Treatment of retinitis pigmentosa with n-acetylcysteine amide

Abstract

To provide novel compositions and methods for treating retinitis pigmentosa.SOLUTION: Provided herein is a method for treating retinitis pigmentosa in a human, which comprises a step of administering to the human a therapeutically effective amount of N-acetylcysteine amide (NACA). Also provided is a method for treating retinitis pigmentosa in an animal comprising a step of administering to the animal a therapeutically effective amount of NACA.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Retinitis pigmentosa (RP) is a term used for a genetically heterogeneous group of inherited retinal degenerations. Findings may be limited to the eyes, or ocular findings may be part of a syndrome, the most common of which is Usher syndrome, in which hearing loss is accompanied by retinal disease. In each disorder, the causative event is a mutation that leads to the death of rod photoreceptors, initially causing night blindness. Rods are the primary oxygen consumers in the retina, and rod loss leads to increased tissue oxygen levels in the outer retina. This activates NADPH oxidase, leading to the accumulation of superoxide radicals in the cytosol and increased production of superoxide radicals in cone mitochondria. Excess superoxide radicals overwhelm superoxide dismutases 1 and 2 (SOD1 and SOD2), triggering a chain reaction by generating other free radicals, including hydroxyl radicals and peroxynitrite, which are even more damaging than superoxide radicals. Free radicals attack proteins, lipids, and DNA, causing specific changes indicative of oxidative damage. Oxidative damage to lipids produces lipid hydroperoxides, which decompose to form 4-hydroxynonenal, malondialdehyde (MDA), and acrolein. The most common change in proteins due to oxidative damage is the formation of carbonyl adducts. By measuring these markers of oxidative damage, such as MDA or carbonyl adducts, the amount of oxidative damage occurring in tissues can be quantitatively assessed. These changes impair the function of macromolecules, and although endogenous repair mechanisms exist, they are overwhelmed by the severe oxidative stress, leading to a decline in cellular function and ultimately to apoptosis. After rods are lost from the photoreceptor layer, the severe oxidative stress in the outer retina causes the slow death of cone cells, usually beginning in the mid-periphery, where cone density is low, and then spreading to the periphery and posterior pole. The spread of cone death to the posterior pole leads to visual field constriction and ultimately to central islands of vision, the loss of which causes blindness.

[0002] Clinical signs of RP include retinal pigmentary changes characterized by "bone spicule-like pigmentation," often perivascular, narrowing of retinal vessels, and optic disc pallor. Spectral domain optical coherence tomography can demonstrate retinal thinning in areas of photoreceptor cell loss, and on segmentation, the loss is seen in the outer nuclear layer.

[0003] Visual field testing shows visual field constriction, and electroretinogram shows reduced amplitude of a- and b-waves. [Background technology]

[0004] Currently, there are no approved therapies to halt disease progression or restore vision. Therapeutic approaches are limited to slowing the degenerative process through sun protection and vitamin A supplementation, treating complications (cataracts and macular edema), and helping patients cope with the social and psychological impacts of blindness. The Argis II artificial retinal system was approved by the FDA in 2013 as an implantable device to treat adults with some forms of RP, but the device does not modify the disease; it only generates light sensations, thereby helping patients locate or locate objects and people. Based on studies in animal models described below, NACA can treat RP in vivo.

[0005] We previously discovered that the well-known thiol antioxidant, N-acetylcysteine ​​(NAC), reduces cone cell death and preserves cone function in a model of RP. N-acetyl-L-cysteine ​​(NAC) is a well-known thiol-containing antioxidant approved by the FDA as an antidote for acetaminophen poisoning. NAC has been used clinically for over 50 years for indications including mucolytic therapy for respiratory conditions resulting in excessive and / or thick mucus production, prevention of contrast-induced nephrotoxicity, treatment of cyclophosphamide-induced hemorrhagic cystitis, and symptom relief for both schizophrenia and bipolar disorder. The effectiveness of NAC is primarily due to its ability to reduce extracellular cysteine ​​to cysteine ​​and its ability as a source of sulfhydryl groups. However, its use is limited by several drawbacks, most notably its poor membrane permeability and a systemic bioavailability of less than 10% as an oral formulation. Disulfide bonds to proteins and deacetylation of NAC in the intestinal mucosa and lumen are likely the most significant factors contributing to its low oral bioavailability. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there remains a need for new compositions and methods for treating retinitis pigmentosa. [Means for solving the problem]

[0007] In one embodiment, the present invention provides a method for treating retinitis pigmentosa in an animal, comprising administering to the animal a therapeutically effective amount of N-acetylcysteine ​​amide (NACA). In one aspect, NACA is provided in or with a pharmaceutically acceptable carrier. In another aspect, NACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, intramedullary, intrathecally, intraventricularly, transdermally, subcutaneously, intraperitoneally, intranasally, enterally, topically, sublingually, or rectally. In another aspect, NACA is administered at a daily dose of about 0.5 to 150 mg / kg. In another aspect, NACE is administered two or three times daily. In another embodiment, the NACA is administered with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. In another embodiment, the dosage is 100, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In another embodiment, the dosage is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, or 7-10 grams per administration. In another embodiment, NACA is delivered orally via mini-tablets, capsules, tablets, effervescent, two-phase release, mixed release, sachets, powders, or liquids. In another embodiment, NACA is administered prophylactically to prevent retinitis pigmentosa. In another embodiment, the animal is a human.

[0008] In another embodiment, the present invention includes a method for treating retinitis pigmentosa, comprising identifying a human in need of such treatment and administering to the human a therapeutically effective amount of N-acetylcysteine ​​amide (NACA) sufficient to treat the retinitis pigmentosa. In one aspect, NACA is provided in or with a pharmaceutically acceptable carrier. In another aspect, NACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, intramedullary, intrathecally, intraventricularly, transdermally, subcutaneously, intraperitoneally, intranasally, enterally, topically, sublingually, or rectally. In another aspect, NACA is administered at a daily dose of about 0.5 to 150 mg / kg. In another aspect, NACE is administered two or three times daily. In another embodiment, NACA is combined with ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sol The NACA is administered with a second active agent selected from at least one of pentose, tartaric acid, or phosphoric acid. In another embodiment, the dosage is 100, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In another embodiment, the dosage is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 1-2, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, or 7-10 grams per administration. In another embodiment, the NACA is orally delivered via a mini-tablet, capsule, tablet, effervescent, dual-release, mixed-release, sachet, powder, or liquid formulation. In another embodiment, NACA is administered prophylactically to prevent retinitis pigmentosa. That is, the present invention relates to the following. 1. A method for the treatment of retinitis pigmentosa in a mammal, comprising administering to the mammal a therapeutically effective amount of N-acetylcysteine ​​amide (NACA); 2. The method according to claim 1, wherein the NACA is provided in or together with a pharmaceutically acceptable carrier; 3. The method of claim 1, wherein the NACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, intramedullary, intrathecally, intraventricularly, transdermally, subcutaneously, intraperitoneally, intranasally, enterally, topically, sublingually, or rectally; 4. The method according to claim 1, wherein NACA is administered at a daily dose of about 0.5 to 150 mg / Kg; 5. The method according to claim 1, wherein NACA is administered twice or three times a day. 6. The method of claim 1, wherein NACA is administered together with a second active agent. 7. The method of claim 1, wherein the NACA is administered in combination with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. 8. The method according to claim 1, wherein the dosage is 100, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. 9. The method of claim 1, wherein the NACA is delivered orally via mini-tablets, capsules, tablets, effervescent, two-stage release, mixed release, sachets, powder, or liquid. 10. The method according to claim 1, wherein NACA is administered prophylactically to prevent retinitis pigmentosa. 11. The method of claim 1, wherein a therapeutically effective amount preferably refers to the amount of a therapeutic agent that reduces at least one of night vision loss, total vision loss, and visual field loss by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more compared to untreated control subjects over a defined period selected from at least one of 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years. 12. The method according to claim 1, wherein the mammal is a human. 13. A method for the treatment of retinitis pigmentosa, comprising the steps of: Identifying a human in need of treatment for retinitis pigmentosa; and administering to the human a therapeutically effective amount of N-acetylcysteine ​​amide (NACA) sufficient to treat retinitis pigmentosa; 14. The method according to claim 13, wherein the NACA is provided in or together with a pharmaceutically acceptable carrier. 15. NACA can be used in the following ways: intraocular, subretinal, intravitreal, oral, intravenous, intramuscular, intramedullary, and subarachnoid spaces. 14. The method according to claim 13, wherein the compound is administered intravenously, intraventricularly, transdermally, subcutaneously, intraperitoneally, intranasally, enterally, topically, sublingually, or rectally. 16. The method according to claim 13, wherein NACA is administered at a daily dose of about 0.5 to 150 mg / Kg. 17. The method according to claim 13, wherein NACA is administered twice or three times a day. 18. The method of claim 13, wherein the NACA is administered in combination with a second active agent selected from at least one of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, or phosphoric acid. 19. The method according to claim 13, wherein the dosage is 100, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. 20. The method of claim 13, wherein the NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, two-stage release, mixed release, sachet, powder, or liquid formulation. 21. The method according to claim 13, wherein NACA is administered prophylactically to prevent retinitis pigmentosa. 22. The method of claim 13, wherein a therapeutically effective amount preferably refers to the amount of a therapeutic agent that reduces at least one of night vision loss, total vision loss, and visual field loss by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more compared to untreated control subjects over a defined period selected from at least one of 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years. [Brief explanation of the drawings]

[0009] For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention taken in conjunction with the accompanying drawings. [Figures 1A-1E]FIG. 1 shows that 7 mg / ml NACA provides better efficacy than 7 mg / ml NAC in protecting retinal function. [Figure 2A-2L] 1 is a photomicrograph showing that 7 mg / ml NACA provides better efficacy than 7 mg / ml NAC in protecting cone cell survival. [Figure 2M] FIG. 1 shows cone cell survival. [Figures 3A-3E] FIG. 1 shows that 7 mg / ml NACA provides better efficacy than 20 mg / ml NAC in protecting retinal function. [Figures 4A-4L] 1 is a photomicrograph showing that 7 mg / ml NACA has a better effect than 20 mg / ml NAC in protecting cone cell survival. [Figure 4M] FIG. 1 shows cone survival. DETAILED DESCRIPTION OF THE INVENTION

[0010] While the making and using of various embodiments of the invention are discussed in detail below, it should be understood that the invention provides many applicable inventive concepts that can be implemented in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not limit the scope of the invention.

[0011] Retinitis pigmentosa ("RP") comprises a large group of inherited visual disorders that cause progressive loss of photoreceptor cells in the retina, resulting in severe visual impairment and often irreversible blindness. The most common form of RP is rod-cone dystrophy, the primary symptom of which is night blindness, which This is followed by progressive loss of daytime peripheral vision and, after several decades, blindness. The general pathology is that rod photoreceptors die early, while light-insensitive morphologically altered cone photoreceptors persist longer.

[0012] N-acetyl-L-cysteine ​​amide (NACA) is also known as (R)-2-(acetylamino)-3-mercapto-propanamide, N-acetyl-L-cysteine ​​amide, or acetylcysteine ​​amide.

[0013] [ka]

[0014] N-acetylcysteine ​​amide (NACA), the amide form of N-acetyl-L-cysteine ​​(NAC), has the structure:

[0015] Currently, there are no approved therapies to halt disease progression or restore vision. Therapeutic approaches are limited to slowing the degenerative process through sun protection and vitamin A supplementation, treating complications (cataracts and macular edema), and helping patients cope with the social and psychological impacts of blindness. The Argis II artificial retinal system was approved by the FDA in 2013 as an implantable device to treat adults with severe RP, but the device does not modify the disease; it only generates light sensations, thereby helping patients locate or locate objects and people. Based on studies in animal models described below, NACA can treat RP in vivo.

[0016] Glutathione (GSH) is a tripeptide, cL-glutamyl-L-cysteinyl-glycine, found in all mammalian tissues. It has several important functions, including detoxifying electrophiles, scavenging ROS, maintaining the thiol status of proteins, and regenerating the reduced forms of vitamins C and E. Because GSH is the predominant non-protein thiol in mammalian cells, it is essential for maintaining intracellular redox balance and the essential thiol status of proteins. It is also essential for the function of several antioxidant enzymes, such as glutathione peroxidase.

[0017] Intracellular GSH levels are determined by the balance between production and loss. Production occurs through de novo synthesis and regeneration of GSH from GSSG by GSSG reductase. Generally, the GSSG reductase system has sufficient capacity to maintain all intracellular GSH in a reduced state, so enhancing this pathway does not significantly increase its effectiveness. The main source of intracellular GSH loss is export from the cell. While intracellular GSH levels range from 1 to 8 mM, extracellular levels are only a few μM. This large concentration gradient essentially prevents GSH from being transported into the cell, and once exported, it is rapidly degraded by γ-glutamyl transpeptidase. Inhibition of the GSH transporter could theoretically increase intracellular GSH levels, but this transporter is not GSH-specific, and its inhibition could be problematic because it could lead to imbalances with other amino acids and peptides. Therefore, intracellular GSH levels are primarily regulated by changes in synthesis.

[0018] GSH is synthesized in the cytosol of almost all cells by two ATP-requiring enzymatic steps: L-glutamate + L-cysteine ​​+ ATP [→] γ-glutamyl-L-cysteine ​​+ ADP + Pi and γ-glutamyl-L-cysteine ​​+ L-glycine + ATP [→] GSH + ADP + Pi. The first reaction is rate-limiting and involves the reaction of glutamate cysteine The first reaction is catalyzed by a 118-kd GSH synthase (GSH, EC 6.3.2.2). GSH consists of a 73-kd heavy catalytic subunit (GCLC) and a 30-kd modifying subunit (GCLM), encoded by separate genes. GSH is regulated by non-allosteric competitive inhibition of GSH (Ki = 2.3 mM) and the availability of L-cysteine. The apparent Km of GLC for glutamate is 1.8 mM, which is approximately 10-fold higher than the intracellular glutamate concentration, making it glutamate-free. However, its Km for cysteine ​​is 0.1-0.3 mM, close to the intracellular concentration. The second reaction is catalyzed by a 118-kd GSH synthase (GS, EC 6.3.2.3), which consists of two identical subunits. Although GS does not appear to be important in regulating GSH synthesis under normal conditions, it may play a role under stress conditions, as GSH levels and GS activity decrease in response to surgical trauma, whereas GCL activity remains unchanged. Furthermore, increased expression of both GCLC and GS resulted in increased GSH levels compared with increased expression of GCLC alone. To maximize the effect of increased synthetic enzymes, increased cysteine ​​levels must be achieved. In cultured neurons, 90% of cysteine ​​uptake occurs via the sodium-dependent excitatory amino acid transporter (EAAT) system. There are five EAATs, and cysteine ​​uptake by neurons is primarily mediated by EAAT3, more commonly known as excitatory amino acid carrier-1 (EAAC1). Under normal circumstances, most EAAC1 resides in the ER and translocates to the plasma membrane only upon activation. This translocation is negatively regulated by glutamate transporter-associated protein 3-18 (GTRAP3-18), and inhibition of GTRAP3-18 increased GSH levels in neurons. Therefore, cysteine ​​internalization poses a problem for the GSH synthesis pathway, but fortunately, it can be bypassed by N-acetylcysteine ​​(NAC), which readily enters cells even in the absence of activated EAAC1. Systemically administered NAC enters the CNS and increases GSH levels, providing benefits in neurodegenerative disorders in which oxidative stress is an important part of the pathology. We have shown that oral administration of NAC promotes long-term cone survival in a model of RP.

[0019] All intracellular organelles, including the cytoplasm, mitochondria, and nucleus, must be protected from oxidative damage. While the present inventors have previously performed gene transfer of enzymes that detoxify reactive oxygen species, this approach requires the expression of two enzymes in the cytoplasm and two in the mitochondria. In contrast, the present invention provides protection of all intracellular organelles with the expression of only two enzymes in the cytosol, because GSH can diffuse ubiquitously throughout the cell.

[0020] NAC is used to treat acetaminophen overdose with a single loading dose of 140 mg / kg, followed by 17 doses of 70 mg / kg every 4 hours starting 4 hours after the first dose. In clinical studies, NAC was administered orally at doses of 400–1000 mg once daily and 200–600 mg three times daily. However, after a single oral dose of 600 mg in humans, NAC is rapidly absorbed and subsequently eliminated. The plasma half-life of NAC has been reported to be 2.5 hours, meaning that NAC is no longer detectable 10–12 hours after administration. During absorption, NAC is rapidly metabolized to cysteine, the direct precursor of glutathione. Based on this evidence, it was expected that NACA would act similarly to NAC in vivo, including as a precursor and / or carrier of NAC. However, the present inventors demonstrate that NACA acts very differently from NAC in the treatment of RP.

[0021] In one embodiment, the present invention provides a method for preventing, ameliorating, or treating a disease or condition associated with oxidative stress in a subject, comprising administering a therapeutically effective amount of NACA to increase the amount of glutathione expressed in the tissues of the subject.

[0022] As used herein, "active oxygen species" or "reactive oxygen species" refers to Reactive oxygen species are those that undergo the transfer of one or two electrons to form superoxide. anion of the form O2" or of the formula O2 2- It is understood that this produces peroxide anions having an OH group or compounds containing an OO single bond, such as hydrogen peroxide and lipid peroxides. Such superoxides and peroxides are highly reactive and can cause damage to cellular components including proteins, nucleic acids, and lipids.

[0023] "Agent" is understood herein to include a therapeutically active compound or a compound with potential therapeutic activity, e.g., an antioxidant. An agent may be a previously known or unknown compound. As used herein, an agent is typically a compound that is not cell-based, although an agent can include a biological therapeutic, e.g., a peptide or nucleic acid therapeutic, e.g., siRNA, shRNA, cytokine, antibody, etc.

[0024] As used herein, "amelioration" or "treatment" is understood to mean alleviating or diminishing at least one sign, symptom, indicator, or effect of a particular disease or condition. For example, amelioration or treatment of retinitis pigmentosa (RP) may be the reduction, delay, or elimination of one or more signs or symptoms of RP, including, but not limited to, decreased night vision, decreased overall visual acuity, narrowed visual field, decreased cone density in one or more quadrants of the retina, thinning of the retina, particularly the outer nuclear layer, decreased a- or b-wave amplitude in a scotopic or photopic electroretinogram (ERG), or any other clinically accepted indicator of pathology or disease progression. Amelioration and treatment may require two or more administrations of an agent, alone or in combination with other therapeutic agents and interventions. Amelioration or treatment need not cure the disease or condition.

[0025] As used herein, "antioxidants" are understood to be molecules that slow down or prevent the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidant. Such reactions can be facilitated by the production of superoxide anions or peroxides. Oxidation reactions can produce free radicals, which initiate chain reactions that damage cells. Antioxidants terminate these chain reactions by scavenging free radical intermediates and inhibit other oxidation reactions by oxidizing themselves. As a result, antioxidants are often reducing agents, such as thiols, ascorbic acid, or polyphenols. Antioxidants include, but are not limited to, α-tocopherol, ascorbic acid, Mn(III) tetrakis(4-benzoic acid)porphyrin, α-lipoic acid, and n-acetylacetone. Contains lucisteine.

[0026] "Co-administration," as used herein, refers to the administration of drugs to a subject Simultaneous administration is understood to mean administering one or more agents to a subject so that they are present and active simultaneously in the context of a therapeutic agent. Simultaneous administration does not require preparing a mixture of the agents or administering the agents simultaneously.

[0027] The term "effective amount" or "effective dose" refers to the amount of an agent that produces the intended pharmacological, therapeutic, or preventative result. A pharmacologically effective amount results in the improvement of one or more signs or symptoms of a disease or condition or the progression of a disease or condition, causing regression of the disease or condition. For example, a therapeutically effective amount preferably refers to the amount of a therapeutic agent that reduces night vision loss, total vision loss, or visual field loss by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more over a defined period of time, e.g., 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, or more, compared to untreated control subjects. More than one administration may be required to provide an effective dose.

[0028] As used herein, the terms "effective" and "effectiveness" include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a treatment to produce a desired biological effect in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (often referred to as side effects) at the cellular, organ, and / or organism level resulting from the administration of a treatment. On the other hand, the term "ineffective" indicates that a treatment does not provide sufficient pharmacological effects to be therapeutically useful, even in the absence of adverse effects, at least in an unstratified population. (For example, a treatment may be ineffective in a subpopulation that can be identified by expression profile(s).) "Low efficacy" means that a treatment produces a therapeutically significantly lower level of pharmacological effectiveness and / or a therapeutically higher level of adverse physiological effects, e.g., higher hepatotoxicity.

[0029] Thus, in the context of drug administration, a drug that is "effective against" a disease or condition indicates that administration in a clinically relevant form will produce a beneficial effect in at least a statistically significant percentage of patients, such as amelioration of symptoms, cure, reduction of disease signs or symptoms, prolongation of life, improvement in quality of life, or any other effect generally recognized as favorable by physicians skilled in the treatment of a particular type of disease or condition.

[0030] As used herein, "ocular diseases associated with oxidative stress" include, but are not limited to, retinitis pigmentosa, macular degeneration including both wet and dry age-related macular degeneration (AMD), diabetic retinopathy, Leber's optic neuropathy, and optic neuritis.

[0031] "Peroxidase" or "peroxide metabolic enzyme" ROOR 1 +Electron donor (2e-) +2H+ →ROH+R 1 Peroxidases are a large family of enzymes that typically catalyze reactions of the form OH. For many of these enzymes, the optimal substrate is hydrogen peroxide, where each R is H, but others are more active with organic hydroperoxides, such as lipid peroxides. Peroxidases can contain a heme cofactor or a redox-active cysteine ​​or selenocysteine ​​residue in the active site.

[0032] The phrase "pharmaceutically acceptable carrier" is art-recognized and includes any pharmaceutically acceptable substance, composition, or vehicle suitable for administering a compound of the invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating substances associated with carrying or transporting the subject agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. For example, pharmaceutically acceptable carriers for administration of cells are typically carriers acceptable for delivery by injection and do not include agents such as surfactants or other compounds that may damage the cells being delivered. Some examples of substances that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and derivatives thereof, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter, and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar, buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffered saline solution; and other non-toxic compatible substances used in pharmaceutical formulations, particularly phosphate buffered saline solution, which is preferred for intraocular delivery.

[0033] Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants Substances can also be present in the composition.

[0034] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0035] Formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, intramuscular, intraperitoneal, intraocular, intravitreal, subretinal, and / or other parenteral routes of administration. The particular route of administration will depend, inter alia, on the particular cells to be targeted. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical industry. The amount of active ingredient which may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

[0036] As used herein, "plurality" is understood to mean two or more. For example, plurality means at least 2, 3, 4, 5, or more.

[0037] As used herein, a "polypeptide" or "peptide" is understood to refer to two or more independently selected natural or unnatural amino acids joined by a covalent bond (e.g., a peptide bond). A peptide can include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more natural or unnatural amino acids joined by peptide bonds. Polypeptides as described herein include full-length proteins (e.g., fully processed proteins) as well as shorter amino acid sequences (e.g., fragments of naturally occurring proteins or synthetic polypeptide fragments).

[0038] As used herein, "prevention" is understood to mean limiting, reducing the rate or severity of, or inhibiting the onset of at least one sign or symptom of a disease or condition, particularly in a subject who is prone to developing the disease or disorder. For example, subjects with mutations in genes such as the opsin gene are prone to developing RP. The age of onset of one or more symptoms of the disease can sometimes be determined by the specific mutation. Prevention may include delaying the onset of one or more signs or symptoms of RP, but need not prevent the appearance of at least one sign or symptom of the disease throughout the subject's lifetime. Prevention may require more than one administration of a drug or therapeutic agent.

[0039] As used herein, a "small molecule" is understood to be a compound, typically an organic compound, having a molecular weight of less than about 1500 Da, 1000 Da, 750 Da, or 500 Da. In one embodiment, small molecules do not include polypeptides or nucleic acids that contain only naturally occurring amino acids and / or nucleotides.

[0040] As used herein, "subject" refers to a living organism. In certain embodiments, a living organism is an animal, and in certain preferred embodiments, the subject is a mammal, and in certain embodiments, the subject is a domesticated mammal or a primate, including a non-human primate. Examples of subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, goats, and sheep. A human subject may also be referred to as a patient.

[0041] A subject "suffering from or suspected of suffering from" a particular disease, condition, or syndrome has a sufficient number of risk factors or exhibits signs or symptoms of the disease, condition, or syndrome. A sufficient number or combination of these traits are present such that a competent individual would diagnose or suspect that the subject is suffering from a disease, condition, or syndrome. Methods for identifying subjects suffering from or suspected of suffering from diseases such as RP and age-related macular degeneration (AMD) are within the ability of one skilled in the art. Subjects suffering from and suspected of suffering from a particular disease, condition, or syndrome need not be two separate groups.

[0042] As used herein, "superoxide dismutase" is understood to be an enzyme that dismutates superoxide into oxygen and hydrogen peroxide. Examples include, but are not limited to, SOD1, SOD2, and SOD3. SOD1 and SOD3 are two isoforms of Cu-Zn-containing superoxide dismutase enzymes present in mammals. Cu-Zn-SOD or SOD1 is found in the intracellular space, while extracellular SOD (ECSOD or SOD3) is found primarily in the extracellular matrix of most tissues.

[0043] As used herein, a "therapeutically effective amount" means an amount of an agent that, when administered in single or multiple doses to a cell or subject, is effective in prolonging survival in a patient with such a disorder, alleviating one or more signs or symptoms of the disorder, preventing or delaying disease beyond that expected in the absence of such treatment, etc.

[0044] A drug or other therapeutic intervention can be administered to a subject alone or in combination with one or more additional therapeutic agents or interventions as a pharmaceutical composition or therapeutic treatment mixed with conventional excipients, e.g., pharmaceutically acceptable carriers.

[0045] Pharmaceuticals may conveniently be administered in unit dosage forms, for example, as described in Remington's Pharmaceutical Sciences (MackPub. Co., Easton, PA, 1985), and are widely available in the pharmaceutical industry. They can be prepared by any known method. Formulations for parenteral administration can contain common excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalenes, etc. In particular, biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of certain drugs.

[0046] The present invention is directed to the use of NACA for the treatment of RP. In one embodiment, the invention includes a method for treating retinitis pigmentosa in a human, comprising administering to the human a therapeutically effective amount of NACA. In some embodiments, NACA is provided in or with a pharmaceutically acceptable carrier. In other embodiments, NACA is administered intraocularly, subretinally, intravitreally, orally, intravenously, intramuscularly, intramedullary, intrathecally, intraventricularly, transdermally, subcutaneously, intraperitoneally, intranasally, enterally, topically, sublingually, or rectally.

[0047] It will be understood that the actual preferred amount of active compound to be used in a given therapy will vary depending, for example, on the particular compound employed, the particular composition formulated, the mode of administration, and the characteristics of the subject, such as the subject's species, sex, weight, general health, and age. Optimal administration rates for a given protocol of administration can be readily ascertained by one of ordinary skill in the art using conventional dosage-determining tests conducted in conjunction with the foregoing guidelines.

[0048] Ranges specified herein are understood to be a shorthand list of all values ​​within the range.

[0049] As used herein, embodiments of the present invention are defined to include pharmaceutically acceptable derivatives thereof. "Pharmaceutically acceptable derivative" means any pharmaceutical salt, ester, salt of an ester, or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of the present invention. Particularly preferred Derivatives are those that increase the bioavailability of the compounds of the invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood, increasing the serum stability of the compound, or decreasing the clearance rate of the compound), or that enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) compared to the parent species. Derivatives include derivatives in which groups that enhance aqueous solubility or active transport across the intestinal membrane have been added to the structures of the formulas described herein.

[0050] Embodiments of the present invention may be modified by adding appropriate functionality to enhance selective biological properties. Such modifications are known in the art and include those that increase biological penetration into a given biological compartment (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter excretion rate. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecyl sulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, metasulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, tosylate, and undecanoate salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium, and N-(alkyl) salts. 4+ Salts are included. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0051] Embodiments of the invention can be administered, for example, by injection, intraocular, intravitreal, subretinal, intravenous, intraarterial, subdermal, intraperitoneal, intramuscular, or subcutaneous, or orally, bucally, nasally, transmucosally, by catheter directly to the diseased organ, topically, or in an ophthalmic preparation, at dosages ranging from about 0.001 to about 100 mg / kg body weight, or more preferably 0.5 to 10 mg / kg body weight according to the requirements of the particular drug. It is understood that when a compound is delivered directly to the eye, considerations such as body weight have less bearing on the dosage.

[0052] The frequency of administration depends on the agent administered, the progression of the disease or disorder in the subject, and other considerations known to those skilled in the art. For example, a composition delivered to the eye has different pharmacokinetic and pharmacodynamic considerations than a composition delivered to an intraocular compartment, e.g., clearance in the subretinal space is very low. Thus, administration may be monthly, once every three months, once every six months, once a year, once every five years, or less frequently. If systemic administration of an antioxidant is performed in conjunction with administration of an expression construct to the subretinal space, it is expected that the antioxidant will be administered more frequently than the expression construct, e.g., once or twice a day or more, once or twice a week or more.

[0053] Dosage can be determined in conjunction with monitoring one or more signs or symptoms of the disease, such as visual acuity, visual field, night vision, etc. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Typical preparations contain from about 1% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound. Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient will depend on the activity of the particular compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or condition, the patient's predisposition to the disease, condition or condition, and the judgment of the attending physician. This depends on a variety of factors, including the

[0054] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension, which may contain a suitable dispersing or wetting agent (for example, TWEEN ( Sterile injectable preparations can also be formulated according to techniques known in the art using acetaminophen (Trademark) 80 and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils have traditionally been used as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, especially their polyoxyethylated varieties, are useful in injectable preparations, as are natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, carboxymethylcellulose, or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions. Other commonly used surfactants such as TWEEN® or SPAN® and / or other similar emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for the formulation.

[0055] In one or more embodiments, NACA is administered at a daily dose of about 0.5-150 mg / kg. In other embodiments, NACA is administered two or three times daily. In another aspect, NACA is administered with a second active agent selected from ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc., oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc., and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0056] In some embodiments, the NACA dosage for administration is 100, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In other embodiments, the dosage for administration is 0.1-0.25, 0.1-0.4, 0.35-0.5, 0.5-1, 102, 1-3, 1-4, 1-5, 1-2.5, 2.5-3.5, 4-6, 5-8, 6-9, or 7-10 grams per administration. In other embodiments, the NACA is delivered orally via mini-tablets, capsules, tablets, effervescent, dual-release, mixed-release, sachets, powders, or liquids. In other embodiments, the NACA is administered prophylactically to prevent RP.

[0057] In another embodiment, the present invention includes a method for treating retinitis pigmentosa (RP), comprising identifying a human in need of such treatment and administering to the human a therapeutically effective amount of NACA sufficient to treat RP. As with the other embodiments defined above, it will be understood that NACA is administered at a daily dose of about 0.5 to 150 mg / kg. In another aspect, NACA is administered two or three times daily. In another aspect, NACA is administered in conjunction with a second active agent, as disclosed above.

[0058] In another embodiment, the dose of NACA for administration is 100, 150, 300, 333, 400, 500, 600, 700, 750, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per administration. In another embodiment, the dose for administration is 0.1 to 0.25, 0.1 to 0.4, 0.35 to 0.5, 0.5 to 1, In another embodiment, the NACA is delivered orally via a mini-tablet, capsule, tablet, effervescent, two-phase release, mixed release, sachet, powder, or liquid formulation. In another embodiment, the NACA is administered prophylactically to prevent RP.

[0059] As used herein, "susceptible" or "prone" or "predisposed to" a particular disease or condition, etc., means an individual who, based on genetic, environmental, health, and / or other risk factors, is more likely to develop the disease or condition than the general population. The increased likelihood of developing the disease may be about a 10%, 20%, 50%, 100%, 150%, 200% or more increase. [Example]

[0060] Starting from postnatal day (P) 14, + / + Mice were given regular drinking water (n=6) or water containing 7 mg / ml NACA, 7 mg / ml NAC, or 20 mg / ml NAC (n=8 for each group). Scotopic and photopic electroretinograms (ERGs) were recorded at P35. Scotopic, photopic, and low-background photopic ERGs were recorded at P50.

[0061] Cone density was measured at P50 in four 230 mm × 230 mm (512 × 512 pixels) areas located 0.5 mm superior, lateral, inferior, and nasal to the center of the optic nerve in retinal flat mounts stained with fluorescein-labeled peanut agglutinin (PNA).

[0062] At P35, rd10 treated with 7 mg / ml NACA + / + Both the mean peak dark-adapted ERG b-wave amplitude and the mean five-peak light-adapted b-wave amplitude increased in mice treated with 7 mg / ml NAC. + / + 2-fold larger than those of mice, and control rd10 + / + At P50, the scotopic and photopic ERG b-waves in NACA-treated mice were found to be three times larger than those in rd10 mice treated with 7 mg / ml NAC. + / + rd10 mice or control + / +The amplitude of the b-wave was three times greater than that of the NAC-treated mice. Figures 1A-1E show that 7 mg / ml NACA provides better protection of retinal function than 7 mg / ml NAC. As shown in Figures 1A-1E, the following were measured: scotopic b-wave amplitude (Figures 1A and 1C), photopic b-wave amplitude (Figures 1B and 1D), and low-background photopic b-wave (Figure 1E). Cone cell density was significantly greater in 3 of 4 quadrants in NACA-treated mice compared with NAC-treated mice, p<0.0001 by ANOVA with Dunnett's correction for multiple comparisons. Figures 2A-2L show photomicrographs showing that 7 mg / ml NACA provides better protection of cone cell survival than 7 mg / ml NAC. Figure 2M shows cone cell survival measured by cone density in the superior, inferior, lateral, and nasal regions.

[0063] rd10 treated with 7mg / ml NACA compared with those treated with 20mg / ml NAC + / + Mice exhibit similar mean peak scotopic ERG b-wave amplitudes at P35. The mean peak photopic b-wave amplitude was 41% higher in NACA-treated mice than in NAC-treated mice (p = 0.024), and both were three-fold higher than controls. At P50, the mean peak scotopic ERG b-wave amplitudes in NAC 20 mg / ml-treated or NACA 7 mg / ml-treated mice exhibited sustained higher amplitudes than those in controls, and the mean b-wave amplitude was significantly greater in NACA-treated mice compared with NAC-treated mice for 10 of 11 stimulus intensities. The mean photopic ERG b-wave amplitude was 50% higher in NACA-treated mice versus NAC-treated mice at all three stimulus intensities (p = 0.001), and four-fold higher than controls. Figures 3A-3E show that 7 mg / ml NACA provides better protection of retinal function than 20 mg / ml NAC. As shown in Figures 3A-3E, The following were measured: scotopic b-wave amplitude (Figures 3A and 3C), photopic b-wave amplitude (Figures 3B and 3D), and low-background photopic b-wave (Figure 3E). Cone cell density was significantly greater in two of the four quadrants in NACA-treated mice compared with NAC-treated mice (Figures 4A-4L). Figures 4A-4L are photomicrographs showing that 7 mg / ml NACA has a better effect than 20 mg / ml NAC in protecting cone cell survival. Figure 4M shows cone survival measured by cone density in the superior, inferior, lateral, and nasal regions.

[0064] Surprisingly, at the same oral dose, or even at a substantially lower dose, rd10 + / + NACA5 showed significantly greater preservation of cone cell function and cone survival compared with NAC in mice, which is surprising because NACA is the precursor of NAC, and a precursor would not have been expected to lead to significantly different in vivo effects.

[0065] It is contemplated that any embodiment discussed herein can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to practice methods of the invention.

[0066] It should be understood that the specific embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.

[0067] All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0068] When used in conjunction with the word "comprising" in the claims and / or specification, the use of the words "a" or "an" may mean "one," but also includes "one or more," "at least one," and " This also matches the meaning of "one or more than one." The use of the term "or" herein is used to mean "and / or" unless the disclosure supports a definition that means only alternatives and "and / or," and unless expressly stated to mean only alternatives or that the alternatives are mutually exclusive. Throughout this specification, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.

[0069] As used in this specification and claims, "comprising" (and any form of "comprising", such as "comprise" and "comprises") , "having" (and "have" and "has" and so on) any form of "having"), "including" (and "includes" and "including" or "containing" (and "contains" and "contain") The term "containing" or "containing any form thereof" is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. In any embodiment of the compositions and methods defined herein, "comprising" may be substituted with "consisting essentially of" or "consisting of." As used herein, "consisting essentially of" means The phrase "consisting of" requires the specified integers or steps as well as those that do not materially affect the nature or function of the claimed invention. As used herein, the term "consisting of" is used to indicate the presence of only the recited integer (e.g., feature, element, characteristic, property, method / method step, or limitation) or group of integers (e.g., feature, element, characteristic, property, method / method step, or limitation).

[0070] As used herein, "or combinations thereof" means A term such as "A, B, C, or a combination thereof" refers to all sequences and combinations of the items listed before the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, if order is important in the particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing this example, combinations containing repeats of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are expressly included. Those of skill in the art will understand that there is typically no limit to the number of items or terms in any combination unless otherwise clear from the context.

[0071] As used herein, without limitation, terms indicating approximation, such as "about," "substantial," or "substantially," are intended to be interpreted as being so modified. The conditions do not necessarily have to be absolute or complete when stated, but refer to conditions that would be considered reasonable by a person skilled in the art. The range of variation in the description depends on the magnitude of the change that can occur, and is within the range that a person skilled in the art can still recognize that the modified feature still has the necessary characteristics and capabilities of the unmodified feature. Generally, but depending on the above considerations, the terms may be modified by approximation words such as "about." The numerical values ​​given herein may vary from the stated value by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12, or 15%.

[0072] Furthermore, the section headings herein are provided for consistency with the suggestions of 37 CFR § 1.77 or to provide other organizational clues. These headings do not limit or characterize the invention(s) set forth in any claims that may arise from this disclosure. Specifically, by way of example, even if a heading refers to a "Technical Field," the scope of such claims should not be limited by language intended to describe the so-called technical field under that heading. Furthermore, the description of a technology in a "Background" section should not be construed as an admission that the technology is prior art to any invention(s) in this disclosure. The "Summary" section should also not be deemed to characterize the invention(s) set forth in the presented claims. Furthermore, any reference to the singular "invention" in this disclosure should not be used to assert that only one novel feature of the disclosure is claimed. Multiple inventions may be set forth according to the limitations of multiple claims in this disclosure, and such claims, therefore, define the invention(s) and their equivalents protected thereby. In all cases, the scope of such claims should be considered on their own merits in light of this disclosure, but should not be constrained by the headings set forth herein.

[0073] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, those skilled in the art will recognize that changes can be made in the compositions and / or methods and in the steps or in the sequence of method steps described herein without departing from the concept, spirit, and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the invention, as defined by the appended claims.

Claims

1. 1. A pharmaceutical composition for treating retinitis pigmentosa in a mammal, comprising: an effective amount of N-acetylcysteinamide (NACA) to be administered in a therapeutically effective solid dose of 100, 150, 300, 333, 400, 500, 600, 700, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg per dose; and a pharmaceutically acceptable carrier.

2. 1. A pharmaceutical composition for preventing retinitis pigmentosa in a mammal, comprising: an effective amount of N-acetylcysteinamide (NACA) administered per dose in a therapeutically effective solid dose of 100, 150, 300, 333, 400, 500, 600, 700, 800, 900, 1,000, 2,500, 5,000, 7,500, or 10,000 mg; and a pharmaceutically acceptable carrier.

3. 3. The pharmaceutical composition of claim 1 or 2, further comprising a second active agent.

4. 3. The pharmaceutical composition of claim 1 or 2, further comprising a second active agent selected from the group consisting of ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and combinations thereof.

5. 3. The pharmaceutical composition of claim 1 or 2, in the form of a minitablet, capsule, tablet, two-stage release, mixed release, sachet, or powder.

6. 3. The pharmaceutical composition for the treatment of retinitis pigmentosa according to claim 1 or 2, wherein the composition reduces at least one of night vision loss, total vision loss, and visual field loss by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% compared to untreated control subjects over a defined period selected from 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, or 5 years.

7. 3. The pharmaceutical composition according to claim 1 or 2, wherein the mammal is a human.

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