CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application Serial Number 61/104176, filed on October 9, 2008, the entirety of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present disclosure relates generally to therapies for treating degenerative inflammatory conditions of the nervous system,

BACKGROUND OF THE INVENTION

[0003] Degenerative-inflammatory conditions of the nervous system (hereafter referred to as "DICNS") are therapeutically intransigent and devastating neurological conditions. For instance, DICNS related conditions are diseases that include, but are not limited to, autoimmune optic neuritis, multiple sclerosis, spinal cord injuries, optic neuropathy (glaucomatous, ischemic, inflammatory, and/or hereditary), diabetic neuropathy, diabetic retinopathy, traumatic brain injury, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and/or the like.

[0004] There are currently challenges to treating DICNS related conditions. These challenges have hampered the reversal of DICNS progression. These challenges have also hampered the prevention of one or more DICNS related conditions. Such challenges necessitate the need for the development of new treatments for DICNS related conditions.

SUMMARY OF THE INVENTION

[0005] In some embodiments, methods are disclosed for treating together at least one inflammatory pathology and at least one neurodegenerative pathology in a patient's nervous system that resulted from one or more DICNS related conditions. Such methods generally include the step of administering a combination therapeutic to a patient to treat at least one inflammatory pathology and at least one neurodegenerative pathology in the patient's nervous system. The combination therapeutic comprises both a polyphenolic stilbene and an acylic polyisoprenoid.

[0006] The DICNS related conditions treatable or preventable with the combination therapeutics of the present disclosure include, but are not limited to, autoimmune optic neuritis, multiple sclerosis, spinal cord injuries, optic neuropathy (glaucomatous, ischemic, inflammatory, and/or hereditary), diabetic neuropathy, diabetic retinopathy, traumatic brain injury, Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, epilepsy, and/or the like. In some embodiments, the DICNS related condition is either in an early stage or an advanced stage. In some embodiments, the combination therapeutic is administered by at least one route selected from orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by an implanted reservoir.

[0007] In further embodiments, the present disclosure provides methods of treating a patient suffering from a DICNS related condition. Such methods generally comprise the step of simultaneously treating the patient's neuroinflammatory DICNS related condition and the patient's neurodegenerative DICNS related condition. This step is accomplished by administering to the patient a composition comprising both a polyphenolic stilbene and an acylic polyisoprenoid.

[0008] Further embodiments of the present disclosure disclose pharmaceutical compositions comprising an effective amount of both a polyphenolic stilbene compound and an acylic polyisoprenoid compound. In such embodiments, the effective amount can be characterized as an amount effective for treating a patient with one or more DICNS related conditions. The pharmaceutical compositions may also comprise a pharmaceutically acceptable carrier or diuluent in some embodiments.

[0009] Further embodiments of the present disclosure disclose methods for both repairing and regenerating axons and glial cells while also preventing continued damage to a patient's nervous system from a DICNS related condition. Such methods generally include the step of administering to a patient a combination therapeutic comprising a polyphenolic stilbene compound and an acylic polyisoprenoid compound. [00010] In various embodiments, the patient to be treated with the methods and compositions of the present disclosure may be at risk of developing a DICNS related condition. In other embodiments, the patient to be treated may have developed a DICNS related condition.

[00011] The foregoing has outlined rather broadly the features of the present disclosure in order that the detailed description that follows may be better understood. Additional features and advantages of the disclosure will be described hereinafter, which form the subject of the claims.

BRIEF DESCRIPTION OF THE FIGURES

[00012] For a more complete understanding of the present disclosure, and the advantages thereof, reference is now made to the following descriptions to be taken in conjunction with the accompanying Figure describing specific embodiments of the disclosure, wherein:

[00013] FIG. 1 is a graphic illustration of the effects of a combination therapy in optic nerves. Specifically, the combination therapy in this illustration studies the effects of trans-Res veratrol (RV or trans-RV) with Geranylgeranylacetone (GGA) on an inflammatory pathology (CD6 immunoreactivity-ir, upper panel) and a neurodegenerative pathology (APP-it, a marker for axon damage, lower panel) in optic nerves. Asterisk (*) denotes significant differences between levels in normal (healthy) control and Automimmune Optic Neuritis (AON) optic nerves. Plus (+) denotes significant differences between drug-treated- AON nerves and untreated- AON nerves. Pound (#) denotes significant differences between drug-treated-AON nerves and normal control optic nerves. One */+/# denotes significance at p<0.02. Two **/++/## denotes significance at p<0.01. Three ***/+++/### denotes significance at PO.001.

DESCRIPTION OF THE INVENTION

[00014] The Description shown herein is by way of example and for purposes of illustrative discussion of the embodiments of the present disclosure. In addition, the Description is presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of various embodiments of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for the fundamental understanding of the invention. Furthermore, the Description taken with the Figure and/or examples make apparent to those skilled in the art how the several forms of the invention may be embodied in practice. [00015] The following definitions and explanations are meant and intended to be controlling in any future construction unless clearly and unambiguously modified in the following Examples or when application of the meaning renders any construction meaningless or essentially meaningless. In cases where the construction of the term would render it meaningless or essentially meaningless, the definition should be taken from Webster's Dictionary, 3 ^r Edition.

[00016] As used herein, all percentages are percentages by weight, unless stated otherwise.

[00017] As used herein, the term "effective amount" means and refers to an amount that is effective in providing at least partial relief to the condition being treated. In various embodiments, an effective amount can ameliorate symptoms of the disease condition, prevent onset of the disease condition, and/or cure the disease condition.

[00018] As used herein, "treating" or "treatment" can be understood to be an amelioration of symptoms, a cure of symptoms, a stabilization of symptoms, a prevention of symptoms, and/or the like.

[00019] As used herein, a "fluid" is a continuous, amorphous substance whose molecules move freely past one another and that has the tendency to assume the shape of its container, for example, a liquid or a gas.

[00020] As used herein, the term "health care provider" is known in the art and specifically includes a physician, a person with authority to prescribe a medication (whether directly or indirectly), and/or a veterinarian. In certain embodiments, a health care provider includes an individual that provides a medication without prescription, such as in providing an over-the- counter medication.

[00021] As used herein, the terms "identifying subjects" and "diagnosing" are used interchangeably with regard to the detection of a "predisposition," "increased propensity," "risk," "increased risk," and the like.

[00022] As used herein, the term "administered to the subject" and/or "to the subject's site" means and refers to delivery of an effective amount of the compound, treatment, formulation and/or medicament. [00023] As used herein, the term "subject" or "patient" refers to any invertebrate or vertebrate species. Since the methods of the present disclosure are particularly useful in the treatment of warm-blooded vertebrates, the "subject" or "patient" in some embodiments may refer to humans, mammals and/or birds.

[00024] There are at least two characteristics common to DICNS: 1) the co — activation of inflammatory and neurodegenerative processes; and 2) the therapeutic requirement to both prevent the continuation of damage to the nervous system, and to repair or regenerate nerve cells that have already been damaged or lost (e.g., axons and glial cells). Such attributes have limited the effectiveness of current therapeutics for treating DICNS related conditions.

[00025] For instance, because the inflammatory and neurodegenerative processes are two separate and distinct branches of pathology that result from a common initiating cause, treatment can be difficult. In particular, when a treatment is directed to one of the above-mentioned pathologies, the un-treated pathology may still cause DICNS related conditions. In fact, treatment of only one of the above-mentioned pathologies may even aggravate disease conditions associated with the other pathology (e.g., axon damage).

[00026] Furthermore, traditional theories about DICNS related conditions have generally assumed that either: 1) inflammatory pathologies in the nervous system directly caused neurodegenerative pathologies, or 2) neurodegenerative pathologies directly caused inflammatory pathologies in the nervous system. E.g., Stokely et al., J. Neuro. Res., 86:2111- 2124 (2008); Stokely et al., J. Neuro. Res., 166:217-218 (2007). Such theories have further hampered the simultaneous treatment of both the inflammatory and neurodegenerative pathologies in DICNS related conditions.

[00027] A second characteristic of DICNS that has hampered therapeutic treatment is the dual requirement to simultaneously 1) repair and regenerate axons and glial cells; and 2) prevent continued damage to a patient's nervous system. The difficulty arises at least partially because such a treatment would require cells of the patient's nervous system to exist in two different stages at the same time, while not developing an instability that may result in either programmed cell death or cancer. In particular, cells of the nervous system, which have reached full maturity and have become stabilized in that mature condition, must be induced to act like highly immature cells so that they can repair and regenerate. However, their neighboring cells must continue to act like fully mature cells and continue to fulfill their mature neurological functions. Such a dichotomy must occur within the environment of a fully mature nervous system.

[00028] As such, prior to this invention, scientists did not actively pursue combination therapies for DICNS related conditions or disorders that treated both the inflammatory and neurodegenerative pathologies. In fact, the rational combination of two drugs that individually resulted in mixed positive and negative therapeutic outcomes, with an aim to simultaneously produce all of the positive outcomes from both drugs while producing none of the negative outcomes of either drug, would generally have not been considered to be possible, as that strategy depends at least partially upon an ability to accurately match the two drugs being combined based upon a clear knowledge of the underlying mechanistic reasons for each drug's mixed therapeutic outcomes. For instance, prior to this invention, trans-3,5,4'-trihydroxystilbene (trans-RV) and geranylgeranylacetone (GGA) had not been used in combination to treat DICNS related conditions.

[00029] Accordingly, in some embodiments, the present disclosure provides a combination therapy that is simultaneously anti-inflammatory, neuroprotective, and regenerative. Such combination therapies generally involve the administration of both a polyphenolic stilbene and an acylic polyisoprenoid. Without being bound by theory, it is envisioned that embodiments of this disclosure can induce the regeneration and remyelination of axons. Therefore, unlike current therapeutics, such embodiments are likely to be capable of treating advanced stages of DICNS. Furthermore, it is envisioned that various embodiments of the present disclosure are capable of preventing disease progression during the early stages of DICNS. Accordingly, it is also envisioned that various embodiments of the present disclosure are capable of effectively treating all stages of DICNS.

[00030] Various embodiments of the present disclosure illustrate a new, non-linear understanding of DICNS, where two branches of pathology (a neuro inflammatory branch and a neurodegenerative branch) both result from a separate upstream cause. Further, various embodiments disclose treatments for both the neuro inflammatory branch and the neurodegenerative branch by the administration of a combination therapy that comprises a polyphenolic stilbene and an acylic polyisoprenoid. In some embodiments, the polyphenolic stilbene is trans-3,5,4'-trihydroxystilbene (Resveratrol or trans-RV). In some embodiments, the acylic polyisoprenoid is geranylgeranylacetone (GGA). In more specific and preferred embodiments, the polyphenolic stilbene is trans-RV, and the acylic polyisoprenoid is GGA.

[00031] By way of background, Resveratrol is a polyphenolic stilbene and a phytoalexin produced naturally by several plants when under attack by pathogens, such as bacteria or fungi. Resveratrol has also been produced by chemical synthesis, and is sold as a nutritional supplement derived primarily from Japanese knotweed. Resveratrol extends the life span of several short-living species of animals. However, this effect has not yet been demonstrated in mammals. In mouse and rat experiments, anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. Most of these results have yet to be replicated in humans. In the only positive human trial, extremely high doses (3-5 g) of resveratrol in a special proprietary formulation have been necessary to significantly lower blood sugar. Resveratrol is found in the skin of red grapes and is a constituent of red wine. The chemical structure is shown below.

[00032] By way of further background, Geranylgeranylacetone (GGA), which is also known as teprenone, is an acylic polyisoprenoid that is known as an anti-ulcer drug and a potent inducer of heat shock proteins (HSPs). The structure of GGA is illustrated below:

[00033] In some embodiments, GGA and trans-RV are in a highly purified state. In other embodiments, GGA and trans-RV may be in a crude state. Applicants also note that other polyphenolic stilbenes and acylic polyisoprenoids are also capable of being used in other embodiments of the present disclosure in various combinations to simultaneously treat the neuroinflammatory and neurodegenerative branches of DICN related conditions.

[00034] In various embodiments, the present disclosure also relates generally to methods of treating at least one DICNS related condition by administering a medicament comprising both a polyphenolic stilbene and an acylic polyisoprenoid. In some embodiments, the polyphenolic stilbene and the acylic polyisoprenoid compounds are formulated in a composition, such as a pharmaceutical composition.

[00035] Various embodiments of the present disclosure further disclose pharmaceutical compositions comprising an effective amount of both a polyphenolic stilbene compound and an acylic polyisoprenoid compound. In such embodiments, the pharmaceutical composition may also comprise a pharmaceutically acceptable carrier or diuluent.

[00036] In addition to the compounds of this invention, pharmaceutically acceptable salts of the compounds of this invention may also be employed in some embodiments to treat DICNS related conditions. In some embodiments, pharmaceutically acceptable salts of the compounds of this invention can include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Non-limiting examples of suitable acid salts include, without limitation, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic acid, while not in themselves pharmaceutically acceptable for all embodiments of the present disclosure, may also be employed in the preparation of acceptable salts. [00037] Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N-(Ci _-4 alkyl) ₄ ⁺ salts. 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.

[00038] Pharmaceutically acceptable carriers that may be used in pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate; disodium hydrogen phosphate; potassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; polyethylene glycol; and wool fat.

[00039] Various methods may be used to administer the compositions of the present disclosure. For instance, in some embodiments, the compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes injection or infusion techniques that may be subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and/or intracranial. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

[00040] The compositions of the present disclosure may also be used in various forms and/or states. For instance, in some embodiments, sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as 1,3-butanediol.

[00041] The compositions of the present disclosure may also be associated with various vehicles and solvents. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be employed as a solvent or suspending medium. In particular, in various embodiments, any bland fixed oil may be employed, including synthetic mono- or di-glycerides. By way of background, fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[00042] Various modes of administering the compositions of the present disclosure may also be employed in various embodiments. For instance, the pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers that can be used include lactose and corn starch. Lubricating agents, such as magnesium stearate, can also be added in some embodiments. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[00043] Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature. Such materials include cocoa butter, beeswax, polyethylene glycols, and/or the like.

[00044] The pharmaceutical compositions of this invention may also be administered topically. Such modes of administration may be ideal when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations may be readily prepared for each of these areas or organs in accordance with methods well known by a person of ordinary skill in the art.

[00045] In more specific embodiments, topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[00046] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00047] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline. In other more preferred embodiments, the ophthalmic pharmaceutical compositions may be formulated as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[00048] The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation. The compositions may also be prepared as solutions in saline. Such compositions may also employ suitable preservatives such as benzyl alcohol, absorption promoters, and/or conventional solubilizing or dispersing agents, such as fluorocarbons.

[00049] The amount of either compound that may be combined with the carrier materials to produce a single dosage form or composition can vary depending upon the host treated and/or the particular mode of administration. Preferably, the compositions are formulated so that a dosage of between about 0.01 to about 100 mg/kg body weight/day of either compound can be administered to a patient in need thereof.

[00050] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of compound can also depend upon the particular composition constituents.

[00051] Depending upon the particular DICNS related condition to be treated or prevented, additional drugs, which are normally administered to treat or prevent that condition may be administered together with the compositions of this invention. For example, chemotherapeutic agents, other anti-proliferative agents, or endothelial interrupters are capable of being combined with a combination treatment of the present disclosure.

[00052] Those additional agents may be administered separately, as part of a multiple dosage regimen, and/or from the endothelial interrupter-containing composition. Alternatively, those agents may be part of a single dosage form, mixed together with the endothelial interrupter in a single composition.

[00053] Formulations of the present disclosure can be packaged in a single dose form or a multi-dose form. In some embodiments, formulations packaged in single dose form are typically for use when formulated. Accordingly, ingredients for long-term storage, such as preservatives, may not be required in those formulations. However, a preservative is capable of use with various other embodiments of the present disclosure, including single dose formulations.

[00054] In some embodiments, formulations packaged in multi-dose form generally require the addition of preservatives to prevent microbial contamination during use. In some embodiments, such preservatives may comprise a naturally occurring or recombinant antimicrobial peptide. The antimicrobial peptide typically would be employed at a concentration between about 0.001% and about 1.0% by weight.

[00055] Formulations suitable for oral administration may be presented as discrete units, such as (1) pills, tablets or capsules with a predetermined amount of active ingredient(s); (2) powders or granules; and/or (3) solutions or suspensions. The active ingredient(s) may also be present as a bolus or paste, or may be contained within liposomes.

[00056] Formulations for rectal administration may be presented as a suppository or enema. Other suitable formulations for rectal administration may also be envisioned by a person of ordinary skill in the art.

[00057] For parenteral administration, suitable formulations can include aqueous and nonaqueous sterile injections. In some embodiments, the formulations may be presented in unit-dose or multi-dose containers, for example. In some embodiments, the formulations may be presented in sealed vials and ampules. In additional embodiments, the formulations may be stored in a freeze dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, such as water, prior to use.

[00058] For making dosage units, such as tablets, the use of conventional additives, such as fillers, colorants, polymeric binders and the like, can be contemplated. In general, any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.

[00059] In various embodiments, the formulation can be administered in more than one application, such as two or more discrete applications. However, in alternate embodiments, the formulation can be administered in one dose.

[00060] For such topical administration, the compositions administered may also include various other ingredients as carriers, including but not limited to surfactants, tonicity substrates, buffers, preservatives, co-solvents and viscosity building substrates.

[00061] From the above disclosure, a person of ordinary skill in the art will recognize that the present disclosure has numerous embodiments and applications. Reference will now be made to more specific embodiments of the present disclosure and experimental results that provide support for such embodiments. However, Applicants note that the disclosure below is for exemplary purposes only and is not intended to limit the scope of the present disclosure in any way. EXAMPLE 1

[00062] FIG. 1 illustrates the effects of an embodiment of the present disclosure. Illustrated are the effects of combination therapies utilizing trans-RV with GGA on inflammatory and neurodegenerative pathologies in optic nerve cells. Asterisk (*) denotes significant differences between levels in normal (healthy) control and Automimmune Optic Neuritis (AON) optic nerves. Plus (+) denotes significant differences between drug-treated- AON nerves and untreated-AON nerves. Pound (#) denotes significant differences between drug-treated-AON nerves and normal control optic nerves. One */+/# denotes significance at p<0.02. Two **/++/## denotes significance at p<0.01. Three ***/+++/### denotes significance at PO.001.

[00063] As illustrated on the upper panel of FIG. 1, the effects of the combination therapy of trans-RV with GGA on inflammatory pathology is demonstrated by CD6-immunoreactivity (-ir), a marker for t-cells infiltrating nervous tissue (FIG. 1, upper panel, third graph). However, Applicants observed that the individual effects of trans-RV and GGA on the above-mentioned pathology was significantly less than their combined effects (FIG. 1, upper panel, first and second graphs compared with third graph).

[00064] As illustrated on the lower panel of FIG. 1, the effects of the combination therapy of trans-RV with GGA on neurodegenerative pathology is demonstrated by APP-it, a marker of axon damage (FIG. 1, lower panel, third graph). Applicants also observed that the individual effects of trans-RV and GGA on the above-mentioned pathology was significantly less than their combined effects (FIG. 1 , lower panel, first and second graphs compared with third graph).

[00065] In brief, Applicants discovered that, when one blocks only a single aspect of a prototypic DICNS disorder (e.g., a fork, branch, or disease condition, such as autoimmune optic neuritis, referred to as AON), the pathological development of the DICNS disorder tends to drive down an unblocked aspect of the DICNS disorder (e.g., alternative fork, branch or disease condition of DICNS pathology), thereby producing a negative therapeutic outcome. Applicants' unique understanding of the development of DICNS disorders as a branched or forked disease or conditioned sequence of events allowed them to develop a combined therapeutic approach which uses two highly purified/synthetic active ingredients (trans-RV and GGA) that were strategically selected because they each individually block one of the branches of developing DICNS pathology.

[00066] Individually, trans-RV and GGA did not provide any positive effects for the alternate pathology branch by themselves (FIG. 1). However, when trans-RV and GGA were coadministered in a combined therapy, all the positive effects from the two active ingredients could be obtained in the absence of the negative and/or null therapeutic effects that would result if either ingredient was used as a single-agent therapeutic (FIG. 1).

[00067] More specifically, it is known that trans-RV reduces immune infiltration and GGA does not. However, co-administration of trans-RV and GGA reduces immune infiltration even further. While GGA reduces nerve damage (axon damage), trans-RV alone actually exacerbates it. However, co-administration of trans-RV and GGA reduces nerve damage (axon damage) even further. Accordingly, Applicants have demonstrated that co-administration of trans-RV and GGA, not separate administration of GGA or trans-RV individually, reduces nerve damage and immune infiltration at the same time.

[00068] This combined therapeutic approach allowed Applicants to overcome the obstacles that have hampered development of fully successful therapies for DICNS disorders. The approach has also significantly increased (p<0.05, ANOVA) markers for the growth cone associated protein 43 (GAP-43), a marker for regenerating axons, as well as markers for 2',3 '-cyclic nucleotide 3 '-phosphodiesterase (CNPase), whose up-regulation is an early sign of remyelination.

[00069] Such results indicate a synergism of the active ingredients when they are used in a combination therapy. In particular, when administered in combination, each ingredient provides more therapeutic benefit than it could provide if administered alone. In a combination therapeutic, each active ingredient also acts to cancel the other active ingredient's negative therapeutic effects. The invented combination therapy, as a whole, is more beneficial than the sum of its parts.

[00070] All patents and publications referenced herein are hereby incorporated by reference. It will be understood that certain of the above-described structures, functions, and operations of the above-described embodiments are not necessary to practice the present disclosure and are included in the description simply for completeness of an exemplary embodiment or embodiments. In addition, it will be understood that specific structures, functions, and operations set forth in the above-described referenced patents and publications can be practiced in conjunction with the present disclosure, but they are not essential to its practice. It is therefore to be understood that the invention may be practiced otherwise than as specifically described without actually departing from the spirit and scope of the present disclosure as defined by the appended claims.