions provided herein. This is beneficial, for example, because 4-HHE, MDA, acrolein, and other reactive aldehydes may cause a subject to develop a variety of disorders of the eye, as described herein.

[0065] In certain example embodiments, the compositions can include one or more aliphatic aldehyde adductors and a pharmaceutically acceptable carrier or excipient. Methods of various embodiments may generally include the step of administering to a subject in need of treatment a composition including one or more aliphatic aldehyde adductors and a pharmaceutically acceptable carrier or excipient. Such methods can be used to treat various conditions and diseases including, for example, asthma, COPD, cancer, diabetes, ophthalmic diseases such as diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa, metabolic syndromes, renal diseases such as polycystic kidney disease, chronic kidney disease, and diabetic nephropathy, infectious diseases such as influenza, COVID-19, ventilator associated pneumonia, autoimmune diseases such as lupus, systemic lupus erythematosus, rheumatoid arthritis (RA), atherosclerosis, cardiovascular disease, sepsis, liver diseases such as alcoholic liver disease, and non-alcoholicfatty liver disease, ageing, and neurologic diseases such as Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease, neuropathic pain, and the like and combinations thereof.

[0066] The aliphatic aldehyde adductors of various embodiments include compounds of general Formula I: (I) and

[0067] R1are — — — C8)alkynyl, substituted or unsubstituted -ara(C1-C6)alkyl, substituted or unsubstituted -(C1- C6)heteroarylalkyl, where the substituents can be selected from the group consisting of halogen, —CN, —NO2, —NH2, —NH(C1-C6)alkyl, —N[(C1-C6)alkyl)]2, —OH, (C1-C6)haloalkyl, —(C1- C6)alkoxy, (C1-C6)haloalkoxy, —SH, (C1-C6)thioalkyl, —SONH2, —SO2NH2, —SO—(C1- C6)alkyl, —SO2—(C1-C6)alkyl, —NHSO2(C1-C6)alkyl, or —NHSO2NH2;

[0068] R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14are each, independently, hydrogen, — OH, or —(C1-C6)alkyl;

[0069] m and p are each, individually, 1, 2, 3 or 4;

[0070] n, o, q, and r are each individually, 0, 1, 2, 3 or 4.

[0071] In some embodiments, R1and R2can each, individually, be hydrogen, -(C1-C6)haloalkyl, - (C1-C6)haloalkoxy, -(C1-C6)perhaloalkyl, or -(C1-C6)perhalo. In some embodiments, R1or R2or R1and R2may each, individually, be hydrogen and —(C1-C8)alkyl. In certain embodiments, R1and R2are hydrogen.

[0072] In some embodiments, R3, R4, R5, R6, R7, R8,R9, R10, R11, R12, R13, and R14may each, individually, be hydrogen and —(C1-C8)alkyl, —(C1-C6)alkyl, —(C1-C3)alkyl, methyl, or ethyl, and in certain embodiments, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14may be hydrogen.

[0073] Further embodiments include compounds of general Formula II: or pharmaceutically

[0074] each R3, each R4, each R9, and each R10is independently hydrogen and —(C1-C8)alkyl, and in some embodiments, R3, R4, R9, and R10are each hydrogen:

[0075] R1and R2are each independently hydrogen and —(C1-C8) alkyl; and

[0076] o and p are each individually an integer from 1 to about 10.

[0077] The aliphatic aldehyde adductors of some embodiments include compounds of general Formula III: or

[0078] each m, n, o, and p are, independently, an integer of 1 to about 10;

[0079] each s and t are, independently, 0 or an integer of 1 to about 10; and

[0080] y and z may each, independently, an integer of 1 to about 10.

[0081] In additional embodiments, the aliphatic aldehyde adductors may be of general Formula IV: or or pharmaceutically

[0082] each n and o are, independently, an integer of 1 to about 10;

[0083] each s is independently, an integer of 1 to about 10; and

[0084] y may be an integer of 1 to about 10.

[0085] Particular examples of aliphatic aldehyde adductors include, but are not limited to 2-amino- 6-((3-aminopropyl)amino)hexanoic acid, (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid, 2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride, (S)-2-amino-6-((3- aminopropyl)amino)hexanoic acid dihydrochloride, 2-amino-5-((6-aminohexyl)amino)pentanoic acid, (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, 2-amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride, (S)-2-amino-5-((6- aminohexyl)amino)pentanoic acid trihydrochloride, 2-amino-5-((5-aminopentyl)amino)pentanoic acid, (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, 2-amino-5-((5- aminopentyl)amino)pentanoic acid trihydrochloride, and (S)-2-amino-5-((5- aminopentyl)amino)pentanoic acid trihydrochloride.

[0086] In certain example embodiments, the aliphatic aldehyde adductor has the following formula (VI) (referred to herein as “REN-101”):

[0087] The various aliphatic aldehyde adductors of the invention contain one or more chiral centers. Embodiments include any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of the invention. Such compounds may exist in, and may be isolated as, pure enantiomeric or diastereomeric forms or as racemic mixtures.

[0088] In certain embodiments, the aliphatic aldehyde adductors may be isolated as an (S) optical isomer with respect to the configuration about the α-carbon of the contained α-amino acid functionality. “Isolated optical isomer,” as used herein, refers to a compound that has been isolated or enriched for the (S) enantiomer of the compound, and in some embodiments, the compound may be substantially purified as the (S) enantiomer from the corresponding optical isomer(s) of the same formula. Preferably, the isolated optical isomer may be at least about 80 wt. % pure, at least 85 wt. % pure, at least 90 wt. % pure, at least 95 wt. % pure, at least 98 wt. % pure, at least about 99 wt. % pure. In some embodiments, the isolated (S) enantiomer is free of the corresponding (R) enantiomer.

[0089] The various aliphatic aldehyde adductors described above can be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization, or chromatography.

[0090] The aliphatic aldehyde adductors may be in salt form when appropriately substituted with groups or atoms capable of forming salts. Such groups and atoms are well known to those of ordinary skill in the art. The term “salts” embraces addition salts or free bases which arecompounds of the invention. The term “pharmaceutically acceptable salt” refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications.

[0091] Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, phosphoric acids, and the like. Appropriate organic acids include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic organic acids, examples of which include formic, acetic, pivalic, propionic, furoic, mucic, isethionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric, camphorosulfonic, galacturonic acid, and the like and combinations thereof.

[0092] Suitable pharmaceutically acceptable base addition salts of aliphatic aldehyde adductors of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, tromethamine, meglumine (N-methylglucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.

[0093] All of these salts may be prepared by conventional means from the corresponding aliphatic aldehyde adductors by reacting the compound with an appropriate acid or base. The salts are in crystalline form and may be prepared by crystallization of the salt from a suitable solvent. The person skilled in the art will know how to prepare and select suitable salt forms for example, as described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use by P. H. Stahl and C. G. Wermuth (Wiley-VCH 2002). In certain example embodiments, the aliphatic aldehyde adductor has the following formula (VII), where the compound of Formula VI is formulated as a salt:(VII)

[0094] The above may form adducts with naturally occurring aldehyde containing moieties such as 4HNE in subjects. By forming such adducts, the aliphatic aldehyde adductors reduce the reactivity of such aldehyde containing compounds, reducing their ability to react with proteins, lipids, and DNA.

[0095] In certain example embodiments, the aldehyde adductors provided herein may reduce or otherwise affect other deleterious compounds, such as via nucleophilic attack. Such compounds include, for example, all-trans-retinyl ester, 11-cis-retinal, 11-cis-retinol, all-trans-retinal, all- trans-retinol, N-retinylidene phosphotidylethanolamine (NRPE), N-retinylidene-N- retinylethanolamine (A2E), and the like.

[0096] Embodiments of the invention further include single unit dosage forms of the aliphatic aldehyde adductors described above for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intra- arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal, or transcutaneous administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

[0097] In certain example embodiments, one or more of the aldehyde adductors described herein may be included in a pharmaceutical composition that is suitable for administration by injection to the eye. Such compositions may be in the form of a solution, a suspension, an emulsion and may include stabilizing agents, antimicrobial agents, or other materials to improve the function ofthe one or more of the aldehyde adductors. In certain example embodiments, one or more of the one or more of the aldehyde adductors described herein are included in a dry or desiccated form of a pharmaceutical composition that can readily be formed or reconstituted into a solution suspension or emulsion suitable for administration by injection or for oral or topical use. Delivery by injection may be suitable for systemic delivery or local delivery such as injection into the eye for treating disorders relating to the eye.

[0098] The composition, shape, and type of dosage forms provided herein may vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients than an oral dosage form used to treat the same disease. See, e.g., Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

[0099] Encompassed herein are pharmaceutical compositions and dosage forms that include one or more compounds that reduce the rate by which an active ingredient decomposes. Such compounds, i.e., “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0100] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. In certain embodiments, the dosage forms provided may include one or more compounds of the invention, or pharmaceutically acceptable salts thereof, in an amount ranging from about 0.10 mg to about 2000 mg, from about 0.10 mg to about 1000 mg, from about 0.10 mg to about 500 mg, from about 0.10 mg to about 200 mg, from about 0.10 mg to about 100 mg, or from about 0.10 mg to about 50 mg. In certain embodiments, the dosage forms provided herein include one or more aliphatic aldehyde adductors, or pharmaceutically acceptable salts thereof, in an amount of about 0.1 mg, about 1 mg, about 2 mg, about 5 mg , about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, or any range or individual value encompassed by these example ranges.

[0101] In certain example embodiments, such as when the aliphatic aldehyde adductor is formulated into a pharmaceutical composition, the aliphatic aldehyde adductor is present in a range from about 0.025% to about 100% by weight of the composition. For example, the when thealiphatic aldehyde adductor is formulated into a pharmaceutical composition at 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70 %, 75%, 80%, 85%, 90%, 95%, 100% or values therebetween.

[0102] In certain example embodiments, pharmaceutical compositions suitable for oral administration may be formulated as discrete dosage forms, examples of which include, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients and may be prepared by some known methods of pharmacy. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990). Such oral dosage forms can be prepared by combining the aliphatic aldehyde adductors in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0103] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by some known methods of pharmacy. In certain embodiments, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

[0104] In certain embodiments, a tablet can be prepared by compression or molding. In certain embodiments, compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form, e.g., powder or granules, optionally mixed with an excipient. In certain embodiments, molded tablets are made by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent.

[0105] Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable foruse in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., AVICEL RC-581). Suitable anhydrous or low moisture excipients or additives include AVICEL- PH-103™ and Starch 1500 LM.

[0106] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In certain embodiments, the binder or filler in pharmaceutical compositions provided herein is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0107] Disintegrants are used in the compositions provided herein to provide tablets the ability to disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms provided herein. The amount of disintegrant used varies based upon the type of formulation. In certain embodiments, the pharmaceutical compositions provided herein comprise from about 0.5 to about 15 weight percent or from about 1 to about 5 weight percent of disintegrant.

[0108] Disintegrants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodiumstarch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0109] Lubricants that are suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, but are not limited to, a syloid silica gel (AEROSIL200, W.R. Grace Co., Baltimore, Md.), a coagulated aerosol of synthetic silica (Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide, Cabot Co. of Boston, Mass.), and mixtures thereof. In certain embodiments, if used at all, lubricants are used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

[0110] In certain embodiments, provided herein is a solid oral dosage form, comprising one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

[0111] In certain embodiments, provided herein is a solid oral dosage form, comprising one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof; and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

[0112] In certain embodiments, the aliphatic aldehyde adductors can be administered by controlled release means or by delivery devices. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference in its entirety. In certain embodiments, such dosage forms are to be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Encompassed herein are singleunit dosage forms suitable for oral administration, including, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

[0113] All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

[0114] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release the drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0115] In certain embodiments, the oral dosage form may be a liquid formulation containing the aliphatic aldehyde adductor encapsulated within a capsule or a gelatin capsule (“gelcap”). The capsule in such embodiments can be made of a substance that degrades or otherwise dissociates when exposed to conditions present in the gastro-intestinal tract of a mammal. Capsules and gelcaps are well known in drug delivery technology and one of skill could select such a capsule as appropriate for delivery of a particular active agent. Once the capsule has dissolved or dissociated from the formulation, the formulation of the invention generally remains intact, especially for hydrophobic formulations, and passes through the GI tract without emulsification or fragmentation.

[0116] In various embodiments, the capsule may include gelatin or synthetic polymers such as hydroxyethyl cellulose and hydroxypropyl methyl cellulose. Gelcaps can be of the hard or soft variety, including, for example, polysaccharide or hypromellose acetate succinate based caps (e.g., Vegicaps brand, available from Catalent). The capsule can also be coated with an enteric coatingmaterial such as AQIAT (Shin-Etsu) to delay release Gelatin capsules are well suited for delivering liquid formulations such as vitamin E and cod-liver oil. Gelatin capsules are stable in storage, but once in the acid environment of the stomach (low pH less than about pH 4-5), the gelcap dissolves over a 1-15 minute period.

[0117] Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra- arterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0118] Some suitable vehicles that can be used to provide parenteral dosage forms provided herein include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0119] Topical and mucosal dosage forms provided herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 and 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea and Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.

[0120] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed herein depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, in certain embodiments, the excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Additional examples of such ingredients can be found, for example, in Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 and 1990).

[0121] In some embodiments, the aliphatic aldehyde adductors can be micronized or nanonized by reducing the size of aggregate particles of the compounds or formulations containing the aliphatic aldehyde adductors. Particle size reduction techniques include, for example, grinding, milling, air-attrition milling, jet milling, ball milling, coacervation, complex coacervation, high pressure homogenization, spray drying and / or supercritical fluid crystallization. In some embodiments, particles can be sized by mechanical impact using, for example, a hammer mill, ball mill, pin mills, and the like. In other embodiments, particles can be sized by fluid energy using, for example, a spiral jet mill, loop jet mill, fluidized bed jet mill, and the like.

[0122] Size reduction is used to increase surface area and / or modulate formulation dissolution properties, and to maintain a consistent average particle size distribution (PSD). Micronization is a process of reducing the average diameter of particles of a solid material. Micronized particles may have an average particle diameter from micrometer-sized (1000 μm to about 0.001 μm) to nanometer-sized (1000 nm to about 0.001 nm). The average diameter of particles of micronized formulations can be less than about 100 μm, less than about 20 μm, less than about 5 μm, about 0.5 μm to about 500 μm, about 1 μm to about 200 μm, about 2 μm to about 100 μm, about 3 μm to about 50 μm, and the like or any range or individual particle diameter encompassed by these example ranges. The average diameter of particles of nanonized formulations can be less than about 100 nm, less than about 20 nm, less than about 5 nm, about 0.5 nm to about 500 nm, about 1 nm to about 200 nm, about 2 nm to about 100 nm, about 3 nm to about 50 nm, and the like or any range or individual particle diameter encompassed by these example ranges. In some embodiments, the formulations may include a combination of particle sizes, for example, micronized particles, nano-sized particles, colloidal particles.

[0123] In some embodiments, the particles may be coated to produce coated microparticles, nanoparticles, microsphere, liposomal particles, crystalline particles, isotropic particles, amorphous particles, anisotropic particles, and the like.

[0124] In certain example embodiments, the compounds or compositions provided herein are preferably formulated into a pharmaceutical composition for ophthalmic administration, such as a topical eye solution (e.g., eye drop), ointment, or gel. For example, the pharmaceuticalcomposition can include one or more of the aldehyde adductors described herein that is formulated into a topical liquid aqueous solution, an emulsion, a suspension, an ointment, or the like that are commonly applied to the surface of the eye. Additional formulations for topical delivery of the compounds can include, for example, nanomicelles, nanoparticles, nanosuspensions, liposomes, dendrimers, in-situ gelling systems, and the like, such as is described in Ocular drug delivery systems: an overview; World J Pharmacol.2013; 2(2): 47–64, which is hereby incorporated herein in its entirety. Additional conventional ophthalmic formulations and components are described in in Int’l Pat. Pub. No. WO2020087021A1, which is also incorporated herein in its entirety.

[0125] In certain example embodiments, compositions including one or more of the aldehyde adductors described herein for delivery to the eye may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, oil-in-water emulsions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, or elixirs. Such compositions may contain excipients such as bulking agents, solubilization agents, taste masking agents, stabilizers, coloring agents, preservatives and other agents known to those ordinarily skilled in the art of pharmaceutical formulation. Methods of Treatment

[0126] As described herein, oxidative stress plays an important role in the development of several age-related diseases, including diseases of the eye. By accelerating and increasing lipid peroxidation in the cell membrane, for example, oxidative stress results in the formation of aldehydes and aldehyde containing compounds that are particularly toxic to the cellular environment. Without being bound by any particular theory, it is thus believed that therapeutic administration of one or more of the aliphatic aldehyde adductors described herein forms adducts in the subject with such aldehyde containing compounds, thereby reducing the reactivity of such aldehyde containing compounds. This in turn is believed to reduce the ability of the aldehyde containing compounds to deleteriously react with proteins, lipids, and DNA.

[0127] Accordingly, provided herein are therapeutic methods of treating a subject having an oxidative disease or conditions, the method including administering to the subject one or more of the one or more of the aldehyde adductors described herein. Such diseases or conditions include, for example, those in which reactive aldehydes either disrupt, or are believed to disrupt or adversely impact, cellular processes such apoptosis, cell division, inflammation, mutation, drug transport, cellular integrity, membrane potential, neurodegeneration, cell-cell interactions,immune cell activation, and / or innate immunity. In certain example embodiments, the disease or conditions includes asthma, COPD, cancer, diabetes, ophthalmic diseases such as diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa, metabolic syndromes, renal diseases such as polycystic kidney disease, chronic kidney disease, and diabetic nephropathy, infectious diseases such as influenza, COVID-19, ventilator associated pneumonia, autoimmune diseases such as lupus, systemic lupus erythematosus, RA, atherosclerosis, cardiovascular disease, sepsis, liver diseases such as alcoholic liver disease, and non-alcoholic fatty liver disease, ageing, and neurologic diseases such as Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease, neuropathic pain, and the like.

[0128] In certain example embodiments, provided is a method for treating a disease or condition of the eye, such as a disease or condition in which oxidative stress causes or contributes to -- or is believed to cause or contribute to -- the condition or disorder. The methods include, for example, administering to the subject an effective amount of one or more of the aldehyde adductors described herein or a pharmaceutical composition thereof. In certain example embodiments, provided is a method of treating or inhibiting progression of an oxidative eye disease or condition, such as an oxidative retinal disease or condition, the method including administering to the subject an effective amount of one or more of the aldehyde adductors described herein or a pharmaceutical composition thereof.

[0129] Examples of eye disorders or conditions include, for example and without limitation, glaucoma, macular degeneration, diabetic retinopathy, hereditary retinal degeneration, Leber’s Congenital Amourosis, Stargardt’s Disease, Keratoconus, age-related macular degeneration (e.g., non-exudative age-related macular degeneration, exudative (wet) AMD), macular edema, ocular rosacea, amblyopia, cataracts, dry eye, iritis, photoreceptor degeneration, retinitis pigmentosa, retrobulbar optic neuritis, loss of conjunctival cells, loss of lacrimal gland cells, central or branch retinal artery occlusions, ocular hypertension, ocular inflammation; neurodegenerative disorders of the retina and optic nerve head, and uveitis. Neurodegenerative disorders of the retina and optic nerve head include, for example, atrophic macular degeneration; retinitis pigmentosa; iatrogenic retinopathy; retinal tears and holes; diabetic retinopathy; sickle cell retinopathy; retinal vein and artery occlusion; and optic neuropathy.

[0130] In certain example embodiments, provided is a method for treating an eye of a subject wherein its normal condition of the eye has been disrupted or changed, the method includingadministering to the subject an effective amount of one or more of the aldehyde adductors described herein or a pharmaceutical composition thereof. For example, one or more of the aldehyde adductors described herein or a pharmaceutical composition thereof may be administered to the subject, thereby improving the condition of the eye and / or returning the eye to a healthy or stable physiological state.

[0131] In certain example embodiments, the aliphatic aldehyde adductor administered to the subject includes one or more compounds of Formula I, the compounds of Formula II, the compounds of Formula III, the compounds of Formula IV, the compounds of Formula V, the compounds of Formula VI, the compounds of Formula VII, or combinations thereof. In certain example embodiments, the aliphatic aldehyde adductor administered to the subject preferably includes one or more of the compounds of formulas VI or VII. Further, any of the aldehyde adductors, including those of formulas VI or VII, can be formulated into a pharmaceutical formulation, such as an ocular formulation for topical administration to the eye as described herein. Additionally or alternatively, the aldehyde adductors, including those of formulas VI or VII, can be formulated into a solid dosage form for oral administration as described herein.

[0132] In certain example embodiments, provided is a method for targeting a reactive aldehyde species in a subject, the method comprising administering to the subject one or more of the aldehyde adductors described herein. For example, the subject may have, or be suspected of having, a pathological level of one or more aldehydes present in the eye, such as of 4- hydroxynonenal (4HNE), 4-hydroxyalkenals, such as 4-hydroxy- 2E-hexenal (4-HHE), 4- hydroxy-2E-nonenal (4HNE), 2-hydroperoxyeicosa- tetraenoic acid (12-HpETE), 12- hydroxyeicostetrae- noic acid (12-HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, and the like and combinations thereof. Administration of one of more of the aldehyde adductors described herein to the subject thus targets the reactive aldehyde species, thereby treating the subject.

[0133] In certain example embodiments, administering an effective amount of an aliphatic aldehyde adductor to a subject includes administering a dosage of about 0.10 mg to about 2000 mg, from about 0.10 mg to about 1000 mg, from about 0.10 mg to about 500 mg, from about 0.10 mg to about 200 mg, from about 0.10 mg to about 100 mg, or from about 0.10 mg to about 50 mg, about 10 mg to about 600 mg, about 50 mg to about 500 mg, about 0.1 mg, about 1 mg, about 2 mg, about 5 mg , about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about20 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 500 mg, or any range or individual value encompassed by these example ranges. In certain example embodiments, administering an effective amount of an aliphatic aldehyde adductor to a subject includes administering a dosage of about 0.10 mg to about 1,000 mg per kg of body weight of the subject, such as about 0.1 mg, about 1 mg, about 2 mg, about 5 mg , about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg per kg, about 250 mg per kg, about 300 mg per kg, about 350 mg per kg, about 400 mg per kg, about 450 mg per kg, about 500 mg per kg, 550 mg per kg, 600 mg per kg, 650 mg per kg, 700 mg per kg, 750 mg per kg, 800 mg per kg, 850 mg per kg, 900 mg per kg, 950 mg per kg, 1,000 mg per kg of body weight of the subject, or any range or individual value encompassed by these example ranges. Depending on the dosage form and amount of the aliphatic aldehyde adductor, the dosage may include one or more dosage forms, for example two 50 mg oral dosage forms may be administered to the subject for a total dosage.

[0134] Administering can be carried out by any conventional means, including, for example, tablets, caplets, capsules, such as soft elastic gelatin capsules, cachets, troches, lozenges, dispersions, suppositories, powders, aerosols (e.g., nasal sprays or inhalers), gels, liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs, liquid dosage forms suitable for parenteral administration to a patient, eye drops or other ophthalmic preparations suitable for topical administration, and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to subject. In some embodiments, the methods may include repeating administering 1, 2, 3, 4, or 5 times per day for 1, 2, 3, 4, 5, 6, or more days, weeks, months, or years.

[0135] The compositions of various embodiments may be administered at a dosage and for a duration that produces controlled plasma levels of an aliphatic aldehyde adductor over a particular period. In some embodiments, the plasma level may be within an appropriate therapeutic range. An appropriate therapeutic range will vary depending on the subject and the specific compound and formulation administered and can range from femtogram / mL to above microgram / mL for a desired period of time. For example, a single dose of a dosage form described above may result in plasma levels of greater than 5 ng / mL for a period of greater than 8 hours. In other embodiments,the plasma level achieved using a single dose may be greater than 5 ng / mL for a period of greater than 10 hours, greater than 12 hours, greater than 14 hours, greater than 16 hours, greater than 18 hours, or greater than 20 hours. In yet other embodiments, the plasma level achieved using a single dose may be greater than 5 ng / mL, greater than 10 ng / mL, greater than 15 ng / mL, greater than 20 ng / mL, greater than 30 ng / mL, greater than 40 ng / mL, or greater than 50 ng / mL for a period of 4, 8, 10, 12, 14, 16, 18, 20 or 24 hours. The maximum plasma concentration of an active agent may be reached at a time following administration from between 0.1 hr to about 24 hr, or from about 0.25 hr to 10 hr, or from about 0.25 hr to 8 hr, or from about 0.5 hr to 6 hr, or from about 0.5 hr to 4 hr, or from about 0.5 hr to 2 hr, or from about 0.5 hr to 1 hr. The time to maximum plasma concentration may be adjusted by adjusting various components of the controlled release carrier system as taught herein.

[0136] The pharmaceutical compositions described herein may be included in a kit, pack, or dispenser, referred to collectively herein as a “kit,” optionally with instructions for administrations of such pharmaceutical compositions. In some embodiments, a kit may include a pharmaceutical composition comprising an aliphatic aldehyde adduct. EXAMPLES

[0137] The compositions and methods are further supported by the information provided in the following Examples. It is to be understood that the embodiments described in the Examples are merely illustrative and are not intended to limit the scope of the present disclosure, which will be limited only by the appended claims.

[0138] As used herein, the following abbreviations apply: eq (equivalents); M (Molar); µM (micromolar); N (Normal); mol (moles); mmol (millimoles); µmol (micromoles); nmol (nanomoles); g (grams); mg (milligrams); kg (kilograms); µg (micrograms); L (liters); ml (milliliters); µl (microliters); cm (centimeters); mm (millimeters); µm (micrometers); nm (nanometers); °C. (degrees Centigrade); h (hours); min (minutes); sec (seconds); msec (milliseconds).Example 1 -- Effect of REN-101 on Retinal Pigment Epithelial Cell Viability

[0139] In this example, retinal pigment epithelial cell (ARPE-19) viability was examined to determine if there is potential cytotoxicity following treatment with REN-101 in addition to determination of the LC50of REN-101.

[0140] For ARPE-19 cell treatment, REN-101 was formulated in 0.9% NaCl. To determine the potential cytotoxicity of REN-101 in ARPE-19 cells, ARPE-19 cells were cultured according to manufacturer’s guidelines (DMEM / F12 with 10% FBS in a humidified incubator at 37 °C in 5% CO2, supplemented with 100 U mL−1 penicillin and 100 µg mL−1 streptomycin). In T75 flasks, cells were propagated and at 90% confluency, were detached using 0.05% (w / v) Trypsin-0.53 mM EDTA, quenched with complete growth media, and centrifuged at 125G for 8 minutes with the supernatant discarded. Cells were then resuspended in complete growth media and sub cultivated at 1:4 ratio in a T75 flask. Cells were sub-cultured every 2-3 days. Only cells between passages 3- 7 were utilized for the experiments.

[0141] At passage 3-7, ARPE-19 cells were seeded into a 96-well plate in triplicate and cultivated with serum (10% FBS) containing DMEM / F12 until 80% confluent. After 24 hours, the ARPE-19 cells were washed with PBS and cultivated under serum free media (DMEM / F2) for another 24 hours. The cells were subsequently treated with REN-101 at eight ½ log concentrations ranging from 10-6to 100 mM. After 24 hours, cell viability was assessed via Alamar blue assay and the data was reported as % cell viability. A total of 3 separate experimental well plates were analyzed, each with 3 replicates per sample for a total of 9 replicates per sample across all experiments. The experimental design is illustrated as follows:

[0142] Cell viaagent (ThermoFisher ScientificTM) according to the manufactures protocol via measurement of resorufin fluorescence. The fluorescent signal of resorufin was quantified using a FLUOstar Omega Microplate Reader at a fluorescence excitation wavelength of 540 nm and an emission wavelength of 590nm. As shown in FIG. 1, REN-101 was non-toxic from 10-5to 101mM and was cytotoxic at 102mM. The LC50 of REN-101 on ARPE-19 Cells was determined to be 52.9 mM.

[0143] Cell viability was also assessed in a buffered REN-101 solution to determine if the observed cytotoxicity following treatment with REN-101 at 102mM, as seen in example 1, was due to acidity induced cytotoxicity versus REN-101 toxicity.

[0144] For ARPE-19 cell treatment, REN-101 was formulated by creating a stock of 200 mM (2376 µl) REN-101 and neutralizing the stock to the same pH as the control media using 1M NaOH (500µl) creating a new stock concentration of 165.22 mM. Subsequent dilutions of REN-101 (10-6to 100 mM) were made from the neutralised stock. To determine the potential cytotoxicity of REN-101 in ARPE-19 cells, ARPE-19 cells were cultured according to manufacturer’s guidelines (DMEM / F12 with 10% FBS in a humidified incubator at 37 °C in 5% CO2, supplemented with 100 U mL−1 penicillin and 100 µg mL−1 streptomycin). In T75 flasks, cells were propagated and at 90% confluency, were detached using 0.05% (w / v) Trypsin-0.53 mM EDTA, quenched with complete growth media and centrifuged at 125G for 8 minutes with the supernatant discarded. Cells were then resuspended in complete growth media and sub cultivated at 1:4 ratio in a T75 flask. Cells were sub-cultured every 2-3 days. Only cells between passages 3-7 were utilized for the experiments.

[0145] At passage 3-7, ARPE-19 cells were seeded into a 96-well plate in triplicate and cultivated with serum (10% FBS) containing DMEM / F12 until 80% confluent. After 24 hours, the ARPE-19 cells were washed with PBS and cultivated under serum free media (DMEM / F2) for another 24 hours. The cells were subsequently treated with REN-101 at eight ½ log concentrations ranging from 10-6to 100 mM. After 24 hours, cell viability was assessed via Alamar blue assay and the data was reported as % cell viability. A total of 3 separate experimental well plates were analyzed, each with 3 replicates per sample for a total of 9 replicates per sample across all experiments. The experimental design is illustrated as follows:

[0146] Cell viay as easu e us g a a a ue e a y eagent (ThermoFisher ScientificTM) according to the manufactures protocol via measurement of resorufin fluorescence. The fluorescent signal of resorufin was quantified using a FLUOstar Omega Microplate Reader ata fluorescence excitation wavelength of 540 nm and an emission wavelength of 590nm. As shown in FIG. 2, neutralisation of REN-101 solution above 10 mM reduced but does not fully attenuate acidity-induced cytotoxicity in ARPE-19 cells. One-way ANOVA: Comparison to untreated control. N=3: Where N = 3 independent experimental repeats (different cell passage) ***P<0.001. Example 2 -- REN-101 Attenuation of 4HNE-induced and H202-Induced Insult

[0147] In this example, the effects of REN-101 treatment on retinal pigment epithelial cell (ARPE-19) viability was examined in response to insults with either 4-Hydroxy-nonenal (4HNE) or H2O2.

[0148] More particularly, to determine the effect of REN-101 on ARPE-19 viability following 4HNE insult cells were cultured as described in Example 1. At passage 3-7, ARPE-19 cells were seeded into a 96-well plate in triplicate and cultivated with serum (10% FBS) containing DMEM / F12 until 80% confluent for 24 hours. The ARPE-19 cells were then washed with PBS and subsequently pre-treated with REN-101 and positive controls Glutathione and Ascorbic acid at the concentrations shown in Table 1, all under serum free media (DMEM / F12). Table 1 -- Reagent Concentrations (4HNE insult and cell viability) Reagent Concentrationg control was included as well. The oxidative insult (4HNE) was added to the appropriate wells 3 hours following pre-treatment. After 24 hours, cell viability was assessed via Alamar blue assay and the data was reported as % cell viability. A total of 3 separate experimental well plates were analyzed, each with 3 replicates per sample for a total of 9 replicates per sample across all experiments. Cell viability was then assessed as described in Example 1, i.e., via the use of alamarBlueTMCell Viability Reagent (ThermoFisher ScientificTM). The experimental design is illustrated as follows:

[0150] To detering H2O2 insult, cells were cultured as described in Example 1. At passage 3-7, ARPE-19 cells were seeded into a 96- well plate in triplicate and cultivated with serum (10% FBS) containing DMEM / F12 until 80% confluent. After 24 hours, the ARPE-19 cells were washed and subsequently cultivated with serum free media (DMEM / F12) along with pre-treatments of either REN-101, Glutathione or Ascorbic acid at the concentrations shown in Table 2. Table 2 -- Reagent Concentrations (H2O2insult and cell viability) Reagent Concentration 12 3 4 5 6l was included as well. The oxidative insult (H2O2) and co-treatment of compounds were added to the appropriate wells 24 hours following pre-treatment. 2 hours later, H2O2containing media was removed and replenished with treatment compounds for a further 24 hours. Cell viability was assessed and the data were reported as % cell viability. A total of 3 separate experimental well plates were analyzed, each with 3 replicates per sample for a total of 9 replicates per sample across all experiments. The experimental design is illustrated as follows:

[0152] As shown in FIGS. 3-4, positive controls attenuated 4HNE-induced cell death (FIG. 3) and H2O2-induced cell death (FIG. 4) compared to 4HNE alone and H2O2 alone, respectively. Further, REN-101 at 10 mM to 10-6mM attenuated 4HNE-induced cell death (with no significant difference between doses) (FIG. 3). Likewise, REN-101 at 10 mM to 10-6mM attenuated H2O2- induced cell death (FIG. 4) (again at no significant difference between dosages). Thus, the REN- 101 imparts a protective effect on retinal pigment epithelial cell viability following insult with LC50doses of 4HNE and H2O2. Example 3 -- REN-101 Attenuation of 4HNE-Induced and H202-Induced Oxidative Stress

[0153] In this example, the effect of REN-101 on mitigation of either 4HNE-induced or H202- induced oxidative stress was examined.

[0154] Briefly, for 4HNE assessment, at passage 3-17, ARPE-19 cells were seeded into 96-well plates at optimised density in triplicate and cultivated with serum-containing DMEM / F12 until 70% confluent. ARPE-19 cells were pre-treated with eight 1∕2 log concentrations of REN-101 and efficacious concentrations of two antioxidants (glutathione and ascorbic acid) and ARPE-19 control cells that received no chemical insults or treatments. ARPE-19 cells were challenged with the 4-HNE concentrations and conditions outlined in Table 3. Table 3 -- Reagent Concentrations (4HNE insult and oxidative stress) Reagent Concentrationing a CellRoxTMkit (ThermoFisher ScientificTM), according to manufacturer's protocol. Fluorescence was measured using a FLUOstar Omega Microplate Reader and the fluorescence signal was captured using a Nikon 6D Live Cell Imaging inverted Microscope. The data is presented as the number of CellROX+ cells / mm2, where a cell was positive for CellROX if it was over the global set threshold for fluorescence intensity. The peak emission of the CellRox Green assay is ~514nm. The experimental design is illustrated as follows:

[0156] For H2O2 assessment, at passage 5-10 ARPE-19 cells were similarly seeded into 96-well plates at optimised density in triplicate and cultivated with serum-containing DMEM / F12 until 70% confluent. ARPE-19 cells were pre-treated with eight 1∕2 log concentrations of REN-101 and efficacious concentrations of two antioxidants (glutathione and ascorbic acid) and ARPE-19 control cells that received no chemical insults or treatments. ARPE-19 cells were challenged with the H2O2 concentrations and conditions outlined in Table 4. Table 4 -- Reagent Concentrations (H2O2insult and oxidative stress) Reagent Concentrationng a CellRoxTMkit (ThermoFisher ScientificTM), according to manufacturer's protocol. Fluorescence was measured using a FLUOstar Omega Microplate Reader. The data is presented as fluorescence intensity. The experimental design is illustrated as follows:

[0158] As shown in FIG. 5, REN-101 improved levels of oxidative stress vs. non-treated cells at all concentrations from 10 mM to 10-6mM. REN-101 concentrations at 10-1mM and 10-4mM were the most effective at reducing oxidative stress due to 4HNE (FIG. 5). As shown in FIG. 6, REN-101 improved levels of oxidative stress vs. non-treated cells at all concentrations from 10 mM to 10-6mM. REN-101 concentrations at 10-1mM and 10-3mM were the most effective at reducing oxidative stress due to H2O2 (FIG. 6). Example 4 -- REN-101 Attenuation of H202-Induced Mitochondrial Superoxide Production

[0159] In this example, the effect of REN-101 on mitigation of H202-induced mitochondrial superoxide was examined.

[0160] At passage 5-7 ARPE-19 cells were seeded into 96-well plates at optimised density in triplicate and cultivated with serum-containing DMEM / F12 until 80% confluent. After 24 hours, the ARPE-19 cells were washed and subsequently cultivated with serum free media (DMEM / F12) along with pre-treatments of either REN-101 or Glutathione at the concentrations shown in Table 5. An untreated (no H2O2or treatment) negative control was also included. The oxidative insult (H2O2) and co-treatment of compounds were added to the appropriate wells 24 hours following pre-treatment. 2 hours later, H2O2 containing media was removed and replenished with treatment compounds for a further 24 hours. Table 5 -- Reagent Concentrations (H2O2 insult and MitoSOXTM) Reagent Concentration[ ] e m oc on r a superox e was measure us ng a MitoSOXTMkit (ThermoFisher ScientificTM), according to manufacturer's protocol. The fluorescence signal was captured using a Nikon 6D Live Cell Imaging Inverted Microscope. Image analysis was performed using ImageJ where integrated density was calculated by multiplying the average fluorescence intensity given off by MSR, with the area of positive MSR staining in the field of view (FOV). Integrated density values positively correlate to the superoxide concentration in cells. The final data output is the fold change in integrated density from untreated control following insult with H2O2. A total of 3separate experimental well plates were analyzed, each with 3 replicates per sample for a total of 9 replicates per sample across all experiments. The experimental design is illustrated as follows:

[0162] A oxide vs. non-treated cells at all concentrations from 10 mM to 10-6mM. Example 5 -- In Vivo Pharmacokinetics / Toxicodynamics (PK / TD)

[0163] In this example pharmacokinetics / toxicodynamics (PK / TD) data for REN-101 for plasma, brain, and eye samples was examined. Briefly, male CD-1 mice were fed a standard laboratory rodent diet and housed in individual cages on a 12-hour light and 12-hour dark cycle with room temperature maintained at 22 ± 30C and relative humidity at 50 ± 20%. Animals fasted overnight before dosing, with food returned after the 6-hour blood samples were obtained. Water was provided ad libitum throughout the study.

[0164] The dosing solution of each test compound was prepared in normal saline (0.9% NaCl in water). Nine animals (3 animals at each time point) were dosed via gavage needle for oral administration at 30 mg / kg (30 mL / kg). All blood samples (55-60 µL per sample) were taken via appropriate vein (saphenous or submandibular vein) along with brain and eye samples at 0.5, 2 and 6 h post dose. Blood samples were collected in Greiner MiniCollect K2EDTA tubes, placed on ice, and within 30 minutes, centrifuged at 15,000g for 5 min to obtain plasma samples. All plasma samples were stored at –700C until analysis. The whole brain and eye were harvested at selected time points, immediately rinsed in water briefly, and blotted dry with a paper towel. The whole brain and both eyes from each animal were weighed and three volumes of PBS buffer (pH 7.4) was added to one volume of each tissue sample which was homogenized by a tissue homogenizer until fine tissue particles were completely dispersed or emulsified. The tissue homogenate samples were stored at –700C until analysis.

[0165] For PK / TD analysis, plasma samples were prepared as follows. Three volumes of acetonitrile containing internal standard was added to one volume of plasma toprecipitate proteins. Samples were centrifuged (3000 g for 10 min) and supernatant removed for analysis by LC- MS / MS. Calibration standards and quality controls were made by preparation of a 1 mg / mL stock solution and subsequently a series of working solutions in methanol:water (1:1, v / v) which were spiked into blank plasma to yield a series of calibration standard samples in the range of 1 ng / mL to 10 µg / mL and quality control samples at three concentration levels (low, middle and high). All incurred PK / PD plasma samples were treated identically to the calibration standards and quality control samples. LC-MS / MS analysis was performed using multiple reaction monitoring for detection of characteristic ions for each drug candidate, additional related analytes and internal standard.

[0166] For the tissue samples, volumes of PBS buffer (pH 7.4) were added to one volume of each tissue sample which was then homogenized to obtain each tissue homogenate sample. Subsequently, three volumes of acetonitrile containing internal standard was added to one volume of each tissue homogenate, and the mixture was vortexed, centrifuged (3000 g for 10 min) and supernatant removed for analysis by LC- MS / MS. Calibration standards were made by preparation of a 1 mg / mL stock solution and subsequently a series of working solutions in methanol:water (1:1, v / v) which were spiked into blank tissue homogenate to yield a series of calibration standard samples in the range of 1 ng / mL to 10 µg / mL. All incurred PK / PD tissue samples were treated identically to the calibration standards. LC-MS / MS analysis was performed utilizing multiple reaction monitoring for detection of characteristic ions for each drug candidate, additional related analytes and internal standard.

[0167] Following oral administration of REN-101 at 30 mg / kg to mice, results showed that the compound is a moderate‐to‐high brain penetrant with its brain‐to‐plasma concentration ratios of 0.807 to 0.929 (Table 6). The compound also highly distributed to the eyes with its eye‐to‐plasma concentration ratios ranging from 1.62 to 1.95 (Table 6).Table 6 -- Plasma and tissue PF / TD data following animal treatment with REN-101.

[0168] This example provided results from a study assessing retinal function via Optical Coherence Tomography (OCT) in Rd10 mice following oral treatment of Ren-101. The Retinal degeneration 10 (rd10, B6.CXB1-Pde6brd10 / J) mouse model is a spontaneous missense point mutation in Pde6b (cGMP phosphodiesterase 6B, rod receptor, beta polypeptide). Pde6b encodes the beta subunit of phosphodiesterase (PDE), a peripheral membrane enzyme involved in the phototransduction cascade in rod photoreceptors. Mutations in PDE are associated with retinitis pigmentosa and night blindness. Mice homozygous for retinal degeneration 10 (rd10) exhibit sclerotic retinal vessels at 4 weeks of age, progressive retinal outer nuclear layer degeneration beginning at 16 days, and a progressive decline in rod and cone ERG a- and b- waves.

[0169] A total of 16 mice (12 x PDE6brd10- / -and 4 x C57BL / 6) aged 14 days were included in the study. See Table 7 for the study design and dosing regimen. Random allocation of same sexed animals to treatment groups was carried out using GraphPad. Sample size was calculated using power analysis. For calculating Rd10 sample size, study parameters (mean and standard deviation) were taken from previous OCT responses (photoreceptor layer thickness) and recorded in a retinal neurodegeneration model where photoreceptors were ablated by 60% to the control (similar to the effects of Rd10 retinal thinning via OCT). For calculating wild type (WT) sample size, study parameters were taken from the WT group in the same model. Rd10 mice were randomized into control or treatment groups at Day 13. The study was blinded to the OCT and ERG assessor. Dosing solutions of Ren-101 and Metformin were prepared at 10mg / mL in 0.9% NaCl. Route of administration was via oral gavage.

[0170] A Spectralis Heidelberg OCT system (Heidelberg Engineering, Heidelberg, Germany), was utilized. OCT assessments were taken at inferior, superior, nasal and temporal orientationsfrom the optic disc on day 20. Measurements were averaged from 500, 1000, 1500 and 2000 μm eccentricities and total neuroretina (mm) and photoreceptor layer thickness was quantified.

[0171] ERG was performed using a Diagnosys Espion system (Diagnosys Technologies, MA, USA) in compliance with the manufacturer’s guidelines. Mice were dark-adapted overnight, with procedures conducted under dim-red light (< 1 lx). Mice were anaesthetized with ketamine (Vetoquinol UK Ltd) and Rompun (Bayer Health Care) after pupil dilation with Atropine Sulfate and Phenylephrine Hydrochloride (Minims). Eyes were moisturized and prevented from drying out via application of Viscotears Liquid Gel (Bausch + Lomb). Scotopic ERG were recorded via mouse corneal ERG electrodes in response to a single white light flash produced by the Diagnosys Espion ERG system. For each animal, 8 light intensities ranging from 0.008 to 25 cds / m2 were applied. A-wave and B-wave amplitudes were subsequently measured using the Espion analysis software (Diagnosys Technologies, USA). Table 7 -- rd10 Retinitis Pigmentosa Mouse Model Study Design Group N Strain Treatment Dose Dosing Dosing Analyses route schedule T T T T T

[0172] As shown in Figures 8 and 9, in the Photoreceptor layer SD-OCT, the 500 and 1000 mg / kg Ren-101 treated rd10 mice exhibited significantly reduced deterioration of rods and cones versus untreated rd10 animals. The 1000 mg / kg Ren-101 treated rd10 animals had a p-value of <0.05 at 1.5 mm and 2.0 mm from the fovea, versus vehicle. The 500mg / kg Ren-101 treated mice exhibited a p-value of 0.01 versus vehicle at all four positions from the fovea. Administration of Ren-101 at doses of 500 mg / kg and 1000 mg / kg surprisingly resulted in preservation of retinal cellstructures compared to vehicle treated animals with the 500 mg / kg dose showing superior retinal preservation over the positive control, 500 mg / kg metformin. The marked improvement in retinal preservation of Ren-101 compared to the known compound metformin underscores the efficacy of Ren-101. Example 6 -- Ren-101, 100 mg / kg, Treated Mice Maintained Visual Function in ABCA4 Mice for 24 Weeks

[0173] This example provides results from a study assessing visual function via optokinetic tracking response (OKT) analysis in ABCA4 mice following treatment with Ren-101. The ABCA4 (Abca4tm1Ght / J) mouse model is widely used to study Stargardt disease and related retinal degenerative conditions. This model was generated by deleting the protein-coding sequence of the Abca4 gene, which encodes a critical transmembrane transporter protein in photoreceptor cells. The absence of functional ABCA4 protein disrupts the clearance of all-trans-retinal from photoreceptor outer segments, leading to the accumulation of toxic bisretinoid compounds such as A2E in the retinal pigment epithelium (RPE). This results in lipofuscin buildup, RPE degeneration, and progressive photoreceptor cell loss, mimicking key pathological features of Stargardt disease.

[0174] A total of 30 mice (24 x ABCA4 and 6 x 129S1 / svlmJ wild type controls) aged 14 days were included in the study. See Table 8 for the study design and dosing regimen. Random allocation of same sexed animals to treatment groups was carried out using GraphPad. Sample size was calculated using power analysis and the study was blinded to the assessor.

[0175] Dosing solutions of Ren-101 and Metformin were prepared at 10mg / mL in 0.9% NaCl. Route of administration was via oral gavage. Table 8 – ABCA4 Stargardt Mouse Model Study Design Group N Strain Treatment Dose Dosing Dosing Analyses 1 1 1and 24 weeks) 1 1, , , ice consistently maintained their visual function at 24 weeks with no decline from the 9-week baseline, demonstrating sustained effectiveness in preserving sight. ABCA4 mice treated with only vehicle had ~20% reduction in visual function when comparing 24 weeks to 9 weeks. In a surprising and unexpected result, administration of Ren-101 at a dose of 100 mg / kg resulted in 99.8% preservation of visual function relative to vehicle-treated animals. This effect demonstrated superior efficacy compared to the positive control, metformin, which, even at a higher dose of 500 mg / kg, exhibited only 95.1% preservation of visual function. The surprising and unexpected improvement in visual function preservation at a lower dose of Ren-101 compared to a higher dose of the known compound metformin demonstrates the efficacy and improved benefit of Ren-101.

Claims

Claims We claim:

1. A method for treating an ophthalmic disease in a subject, the method comprising administering to the subject an aliphatic aldehyde adductor, wherein the aliphatic aldehyde adductor comprises any one or more of the compounds of Formulas I-VII or pharmaceutically acceptable salts thereof: (I)R1and R2are each, individually, hydrogen, —(C1-C8)alkyl, —(C1-C8)alkenyl, —(C1-C8)alkynyl, substituted or unsubstituted -ara(C1-C6)alkyl, substituted or unsubstituted -(C1-C6)heteroarylalkyl, where the substituents can be selected from the group consisting of halogen, —CN, —NO2, — NH2, —NH(C1-C6)alkyl, —N[(C1-C6)alkyl)]2, —OH, (C1-C6)haloalkyl, —(C1-C6)alkoxy, (C1- C6)haloalkoxy, —SH, (C1-C6)thioalkyl, —SONH2, —SO2NH2, —SO—(C1-C6)alkyl, —SO2— (C1-C6)alkyl, —NHSO2(C1-C6)alkyl, or —NHSO2NH2; R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14are each, independently, hydrogen, —OH, or —(C1-C6)alkyl; m and p are each, individually, 1, 2, 3 or 4; and n, o, q, and r are each individually, 0, 1, 2, 3 or 4; (II)each R3, each R4, each R9, and each R10is independently hydrogen and —(C1-C8)alkyl, and in some embodiments, R3, R4, R9, and R10are each hydrogen; R1and R2are each independently hydrogen and —(C1-C8) alkyl; and o and p are each individually an integer from 1 to about 10;(III) whereineach m, n, o, p are, an each s and t are, independently, 0 or an integer of 1 to about 10; and y and z may each, independently, an integer of 1 to about 10; (IV) whereineach n and o are, independently, an integer of 1 to about 10; each s is independently, an integer of 1 to about 10; and y may be an integer of 1 to about 10; (V)each n and o are, independently, an integer of 1 to about 10; each s is independently, an integer of 1 to about 10; and y may be an integer of 1 to about 10; (VI)(VII) .

2. The method of claim 1, wherein the aliphatic aldehyde adductor comprises the compound of Formula VI or VII.

3. The method of claim 1, wherein the aliphatic aldehyde adductor is selected from the group consisting of 2-amino-6-((3-aminopropyl)amino)hexanoic acid, (S)-2-amino-6-((3- aminopropyl)amino)hexanoic acid, 2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride, (S)-2-amino-6-((3-aminopropyl)amino)hexanoic acid dihydrochloride, 2-amino- 5-((6-aminohexyl)amino)pentanoic acid, (S)-2-amino-5-((6-aminohexyl)amino)pentanoic acid, 2- amino-5-((6-aminohexyl)amino)pentanoic acid trihydrochloride, (S)-2-amino-5-((6- aminohexyl)amino)pentanoic acid trihydrochloride, 2-amino-5-((5-aminopentyl)amino)pentanoic acid, (S)-2-amino-5-((5-aminopentyl)amino)pentanoic acid, 2-amino-5-((5- aminopentyl)amino)pentanoic acid trihydrochloride, and (S)-2-amino-5-((5- aminopentyl)amino)pentanoic acid trihydrochloride.

4. The method of claim 1, wherein the ophthalmic disease is glaucoma, macular degeneration, diabetic retinopathy, hereditary retinal degeneration, age-related macular degeneration, non-exudative age-related macular degeneration, exudative (wet) AMD, macular edema, ocular rosacea, amblyopia, cataracts, dry eye, iritis, photoreceptor degeneration, retinitis pigmentosa, Stargardt disease, Leber Congenital Amaurosis, keratoconus, retrobulbar optic neuritis, loss of conjunctival cells, loss of lacrimal gland cells, central or branch retinal artery occlusions, ocular hypertension, ocular inflammation; neurodegenerative disorders of the retina and optic nerve head, uveitis, or a neurodegenerative disorder.

5. The method of claim 4, wherein the neurodegenerative disorder comprises atrophic macular degeneration, retinitis pigmentosa, iatrogenic retinopathy, retinal tears or holes, diabetic retinopathy, sickle cell retinopathy, retinal vein or artery occlusion, optic neuropathy, Stargardt disease, or Leber Congenital Amaurosis.

6. The method of any of claims 1-5, wherein the aldehyde adductor targets a reactive aldehyde.

7. The method of claim 6, wherein the reactive aldehyde is 4-hydroxynonenal (4HNE), 4- hydroxy-2E-hexenal (4-HHE), 2-hydroperoxyeicosa-tetraenoic acid (12-HpETE), 12- hydroxyeicostetrae-noic acid (12-HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, retinaldehydes, 11-cis retinal, all trans retinal, all trans retinal dimers, all trans retinyl esters, retinol (vitamin A1), or a combinations thereof.

8. The method of any of claims 1-7, wherein the aliphatic aldehyde adductor is formulated into a pharmaceutical composition for oral, mucosal, parenteral, topical, or transdermal delivery.

9. The method of claim 8, wherein the pharmaceutical composition is an ophthalmic solution or gel.

10. The method of claim 8, wherein the pharmaceutical composition is a solid dosage form for oral delivery.

11. The method of any of claims 1-10, wherein the aliphatic aldehyde adductor is administered to the subject at a dosage of about 10 mg to about 600 mg per kilogram body weight of the subject.

12. The method of claim 11, wherein the dosage is about 50-500 mg per kilogram body weight of the subject.

13. A method of targeting a reactive aldehyde species in a subject, the method comprising administering to the subject one or more of the aliphatic aldehyde adductors set forth in Formulas I-VII.

14. The method of claim 13, wherein the aliphatic aldehyde adductor is set forth in Formula VI or VII.

15. The method of claim 13, wherein the reactive aldehyde species is 4-hydroxynonenal (4HNE), 4-hydroxy-2E-hexenal (4-HHE), 2-hydroperoxyeicosa-tetraenoic acid (12-HpETE), 12- hydroxyeicostetrae-noic acid (12-HETE), and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), malondialdehyde (MDA), acrolein, retinaldehydes, 11-cis retinal, all trans retinal, all trans retinal dimers, all trans retinyl esters, retinol (vitamin A1), or a combinations thereof.

16. The method of any of claims 13-15, wherein the aliphatic aldehyde adductor is formulated into a pharmaceutical composition for oral, mucosal, parenteral, topical, or transdermal delivery.

17. The method of claim 16, wherein the pharmaceutical composition is an ophthalmic solution or gel.

18. The method of claim 16, wherein the pharmaceutical composition is a solid dosage form for oral delivery.

19. The method of any of claims 13-18, wherein the aliphatic aldehyde adductor is administered to the subject at a dosage of about 10 mg to about 600 mg per kilogram body weight of the subject.

20. Use of one or more of the compounds of Formulas I-VII in a medicament for treating a disease or condition of the eye.

21. The use of one or more of the compounds of claim 20, wherein the compound is set forth in Formula VI or VII.

22. The use of the compounds of any of claims 20 or 21, wherein the eye condition is glaucoma, macular degeneration, diabetic retinopathy, hereditary retinal degeneration, age-related macular degeneration, non-exudative age-related macular degeneration, exudative (wet) AMD), macular edema, ocular rosacea, amblyopia, cataracts, dry eye, iritis, photoreceptor degeneration, retinitis pigmentosa, Stargardt disease, Leber Congenital Amaurosis, keratoconus, retrobulbar optic neuritis, loss of conjunctival cells, loss of lacrimal gland cells, central or branch retinal artery occlusions, ocular hypertension, ocular inflammation; neurodegenerative disorders of the retina and optic nerve head, uveitis, or a neurodegenerative disorder.

23. A method for treating an oxidative retinal disease in a subject, comprising administering to the subject one or more of the compounds of Formulas I-VII.

24. The method of claim 22, wherein the compound is set forth in Formula VI or VII.

25. The method of claim 23 or 24, wherein the oxidative retinal disease is glaucoma, macular degeneration, diabetic retinopathy, hereditary retinal degeneration, age-related macular degeneration, non-exudative age-related macular degeneration, exudative (wet) AMD), macular edema, ocular rosacea, amblyopia, cataracts, dry eye, iritis, photoreceptor degeneration, retinitispigmentosa, Stargardt disease, Leber Congenital Amourosis, keratoconus, retrobulbar optic neuritis, loss of conjunctival cells, loss of lacrimal gland cells, central or branch retinal artery occlusions, ocular hypertension, ocular inflammation; neurodegenerative disorders of the retina and optic nerve head, uveitis, or a neurodegenerative disorder.

26. The method of any of claims 1-5, wherein the aldehyde adductor reduces the level of an all-trans-retinyl ester, 11-cis-retinal, 11-cis-retinol, all-trans-retinal, all-trans-retinol, N- retinylidene phosphotidylethanolamine (NRPE), or N-retinylidene-N-retinylethanolamine (A2E).

27. The method of claim 26, wherein the reduction occurs via nucleophilic attack.

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