WO2023244968A1

WO2023244968A1 - Methods of treating autoimmune disorders with histone deacetylase inhibitors

Info

Publication number: WO2023244968A1
Application number: PCT/US2023/068289
Authority: WO
Inventors: Ivor Royston; Ayman ELGUINDY
Original assignee: Viracta Subsidiary Inc
Current assignee: Viracta Subsidiary Inc
Priority date: 2022-06-13
Filing date: 2023-06-12
Publication date: 2023-12-21
Anticipated expiration: 2024-12-13

Abstract

Described herein are methods of treating autoimmune diseases of the central nervous system and multiple sclerosis with a combination of an HDAC inhibitor and an antiviral drug.

Description

METHODS OF TREATING AUTOIMMUNE DISORDERS WITH HISTONE DEACETYLASE INHIBITORS CROSS REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63/351, 629, filed June 13, 2022, which is incorporated by reference herein in its entirety.

SUMMARY OF THE INVENTION

[0002] Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein -Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. Similar to all herpesviruses, EBV has a biphasic life cycle, latent and lytic. In healthy sero-positive individuals, EBV persists in a sub set of memory B cells and is predominantly present in a latent state. This description is directed to treating active multiple sclerosis that include the clinically isolated syndrome of relapsing MS and active progressive MS, EBV reactivation is likely to lead to virus production and an expanded population of latently infected B cells that contribute to the active disease of MS.

[0003] Described herein in one aspect, is a method of inducing expression of a viral kinase in an individual with a latent viral infection comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby inducing expression of the viral kinase.

[0004] Described herein in one aspect, method of inducing expression of a viral kinase in a non-cancerousB cell of the central nervous system of an individual, the method comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby inducing expression of the viral kinase in the non-cancerousB cell of the central nervous system.

[0005] Described herein in one aspect, method of treating an autoimmune disease of the central nervous system in an individual, the method comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby treating the autoimmune disease of the central nervous system. [0006] Described herein in one aspect, method of treating active multiple sclerosis in an individual, the method comprising administering to the individual nanatinostat and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby treating the active multiple sclerosis.

[0007] Described herein in one aspect is a method of inducing expression of a viral kinase in an individual with a latent viral infection comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby inducing expression of the viral kinase. In certain embodiments, the individual is not afflicted with a cancer or a tumor. In certain embodiments, the latent viral infection is a cytomegalovirus or Epstein -Barr virus infection. In certain embodiments, the latent viral infection is an Epstein-Barr virus infection. In certain embodiments, the viral kinase is BGLF4. In certain embodiments, the latent viral infection is a cytomegalovirus infection. In certain embodiments, the viral kinase is UL97. In certain embodiments, expression of the viral kinase is induced in a B cell of the individual. In certain embodiments, the B cell is non-cancerous. In certain embodiments, the B cell is not mitotic. In certain embodiments, the B cell is in the central nervous system of the individual. In certain embodiments, the HDACi is selected from vorinostat, romidepsin, mocetinostat, belinostat, pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide, domatinostat, entinostat, nanatinostat and combinations thereof. In certain embodiments, the HDACi is nanatinostat. In certain embodiments, the HDACi is administered at a dose of about 5 milligrams per day to about 40 milligrams per day . In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day to about 30 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day to about 20 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 20 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 30 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 40 milligrams per day. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 3 days of the 7 day schedule. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 4 days of the 7 day schedule. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 5 days of the 7 day schedule. In certain embodiments, the schedule is repeated. In certain embodiments, the HDACi is administered q.d., b.i.d., ort.i.d. In certain embodiments, the antiviral is a nucleoside analog or nucleotide analog. In certain embodiments, the antiviral is selected from the list consisting of aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof. In certain embodiments, the antiviral is valganciclovir. In certain embodiments, the antiviral is administered at a total daily dose of 1,800 milligrams. In certain embodiments, the antiviral is administered at a total daily dose of 900 milligrams. In certain embodiments, the antiviral is administered at a total daily dose of 450 milligrams. In certain embodiments, the antiviral is administered according to a 7 day schedule, wherein the antiviral is administered every day of the treatment schedule. In certain embodiments, the antiviral is administered according to a 7 day schedule, wherein the antiviral is not administered on one or more days of the treatment schedule. In certain embodiments, the individual is afflicted with an autoimmune disease of the central nervous system. In certain embodiments, the autoimmune disease of the central nervous system comprises multiple sclerosis. In certain embodiments, the multiple sclerosis is active multiple sclerosis. In certain embodiments, the multiple sclerosis is relapsing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is relap sing-remitting MS (RRMS). In certain embodiments, the multiple sclerosis is primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is secondary-progressive MS (SPMS).

[0008] Described herein in another aspect is a method of inducing expression of a viral kinase in a non-cancerous B cell of the central nervous system of an individual, the method comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby inducing expression of the viral kinase in the non-cancerous B cell of the central nervous system. In certain embodiments, the individual is not afflicted with a cancer or a tumor. In certain embodiments, the viral kinase is a cytomegalovirus or Ep stein -Barr virus kinase. In certain embodiments, the viral kinase is an Epstein -Barr virus kinase. In certain embodiments, the viral kinase is BGLF4. In certain embodiments, the viral kinase is a cytomegalovirus kinase. In certain embodiments, the viral kinase is UL97. In certain embodiments, theB cell is not mitotic. In certain embodiments, the HDACi is selected from vorinostat, romidepsin, mocetinostat, belinostat, pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide, domatinostat, entinostat, nanatinostat and combinations thereof. In certain embodiments, the HDACi is nanatinostat. In certain embodiments, the HDACi is administered at a dose of about 5 milligrams per day to about 40 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day to about 30 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day to about 20 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 20 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 30 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 40 milligrams per day. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 3 days of the 7 day schedule. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 4 days of the 7 day schedule. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 5 days of the 7 day schedule. In certain embodiments, the schedule is repeated. In certain embodiments, theHDACi is administered q.d., b.i.d., or t.i.d. In certain embodiments, the antiviral is a nucleoside analog or nucleotide analog. In certain embodiments, the antiviral is selected from the list consisting of aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof. In certain embodiments, the antiviral is valganciclovir. In certain embodiments, the antiviral is administered at a total daily dose of 1 ,800 milligrams. In certain embodiments, the antiviral is administered at a total daily dose of 900 milligrams. In certain embodiments, the antiviral is administered at a total daily dose of 450 milligrams. In certain embodiments, the antiviral is administered according to a 7 day schedule, wherein the antiviral is administered every day of the treatment schedule. In certain embodiments, the antiviral is administered according to a 7 day schedule, wherein the antiviral is not administered on one or more days of the treatment schedule. In certain embodiments, the individual is afflicted with an autoimmune disease of the central nervous system. In certain embodiments, the autoimmune disease of the central nervous system comprises multiple sclerosis. In certain embodiments, the multiple sclerosis is active multiple sclerosis. In certain embodiments, the multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is relapsingremitting MS (RRMS). In certain embodiments, the multiple sclerosis is primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is secondary-progressive MS (SPMS).

[0009] Also described herein in another aspect is a method of treating an autoimmune disease of the central nervous system in an individual, the method comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby treating the autoimmune disease of the central nervous system. In certain embodiments, the individual is not afflicted with a cancer or a tumor. In certain embodiments, the individual has a latent cytomegalovirus or Epstein -Barr virus infection. In certain embodiments, the individual has a latent Epstein -Barr virus infection. In certain embodiments, the individual has a latent cytomegalovirus virus infection. In certain embodiments, the HDACi is selected from vorinostat, romidepsin, mocetinostat, belinostat, pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide, domatinostat, entinostat, nanatinostat and combinations thereof. In certain embodiments, the HDACi is nanatinostat. In certain embodiments, the HDACi is administered at a dose of about 5 milligrams per day to about 40 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day to about 30 milligrams per day In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day to about 20 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 20 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 30 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 40 milligrams per day. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 3 days of the 7 day schedule. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 4 days of the 7 day schedule. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 5 days of the 7 day schedule. In certain embodiments, the schedule is repeated. In certain embodiments, theHDACi is administered q.d., b.i.d., or t.i.d. In certain embodiments, the antiviral is a nucleoside analog or nucleotide analog. In certain embodiments, the antiviral is selected from the list consisting of aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof. In certain embodiments, the antiviral is valganciclovir. In certain embodiments, the antiviral is administered at a total daily dose of 1 ,800 milligrams. In certain embodiments, the antiviral is administered at a total daily dose of 900 milligrams. In certain embodiments, the antiviral is administered at a total daily dose of 450 milligrams. In certain embodiments, the antiviral is administered according to a 7 day schedule, wherein the antiviral is administered every day of the treatment schedule. In certain embodiments, the antiviral is administered according to a 7 day schedule, wherein the antiviral is not administered on one or more days of the treatment schedule. In certain embodiments, the autoimmune disease of the central nervous system comprises multiple sclerosis. In certain embodiments, the multiple sclerosis is active multiple sclerosis. In certain embodiments, the multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is relapsingremitting MS (RRMS). In certain embodiments, the multiple sclerosis is primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is secondary-progressive MS (SPMS).

[0010] Described herein in another aspect is a method of treating active multiple sclerosis in an individual, the method comprising administering to the individual nanatinostat and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby treating the active multiple sclerosis. In certain embodiments, the individual is not afflicted with a cancer or a tumor. In certain embodiments, the individual has a latent cytomegalovirus or Epstein -Barr virus infection. In certain embodiments, the individual has a latent Epstein -Barr virus infection. In certain embodiments, the individual has a latent cytomegalovirus virus infection. In certain embodiments, the HDACi is administered at a dose of about 5 milligrams per day to about 40 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day to about 30 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day to about 20 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 10 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 20 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 30 milligrams per day. In certain embodiments, the HDACi is administered at a dose of about 40 milligrams per day. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 3 days of the 7 day schedule. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 4 days of the 7 day schedule. In certain embodiments, the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 5 days of the 7 day schedule. In certain embodiments, the schedule is repeated. In certain embodiments, the HDACi is administered q.d., b.i.d., or t.i.d. In certain embodiments, the antiviral is a nucleoside analog or nucleotide analog. In certain embodiments, the antiviral is selected from the list consisting of aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof. In certain embodiments, the antiviral is valganciclovir. In certain embodiments, the antiviral is administered at a total daily dose of 1 ,800 milligrams. In certain embodiments, the antiviral is administered at a total daily dose of 900 milligrams. In certain embodiments, the antiviral is administered at a total daily dose of 450 milligrams. In certain embodiments, the antiviral is administered according to a 7 day schedule, wherein the antiviral is administered every day of the treatment schedule. In certain embodiments, the antiviral is administered according to a 7 day schedule, wherein the antiviral is not administered on one or more days of the treatment schedule. In certain embodiments, the active multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary-progressive MS (MS). In certain embodiments, the multiple sclerosis is relap sing-remitting MS (RRMS). In certain embodiments, the multiple sclerosis is primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is secondary -progressive MS (SPMS).

INCORPORATION BY REFERENCE

[0011] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorp orated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0013] FIG. 1 illustrates that nanatinostat crosses the blood brain barrier.

[0014] FIG. 2 A illustrates induction of EBV Zebra (BZLF1) in B cells of healthy individuals by western blot.

[0015] FIG.2B illustrates induction of EBV Zebra (BZLF1) in B cells of healthy individuals by flow cytometry.

[0016] FIG. 3 illustrates an experimental plan for analyzing the combination of nanatinostat and valganciclovir in a mouse model.

[0017] FIG. 4 A illustrates a pilot experiment (pilot experiment 1) to optimize donor PBMC superinfection andNanatinostat-ganciclovir (Nano-GCV) treatment in HuPBMC mice.

[0018] FIG. 4B illustrates a pilot experiment (pilot experiment 2) to optimize donor PBMC superinfection andNanatinostat-ganciclovir (Nano-GCV) treatment in HuPBMC mice.

[0019] FIG. 4C illustrates an experimental design usingPBMCs derived from both RRMS (relapsing-remitting multiple sclerosis) diagnosed and unaffected EBV seropositive (VCA and EBNA-1 IgG⁺) blood donors. DETAILED DESCRIPTION OF THE INVENTION

[0020] Described herein in one aspect, is a method of inducing expression of a viral kinase in an individual with a latent viral infection comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby inducing expression of the viral kinase.

[0021] Described herein in one aspect, method of inducing expression of a viral kinase in a non-cancerousB cell of the central nervous system of an individual, the method comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby inducing expression of the viral kinase in the non-cancerousB cell of the central nervous system.

[0022] Described herein in one aspect, method of treating an autoimmune disease of the central nervous system in an individual, the method comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby treating the autoimmune disease of the central nervous system.

[0023] Described herein in one aspect, method of treating active multiple sclerosis in an individual, the method comprising administering to the individual nanatinostat and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby treating the active multiple sclerosis.

DEFINITIONS

[0024] The terms “viral,” “virus-associated,” and “virally -induced” with reference to disorders are used interchangeably throughout the instant specification.

[0025] The term “obtaining” as in “obtaining the composition” is intended to include purchasing, synthesizing, or otherwise acquiring the composition (or agent(s) of the composition).

[0026] The terms “comprises”, “comprising”, are intended to have the broad meaning ascribed to them and can mean “includes”, “including” and the like.

[0027] The term “subject”, “patient” or “individual” are used interchangeably herein and refer to mammals and non-mammals, e.g., suffering from a disorder described herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of nonmammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0028] The terms “treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, inhibiting or reducing symptoms, reducing or inhibiting severity of, reducing incidence of, prophylactic treatment of, reducing or inhibiting recurrence of, delaying onset of, delaying recurrence of, abating or ameliorating a disease or condition symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arrestingthe development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms further include achieving a therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated, and/or the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient.

[0029] Dosages are referred to herein as QD, BID or TID. QD refers to dosing once a day. BID refers to dosing twice daily of the listed dose. TID refers to dosing three times a day of the listed dose. For example, 1 Omg BID refers to two 10 mg dosage units deliver daily. BID doses may be spaced apart such that they are at least about 16, 12, 10, or 8 hours apart. TID doses may be spaced at about 4, 6, or 8-hour intervals.

[0030] The terms “prevent,” “preventing” or “prevention,” and other grammatical equivalents as used herein, include preventing additional symptoms, preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arrestingthe development of the disease or condition and are intended to include prophylaxis. The terms further include achieving a prophylactic benefit. For prophylactic benefit, the compositions are optionally administered to a patient at risk of developing a particular disease, to a patient reporting one or more of the physiological symptoms of a disease, or to a patient at risk of reoccurrence of the disease.

[0031] The terms “effective amount” or “therapeutically effective amount” as used herein, refer to a sufficient amount of at least one agent being administered which achieve a desired result, e.g., to relieve to some extent one or more symptoms of a disease or condition being treated. In certain instances, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In certain instances, an “effective amount” for therapeutic uses is the amount of the composition comprising an agent as set forth herein required to provide a clinically significant decrease in a disease. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0032] The terms “administer,” “administering”, “administration,” and the like, as used herein, refer to the methods that are used to enable delivery of agents or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Administration techniques that in some instances are employed with the agents and methods described herein include, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics (current edition), Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In certain embodiments, the agents and compositions described herein are administered orally. In some embodiments, the compositions described herein are administered parenterally.

[0033] The term “pharmaceutically acceptable” as used herein, refers to a material that does not abrogate the biological activity or properties of the agents described herein, and is relatively nontoxic (i.e., the toxicity of the material significantly outweighs the benefit of the material). In some instances, a pharmaceutically acceptable material is administered to an individual without causing significant undesirable biological effects or significantly interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0034] The term “pharmaceutically acceptable excipient,” as used herein, refers to carriers and vehicles that are compatible with the active ingredient (for example, a compound of the invention) of a pharmaceutical composition of the invention (and preferably capable of stabilizing it) and not deleterious to the subject to be treated. For example, solubilizing agents that form specific, more soluble complexes with the compounds of the invention can be utilized as pharmaceutical excipients for delivery of the compounds. Suitable carriers and vehicles are known to those of extraordinary skill in the art. The term “excipient” as used herein will encompass all such carriers, adjuvants, diluents, solvents, or other inactive additives. Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The pharmaceutical compositions of the invention can also be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like, which do not deleteriously react with the active compounds of the invention.

[0035] The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

HERPESVIRUSES

[0036] Herpesviruses are a large family of DNA viruses that include Herpes simplex viruses (HSVs) 1 and 2, Varicella zoster virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesviruses (HHVs) 6A, 6B, 7 and 8, which can cause various diseases in humans. Herpesviruses have two stages of replication, the lytic and the latent. Soon after primary infection, immunological surveillance by the host force herpesviruses to enter the latent state of infection, where only a few selected genes are expressed. Conventional anti-herpesvirus drugs, such as ganciclovir, acyclovir, etc., fail to act on these latently -infected cells because the viral enzyme thymidine kinase (TK) or protein kinase (PK), which is necessary for the conversion of the prodrugs to their toxic metabolites, is not expressed in latently -infected cells. The methods and compositions described herein are useful for treating central nervous system autoimmune diseases in individuals latently infected with Epstein -Barr virus (EBV) and/or cytomegalovirus (CMV). In certain embodiments, the individual is latently infected with EBV. In certain embodiments, the individual is latently infected with CMV. Individuals latently infected with either virus can be determined by a past infection with either virus, or determined by a serum antibody response in the absence of active disease.

HISTONE DEACETYLASE INHIBITORS

[0037] The methods of the provided invention comprise use of one or more pharmaceutical compositions provided herein comprising a histone deacetylase inhibitor (HDACi) to induce expression of a gene product in a virus-infected cell (i.e., an inducing agent). The gene product expressed can be a viral enzyme or a cellular enzyme or activity that is largely expressed in virus-infected cells. Expression products that can be targeted include enzymes involved with DNA replication, for example, for repair or replication of the genome, assembly of complete virus particles, generation of viral membrane or walls, RNA transcription or protein translation or combinations of these activities. Interference with these processes can be performed by inducing and then acting on an enzyme and, preferably, a critical enzyme in the process. [0038] In some embodiments, the viral inducing agent is an HD AC inhibitor. In certain embodiments, the HD AC inhibitor is selected from the list consisting of : vorinostat, romidepsin, mocetinostat, belinostat, pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide, domatinostat, entinostat, and nanatinostat. In certain embodiments, the HD AC inhibitor is vorinostat. In certain embodiments, the HD AC inhibitor is romidepsin. In certain embodiments, the HD AC inhibitor is mocetinostat. In certain embodiments, the HD AC inhibitor is belinostat. In certain embodiments, the HD AC inhibitor is pracinostat. In certain embodiments, the HD AC inhibitor is givinostat. In certain embodiments, the HD AC inhibitor is panobinostat. In certain embodiments, the HD AC inhibitor is CUDC-101 . In certain embodiments, the HD AC inhibitor is CDX101 . In certain embodiments, the HD AC inhibitor is chidamide. In certain embodiments, the HD AC inhibitor is entinostat. In certain embodiments, the HD AC inhibitor is domatinostat. In certain embodiments, the HD AC inhibitor is nanatinostat. Nanatinostat is also referred to as CHR-3996 and VRx-3996, which is chemically identical). The chemical formula of nanatinostat is 2-((lR,5S,6s)-6-(((6-fluoroquinolin-2-yl)methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)-N- hydroxypyrimidine-5-carboxamide. Nanatinostat is a selective Class I HD AC inhibitor and is disclosed in U.S. PatentNo. 7,932,246, whichis incorporated by reference herein in its entirety. In certain embodiments, the HDACi results in Histone 3 acetylation in the peripheral blood mononuclear cells of the individual to which it is administered.

INDUCED GENES INCLUDING VIRAL-ASSOCIATED GENES

[0039] HDACi (agents that induce expression) may act directly on the viral genome or indirectly through a cellular factor required for viral expression. For example, viral gene expression can be regulated through the regulation of the expression of viral transcription factors such as ZTA, RTA, tat, and tax, cellular transcription factors such as AP-1, AP-2, Spl, NF-KB, and other transcriptional activators and/or repressors (factors), co-activators and co- repressors, histone acetylators and deacetylators, DNA methylases and demethylases, oncogenes or proto - oncogenes, or protein kinase C. These proteins act to regulate and thereby control expression of specific viral and/or other cellular genetic elements. According to the methods of the invention, control over their expression can lead to control over the infection. Other gene products, both viral and cellular in origin, whose expression can be regulated with inducing agents include proteases, polymerases, reverse transcriptases, cell-surface receptors, major histocompatibility antigens, growth factors, and combination of these products.

[0040] Additional genes whose expression or transcriptional regulation are altered in the presence of butyric acid include the oncogenes myc, ras, myb, abl and src. The activities of these gene products, as well as the activities of other oncogenes, are describedin Slamon, J.D., etal. 1984 Science 224:256-62. Anti-proliferative activity also includes the ability to repress tumor angiogenesis through the blockade of angiogenesis factor activity, production or release, transcriptional regulation, or the ability to modulate transcription of genes under angiogenesis or growth factor or hormonal control. Either would be an effective therapy, particularly against both prostatic neoplasia and breast carcinomas. Further activities that effect transcription and/or cellular differentiation include increased intracellular cAMP levels, inhibition of histone acetylation, and inhibition of genomic methylation. Each of these activities is directly related to gene expression, and increased expression can sensitize infected cells to a specific anti-viral agent.

[0041] In some embodiments, a gene induced by the HDACi is a viral kinase. In certain embodiments, the expression of the viral kinase is induced in a B cell of the individual. In certain embodiments, the B cell is non -cancerous. In certain embodiments, the B cell is not mitotic (e.g., has not entered the cell cycle). In other embodiments, inducing agents include HD AC inhibitors that induce EBV-PK activity (also known BGLF4) in EBV latently infected B cells. Expression of EBV-PK/BGLF4 sensitizes a cell to an antiviral agent. In certain instances, HD AC inhibitors induce EBV-PK. In some instances, HD AC inhibitors induce CMV-PK. In some instances, HD AC inhibitors induce UL97.

[0042] Preliminary in vitro studies according to the invention demonstrate that induction of EBV-PK activity in EBV patient-derived non-tumor cells using these drugs is possible. Treatment of patients with viral-associated autoimmune disorders such as EBV with inducing agents to induce the expression of EBV-TK/EBV-PK, and GCV or other similar antivirals, to eliminate EBV-TK/EBV-PK expressing tumor cells, maybe an effective, non-toxic therapy for autoimmune disorders. This therapeutic regimen does not depend on the associated viral genome being the cause of the autoimmune disease. Without wishing to be bound by theory, it is believed that just the presence of the EBV genome in latent form would make the autoimmune disorder susceptible to this combination protocol.

[0043] In some embodiments, an inducing agent induces viral gene expression by more than 4- fold after 24 hours of treatment. In certain embodiments, an HD AC inhibitor induces TK or EBV-PK expression by more than 4 -fold after 24 hours of treatment. In some embodiments, an HD AC inhibitor induces viral gene expression after about 48 hours, about 36 hours, about 24 hours, about 18 hours, about 12 hours, about 8 hours, about 6 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, or about 30 minutes. In certain embodiments, an HD AC inhibitor induces viral gene expression in less than 48 hours, less than 36 hours, less than 24 hours, less than 18 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hours, or less than 30 minutes. In some embodiments, an HD AC inhibitor induces viral gene expression in more than 48 hours, more than 36 hours, more than 24 hours, more than 18 hours, more than 12 hours, more than 8 hours, more than 6 hours, more than 4 hours, more than 3 hours, more than 2 hours, more than 1 hour, or more than 30 minutes. In certain embodiments, an HD AC inhibitor induces viral gene expression after more than 30 minutes and less than 24 hours.

ANTIVIRAL AGENTS

[0044] Anti-viral agents that can be used in the compositions and methods of the provided invention can include, for example, substrates and substrate analogs, inhibitors and other agents that severely impair, debilitate or otherwise destroy virus-infected cells. Substrate analogs include amino acid and nucleoside analogs. Substrates can be conjugated with toxins or other viricidal substances. Inhibitors include integrase inhibitors, protease inhibitors, polymerase inhibitors and transcriptase inhibitors such as reverse transcriptase inhibitors.

[0045] Antiviral agents that can be used in the compositions and methods of the provided invention can include, for example, ganciclovir, valganciclovir, oseltamivir (Tamiflu™), zanamivir (Relenza™), abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtri citab in e, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitors (e.g., enfuvirtide), ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, protease inhibitor, raltegravir, reverse transcriptase inhibitor, ribavirin, rimantadine, ritonavir, pyrimidine antiviral, saquinavir, stavudine, synergistic enhancer (antiretroviral), tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir (Valtrex™), vicriviroc, vidarabine, viramidine, zalcitabine, and zidovudine.

[0046] In a specific embodiment, the antiviral agent is aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof.

[0047] In some embodiments, the antiviral agent is a nucleoside analog. Examples of nucleoside analogs include acyclovir (ACV), ganciclovir (GCV), valganciclovir, famciclovir, foscarnet, ribavirin, zalcitabine (ddC), zidovudine (AZT), stavudine (D4T), larnivudine (3TC), didanosine (ddl), cytarabine, dideoxy adenosine, edoxudine, floxuridine, idozuridine, inosine pranobex, 2'- deoxy-5-(methylamino)uridine, trifluridine and vidarabine. Examples of a few protease inhibitors that show particular promise in human therapy include saquinivir, ritonavir and indinavir. Other anti-viral agents include interferons (e.g. a-, P-, y-interferon), cytokines such as tumor necrosis factor (TNF) or interleukins, cell receptors and growth factor antagonists, which can be purified or recombinantly produced.

[0048] In some embodiments, the antiviral agent is administered at a dose of less than 3000 mg/day. In some embodiments, the antiviral agent is administered at a dose of about 10 mg/day, about 20 mg/day, about 50 mg/day, about 100 mg/day, about 150 mg/day, about 200 mg/day, about 250 mg/day, about 300 mg/day, about 350 mg/day, about 400 mg/day, about 450 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about 1200 mg/day, about 1250 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day, about 1750 mg/day, about 1800 mg/day, about 1900 mg/day, about 2000 mg/day, about 2250 mg/day, about 2500 mg/day, about 2750 mg/day, about 3000 mg/day, about 3250 mg/day, about 350 Omg/day, about 3750 mg/day, about 4000 mg/day, about 4250 mg/day, about4500 mg/day, about4750 mg/day, or about 5000 mg/day. In certain embodiments, the antiviral agent is administered at a dose of less than 10 mg/day, less than 20 mg/day, less than 50 mg/day, less than 100 mg/day, less than 150 mg/day, less than 200 mg/day, less than 250 mg/day, less than 300 mg/day, less than 350 mg/day, less than 400 mg/day, less than 450 mg/day, less than 500 mg/day, less than 600 mg/day, less than 700 mg/day, less than 800 mg/day, less than 900 mg/day, less than 1000 mg/day, less than 1200 mg/day, less than 1250 mg/day, less than 1400 mg/day, less than 1500 mg/day, less than 1600 mg/day, less than 1750 mg/day, less than 1800 mg/day, less than 1900 mg/day, less than 2000 mg/day, less than 2250 mg/day, less than 2500 mg/day, less than 2750 mg/day, less than 3000 mg/day, less than 3250 mg/day, less than 3500 mg/day, less than 3750 mg/day, less than 4000 mg/day, less than 4250 mg/day, less than 4500 mg/day, less than 4750 mg/day, or less than 5000 mg/day. In some embodiments, the antiviral agent is administered at a dose of more than 10 mg/day, more than 20 mg/day, more than 50 mg/day, more than 100 mg/day, more than 150 mg/day, more than 200 mg/day, more than 250 mg/day, more than 300 mg/day, more than 350 mg/day, more than 400 mg/day, more than 450 mg/day, more than 500 mg/day, more than 600 mg/day, more than 700 mg/day, more than 800 mg/day, more than 900 mg/day, more than 1000 mg/day, more than 1200 mg/day, more than 125 O mg/day, more than 1400 mg/day, more than 1500 mg/day, more than 1600 mg/day, more than 1750 mg/day, more than 1800 mg/day, more than 1900 mg/day, more than 2000 mg/day, more than 2250 mg/day, more than 2500 mg/day, more than 2750 mg/day, more than 3000 mg/day, more than 3250 mg/day, more than 3500 mg/day, more than 3750 mg/day, more than 4000 mg/day, more than 4250 mg/day, more than 4500 mg/day, more than 4750 mg/day, or more than 5000 mg/day. In certain embodiments, the antiviral agent is administered at a dose of more than 10 mg/day and less than 5000 mg/day. In some embodiments, the antiviral agent is administered at a dose of more than 200 mg/day and less than 1000 mg/day. In certain embodiments, the antiviral agent is administered once a day (q.d, QD.), twice a day (b.i.d., BID), or thrice a day (t.i.d., TID). In some embodiments, the antiviral agent is administered daily, once a week, twice a week, three times a week, four times a week, or five times a week.

[0049] In certain embodiments, the antiviral agent is ganciclovir. In some embodiments, ganciclovir is administered at a total daily dose of 3000 mg/day. In certain embodiments, ganciclovir is administered at a dose of 1000 mg three times a day. In some embodiments, ganciclovir is administered at a dose of about 100 mg/day, about 250 mg/day, about 500 mg/day, about 750 mg/day, about 1000 mg/day, about 1500 mg/day, about 2000 mg/day, about 2500 mg/day, about 3000 mg/day, about 3500 mg/day, or about 4000 mg/day. In certain embodiments, ganciclovir is administered at a dose of less than 100 mg/day, less than 250 mg/day, less than 500 mg/day, less than 750 mg/day, less than 1000 mg/day, less than 1500 mg/day, less than 2000 mg/day, less than 2500 mg/day, less than 3000 mg/day, less than 3500 mg/day, or less than 4000 mg/day. In some embodiments, ganciclovir is administered at a dose of more than 100 mg/day, more than 250 mg/day, more than 500 mg/day, more than 750 mg/day, more than 1000 mg/day, more than 1500 mg/day, more than 2000 mg/day, more than 2500 mg/day, more than 3000 mg/day, more than 3500 mg/day, or more than 4000 mg/day. In certain embodiments, ganciclovir is administered at a dose of more than 500 mg/day and less 4000 mg/day. In some embodiments, ganciclovir is administered at a dose of more than 1000 mg/day and less than 3000 mg/day. In some embodiments, ganciclovir is administered once a day, twice a day, or three times a day. In certain embodiments, ganciclovir is administered once a week, twice a week, three times a week, four times a week, five times a week, or daily.

[0050] In some embodiments, the antiviral agent is valganciclovir. In certain embodiments, valgancicloviris administered at a total daily dose of 900 mg/day. In some embodiments, valganciclovir is administered at a dose of 900 mg once a day. In certain embodiments, valganciclovir is administered at a total daily dose of 1800 mg/day . In some embodiments, valganciclovir is administered at a dose of 900 mg twice a day.

[0051] Valganciclovir and other antivirals maybe dosed at a lower level in response to certain known toxicities, such as renal or liver toxicity. Such reductions can be in accordance with label instructions Any of the doses described herein can be reduced by 25% or 50% in response to such toxicities. In some embodiments, valganciclovir is administered at a dose of 450 mg twice a day. In some embodiments, valganciclovir is administered at a dose of 450 mgtwice a day. In certain embodiments, antiviral treatment may be halted or one or more doses of a schedule may be skipped in response to renal or liver toxicity. In certain embodiments, an antiviral may notbe administered for one, two, three, four, five, or six days of schedule. In certain embodiments, valganciclovir may notbe administered for one, two, three, four, five, or six days of schedule. In certain embodiments the schedule is seven days.

[0052] In some embodiments, valganciclovir is administered at a dose of about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1000 mg/day, about

1100 mg/day, about 1200 mg/day, about 1300 mg/day, about 1400 mg/day, about 1500 mg/day, about 1600 mg/day, about 1700 mg/day, about 1800 mg/day, about 1900 mg/day, or about 2000 mg/day. In certain embodiments, valganciclovir is administered at a dose of less than 100 mg/day, less than 200 mg/day, less than 300 mg/day, less than 400 mg/day, less than 500 mg/day, less than 600 mg/day, less than 700 mg/day, less than 800 mg/day, less than 900 mg/day, less than 1000 mg/day, less than 1100 mg/day, less than 1200 mg/day, less than 1300 mg/day, less than 1400 mg/day, less than 1500 mg/day, less than 1600 mg/day, less than 1700 mg/day, less than 1800 mg/day, less than 1900 mg/day, or less than 2000 mg/day. In some embodiments, valganciclovir is administered at a dose of more than 100 mg/day, more than 200 mg/day, more than 300 mg/day, more than 400 mg/day, more than 500 mg/day, more than 600 mg/day, more than 700 mg/day, more than 800 mg/day, more than 900 mg/day, more than 1000 mg/day, more than 1100 mg/day, more than 1200 mg/day, more than 1300 mg/day, more than 1400 mg/day, more than 1500 mg/day, more than 1600 mg/day, more than 1700 mg/day, more than 1800 mg/day, more than 1900 mg/day, or more than 2000 mg/day. In certain embodiments, valganciclovir is administered at a dose of more than 100 mg/day and less 2000 mg/day. In some embodiments, valganciclovir is administered at a dose of more than 500 mg/day and less than 1500 mg/day. In some embodiments, valganciclovir is administered once a day, twice a day, or three times a day. In certain embodiments, valganciclovir is administered once a week, twice a week, three times a week, four times a week, five times a week, or daily. In certain embodiments, valganciclovir is administered daily at a dose of about 900 milligrams. In certain embodiments, valganciclovir is administered daily at a dose of about

800 milligrams. In certain embodiments, valganciclovir is administered daily at a dose of about

700 milligrams. In certain embodiments, valganciclovir is administered daily at a dose of about

600 milligrams. In certain embodiments, valganciclovir is administered daily at a dose of about

500 milligrams. In certain embodiments, valganciclovir is administered daily at a dose of about

450 milligrams. In certain embodiments, valganciclovir is administered daily at a dose of about

400 milligrams. In certain embodiments, the valganciclovir is administered daily even on days when no HDACi is administered.

[0053] In certain embodiments a dosing holiday can be applied to treatment with valganciclovir. In certain embodiments, the schedule is 7 days and valganciclovir is not dosed for 1, 2, 3, 4, 5, or 6 days of the schedule. In certain embodiments, the schedule is 7 days and valganciclovir is dosed at 450 mg total daily dose on 1, 2, 3, 4, 5, or 6 days of the schedule. In certain embodiments, the schedule is 7 days and valganciclovir is dosed at 900 mg total daily dose on 1, 2, 3, 4, 5, or 6 days of the schedule.

METHODSAND COMPOSITIONS

[0054] In one aspect, provided herein are methods for treating and/or preventing an autoimmune disorder in an individual with a latent herpesvirus infection. In certain embodiments, the autoimmune disorder of the central nervous system. In certain embodiments, the central nervous system autoimmune disease is associated with autoantibody production. In certain embodiments, the central nervous system autoimmune disorder is multiple sclerosis. In certain embodiments, the multiple sclerosis is active multiple sclerosis. In certain embodiments, the multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is relap sing-remitting MS (RRMS). In certain embodiments, the multiple sclerosis is primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is secondary -progressive MS (SPMS).

[0055] In certain embodiments, the autoimmune disease afflicts an individual with a latent EBV infection. In certain embodiments, the autoimmune disease afflicts an individual with a latent CMV infection. In certain embodiments, the autoimmune disease is multiple sclerosis. In certain embodiments, the multiple sclerosis is active multiple sclerosis. In certain embodiments, the multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is relapsing- remitting MS (RRMS). In certain embodiments, the multiple sclerosis is primary -progressive MS (MS). In certain embodiments, the multiple sclerosis is secondary -progressive MS (SPMS). In certain embodiments, the methods comprise administering a viral inducing agent (e.g., an HD AC inhibitor) and an antiviral agent. In some embodiments, the methods comprise administering an HD AC inhibitor and an antiviral agent. In certain embodiments, the HD AC inhibitor and the antiviral agent are co -formulated. In some embodiments, the methods comprise administering an HD AC inhibitor and an antiviral agent. In certain embodiments, the HD AC inhibitor and the antiviral agent are formulated separately. In certain embodiments, the antiviral agent is administered daily while the HDACi is administered on only certain days. In certain embodiments, the HDACi is nanatinostat. In certain embodiments, the HDACi is administered with food or another nutritional supplement. In certain embodiments, the nanatinostat is administered with food or another nutritional supplement. In certain embodiments, the antiviral agent is not administered for 1, 2, 3, 4, 5, 6, or 7 days of the dosage schedule.

[0056] In certain embodiments, HDACi is administered at a total daily dose of about 5 milligrams to about 50 milligrams. In certain embodiments, HDACi is administered at a total daily dose of about 5 milligrams to about 10 milligrams, about 5 milligrams to about 15 milligrams, about 5 milligrams to about 20 milligrams, about 5 milligrams to about 25 milligrams, about 5 milligrams to about 30 milligrams, about 5 milligrams to about 35 milligrams, about 5 milligrams to about 40 milligrams, about 5 milligrams to about 45 milligrams, about 5 milligrams to about 50 milligrams, about 10 milligrams to about 15 milligrams, about 10 milligrams to about 20 milligrams, about 10 milligrams to about 25 milligrams, about 10 milligrams to about 30 milligrams, about 10 milligrams to about 35 milligrams, about 10 milligrams to about 40 milligrams, about 10 milligrams to about 45 milligrams, about 10 milligrams to about 50 milligrams, about 15 milligrams to about 20 milligrams, about 15 milligrams to about 25 milligrams, about 15 milligrams to about 30 milligrams, about 15 milligrams to about 35 milligrams, about 15 milligrams to about 40 milligrams, about 15 milligrams to about 45 milligrams, about 15 milligrams to about 50 milligrams, about 20 milligrams to about 25 milligrams, about 20 milligrams to about 30 milligrams, about 20 milligrams to about 35 milligrams, about 20 milligrams to about 40 milligrams, about 20 milligrams to about 45 milligrams, about 20 milligrams to about 50 milligrams, about 25 milligrams to about 30 milligrams, about 25 milligrams to about 35 milligrams, about 25 milligrams to about 40 milligrams, about 25 milligrams to about 45 milligrams, about 25 milligrams to about 50 milligrams, about 30 milligrams to about 35 milligrams, about 30 milligrams to about 40 milligrams, about 30 milligrams to about 45 milligrams, about 30 milligrams to about 50 milligrams, about 35 milligrams to about 40 milligram s, ab out 35 milligram s to ab out 45 milligram s, ab out 35 milligram s to ab out 50 milligrams, about 40 milligrams to about 45 milligrams, about 40 milligrams to about 50 milligrams, or about 45 milligrams to about 50 milligrams. In certain embodiments, HDACi is administered at a total daily dose of about 5 milligrams, about 10 milligrams, about 15 milligrams, about 20 milligrams, about 25 milligrams, about 30 milligrams, about 35 milligrams, about 40 milligrams, about 45 milligrams, or about 50 milligrams. In certain embodiments, HDACi is administered at a total daily dose of at least about 5 milligrams, about 10 milligrams, about 15 milligrams, about 20 milligrams, about 25 milligrams, about 30 milligrams, about 35 milligrams, about 40 milligrams, or about 45 milligrams. In certain embodiments, HDACi is administered at a total daily dose of at most about 10 milligrams, about 15 milligrams, about 20 milligrams, about 25 milligrams, about 30 milligrams, about 35 milligrams, about 40 milligrams, about 45 milligrams, or about 50 milligrams.

[0057] In certain embodiments, nanatinostat is administered at a total daily dose of about 5 milligrams to about 50 milligrams. In certain embodiments, nanatinostat is administered at a total daily dose of about 5 milligrams to about 10 milligrams, about 5 milligrams to about 15 milligrams, about 5 milligrams to about 20 milligrams, about 5 milligrams to about 25 milligram s, ab out 5 milligram s to ab out 30 milligram s, ab out 5 milligram s to ab out 35 milligrams, about 5 milligrams to about 40 milligrams, about 5 milligrams to about 45 milligrams, about 5 milligrams to about 50 milligrams, about 10 milligrams to about 15 milligrams, about 10 milligrams to about 20 milligrams, about 10 milligrams to about 25 milligrams, about 10 milligrams to about 30 milligrams, about 10 milligrams to about 35 milligrams, about 10 milligrams to about 40 milligrams, about 10 milligrams to about 45 milligrams, about 10 milligrams to about 50 milligrams, about 15 milligrams to about 20 milligrams, about 15 milligrams to about 25 milligrams, about 15 milligrams to about 30 milligrams, about 15 milligrams to about 35 milligrams, about 15 milligrams to about 40 milligrams, about 15 milligrams to about 45 milligrams, about 15 milligrams to about 50 milligrams, about 20 milligrams to about 25 milligrams, about 20 milligrams to about 30 milligrams, about 20 milligrams to about 35 milligrams, about 20 milligrams to about 40 milligrams, about 20 milligrams to about 45 milligrams, about 20 milligrams to about 50 milligrams, about 25 milligrams to about 30 milligrams, about 25 milligrams to about 35 milligrams, about 25 milligrams to about 40 milligrams, about 25 milligrams to about 45 milligrams, about 25 milligrams to about 50 milligrams, about 30 milligrams to about 35 milligram s, ab out 30 milligram s to ab out 40 milligram s, ab out 30 milligram s to ab out 45 milligrams, about 30 milligrams to about 50 milligrams, about 35 milligrams to about 40 milligrams, about 35 milligrams to about 45 milligrams, about 35 milligrams to about 50 milligrams, about 40 milligrams to about 45 milligrams, about 40 milligrams to about 50 milligrams, or about 45 milligrams to about 50 milligrams. In certain embodiments, nanatinostat is administered at a total daily dose of about 5 milligrams, about 10 milligrams, about 15 milligrams, about 20 milligrams, about 25 milligrams, about 30 milligrams, about 35 milligrams, about 40 milligrams, about 45 milligrams, or about 50 milligrams. In certain embodiments, nanatinostat is administered at a total daily dose of at least about 5 milligrams, about 10 milligrams, about 15 milligrams, about 20 milligrams, about 25 milligrams, about 30 milligrams, about 35 milligrams, about 40 milligrams, or about 45 milligrams. In certain embodiments, nanatinostat is administered at a total daily dose of at most about 10 milligrams, about 15 milligrams, about 20 milligrams, about 25 milligrams, about 30 milligrams, about 35 milligrams, about 40 milligrams, about 45 milligrams, or about 50 milligrams.

[0058] In some embodiments, the compositions, HDACi, or antivirals are administered on schedule in an intermittent manner. In certain embodiments, this allows for a “dose holiday” a “dose-hold” or a “structured treatment interruption,” which allows for the management of negative side-effects. Suitable schedules may include a total duration of a calendar week (e.g., 7 days) or any multiple thereof according to the methods described herein. In certain embodiments, the HDACi and anti-viral agent are administered for at least one, two, three, four, five, or six days, of schedule, and no dosage amount or a reduced dosage amount of HDACi is administered for one, two, three, four, five, or six days of the schedule. In certain embodiments, the HDACi and anti-viral agent are administered on a 7-day schedule for at least one, two, three, four, five, or six days, of schedule, and no dosage amount or a reduced dosage amount of HDACi is administered for one, two, three, four, five, or six days of the schedule. In certain embodiments, the schedule is a week, and is repeated until a clinically suitable outcome is determined or reached. In certain embodiments, the schedule is a week, and is repeated for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In certain embodiments, the HDACi is administered for one week followed by a week of no administration. In certain embodiments, nanatinostat is administered for one week followed by a week of no administration. In certain embodiments, the antiviral is administered on every day of the schedule. [0059] In certain embodiments, the HDACi has an elimination half-life of less than 34 hours. In certain embodiments, the HDACi has an elimination half-life of less than 20 hours. In certain embodiments, the HDACi has an elimination half-life of less than 12 hours. In certain embodiments, the HDACi has an elimination half-life of less than 6 hours. In certain embodiments, the HDACi has an elimination half-life of less than 4 hours.

[0060] In certain embodiments, the HDACi is not detectable in the blood of a subject 48 hours after a dose is administered. In certain embodiments, the HDACi is not detectable in the blood of a subject 36 hours after a dose is administered. In certain embodiments, the HDACi is not detectable in the blood of a subject 24 hours after a dose is administered. In certain embodiments, the HDACi is not detectable in the blood of a subject 12 hours after a dose is administered. In certain embodiments, the dose is about 50, 40, 30, 20, 15, 10, or 5 milligrams. [0061] In certain embodiments, the dose schedule is a week, and an HDACi is administered for 1 day of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 2 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 3 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 4 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 5 day s of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 6 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 1 and 6 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 2 and 6 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 3 and 6 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 4 and 6 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 5 or 6 days of the dose schedule.

[0062] In certain embodiments the dose schedule is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days and an HDACi is not administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 days of the schedule. In certain embodiments the HDACi is nanatinostat. In certain embodiments, the antiviral is administered on every day of the schedule, or may be reduced based on liver or kidney toxicity. In certain embodiments the antiviral is ganciclovir or valganciclovir. [0063] In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 1 and 5 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 2 and 5 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 3 and 5 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 4 or 5 days of the dose schedule.

[0064] In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 1 and 4 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered from between 2 and 4 days of the dose schedule. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 3 or 4 days of the dose schedule.

[0065] In certain embodiments, the HDACi is administered QD at 30 milligrams. In certain embodiments, the HDACi is administered QD at 25 milligrams. In certain embodiments, the HDACi is administered QD at 20 milligrams. In certain embodiments, the HDACi is administered QD at 15 milligrams. In certain embodiments, the HDACi is administered QD at 10 milligrams. In certain embodiments, the HDACi is administered BID at 20 milligrams. In certain embodiments, the HDACi is administered BID at 15 milligrams. In certain embodiments, the HDACi is administered BID at 10 milligrams. In certain embodiments, the HDACi is administered BID at 5 milligrams. In certain embodiments, the HDACi is administered TTD at 15 milligrams. In certain embodiments, the HDACi is administered TTD at 10 milligrams. In certain embodiments, the HDACi is administered TTD at 5 milligrams. In certain embodiments, the HDACi is administered TID between about 5 milligrams and about 15 milligrams. In certain embodiments, an antiviral is administered daily during the schedule. In certain embodiments, the antiviral is valganciclovir, and the valganciclovir is administered at a dose of 900 milligrams or 450 milligrams.

[0066] In certain embodiments, the dose schedule is a week, and an HDACi is administered for 1 day followed by 6 days of no HDACi treatment. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 2 days followed by 5 days of no HDACi treatment. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 3 days followed by 4 days of no HDACi treatment. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 4 days followed by 3 days of no HDACi treatment. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 5 days followed by 2 days of no HDACi treatment. In certain embodiments, the dose schedule is a week, and an HDACi is administered for 6 days followed by 1 day of no HDACi treatment. In certain embodiments, the dose schedule is a week, and an HDACi is administered every other day on days 1, 2, 5, and 7. In certain embodiments, the dose schedule is a week, and an HDACi is administered every other day on days 2, 4, and 6. In certain embodiments, the HDACi has an elimination half-life of less than 34 hours. In certain embodiments, the HDACi has an elimination half-life of less than 20 hours. In certain embodiments, the HDACi has an elimination half-life of less than 12 hours. In certain embodiments, the HDACi has an elimination half-life of less than 6 hours. In certain embodiments, an antiviral is administered daily during the schedule. In certain embodiments, the antiviral is valganciclovir, and the valgancicloviris administered at a dose of 900 milligrams or 450 milligrams.

[0067] In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 1 day of the dose schedule. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 2 days of the dose schedule. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 3 days of the dose schedule. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 4 days of the dose schedule. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 5 days of the dose schedule. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 6 days of the dose schedule. In certain embodiments, an antiviral is administered daily during the schedule. In certain embodiments, the antiviral is valganciclovir, and the valganciclovir is administered at a dose of 900 milligrams or 450 milligrams. In certain embodiments, the valganciclovir is not administered for 1, 2, 3, 4, 5, 6, or 7 days of a week-long schedule.

[0068] In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 1 day followed by 6 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 2 days followed by 5 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 3 days followed by 4 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 4 days followed by 3 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 5 days followed by 2 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered for 6 days followed by 1 day of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 1, 2, 5, and 7. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 2, 4, and 6. In certain embodiments, the nanatinostat is administered QD and 30 milligrams. In certain embodiments, the nanatinostat is administered QD at 20 milligrams. In certain embodiments, the nanatinostat is administered QD at 15 milligrams. In certain embodiments, the nanatinostat is administered QD at 10 milligrams. In certain embodiments, the nanatinostat is administered BID at 15 milligrams. In certain embodiments, the nanatinostat is administered BID at 10 milligrams. In certain embodiments, the nanatinostat is administered BID at 5 milligrams. In certain embodiments, the nanatinostat is administered TID at 15 milligrams. In certain embodiments, the nanatinostat is administered TID at 10 milligrams. In certain embodiments, the nanatinostat is administered TID at 5 milligrams. In certain embodiments, an antiviral is administered daily during the schedule. In certain embodiments, an antiviral is not administered for one day of the treatment schedule. In certain embodiments, the antiviral is valganciclovir, and the valganciclovir is administered at a dose of 900 milligrams or 450 milligrams.

[0069] In certain embodiments, the dose schedule is a week, and nanatinostat is administered 20mg QD for 1 day followed by 6 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 20mg QD for 2 days followed by 5 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 20mg QD for 3 days followed by 4 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 20mg QD for 4 days followed by 3 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 20mg QD for 5 days followed by 2 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 20mg QD for 6 days followed by 1 day of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 1, 2, 5, and 7. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 2, 4, and 6. In certain embodiments, an antiviral is administered daily during the schedule. In certain embodiments, the antiviral is valganciclovir, and the valganciclovir is administered at a dose of 900 milligrams or 450 milligrams.

[0070] In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg QD for 1 day followed by 6 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered lOmg QD for 2 days followed by 5 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg QD for 3 days followed by 4 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg QD for 4 days followed by 3 days of no HDACi treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg QD for 5 days followed by 2 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg QD for 6 days followed by 1 day of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 1, 2, 5, and 7. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 2, 4, and 6. In certain embodiments, an antiviral is administered daily during the schedule. In certain embodiments, the antiviral is valganciclovir, and the valganciclovir is administered at a dose of 900 milligrams or 450 milligrams.

[0071] In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg BID for 1 day followed by 6 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg BID for 2 days followed by 5 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg BID for 3 days followed by 4 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg BID for 4 days followed by 3 days of no HDACi treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg BID for 5 days followed by 2 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 1 Omg BID for 6 days followed by 1 day of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 1, 2, 5, and 7. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 2, 4, and 6. In certain embodiments, an antiviral is administered daily during the schedule. In certain embodiments, an antiviral is administered at a lower dosage on certain days of the treatment schedule. In certain embodiments, the antiviral is valganciclovir, and the valganciclovir is administered at a dose of 900 milligrams or 450 milligrams.

[0072] In certain embodiments, the dose schedule is a week, and nanatinostat is administered 5mgBID for 1 day followed by 6 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 5mgBID for 2 days followed by 5 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 5mg BID for 3 days followed by 4 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 5 mg BID for 4 days followed by 3 days of no HD ACi treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 5mgBID for 5 days followed by 2 days of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered 5mgBID for 6 days followed by 1 day of no nanatinostat treatment. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 1, 2, 5, and 7. In certain embodiments, the dose schedule is a week, and nanatinostat is administered every other day on days 2, 4, and 6. In certain embodiments, an antiviral is administered daily during the schedule. In certain embodiments, the antiviral is valganciclovir, and the valganciclovir is administered at a dose of 900 milligrams or 450 milligrams.

[0073] The HD ACi can be given with food or a meal, or a type of nutritional supplement. In certain embodiments, nanatinostat is given with food or a meal or a type of nutritional supplement. Dosing the HD ACi with food can be combined with the above-mentioned schedules to further increase the Cmax and bioavailability of the HD ACi or nanatinostat.

[0074] Also envisioned herein is dose packaging to efficiently and easily implement the dose schedule mentioned above. The packaging can be, for example, a blister pack or other sealable packing that allows the HD ACi and antiviral doses for any given day to be accessed. In certain embodiments, the HD ACi and antiviral agent can be packaged so that the formulations of each are separate (e.g., one day’s dose comprises HD ACi and antiviral agent separated. In certain embodiments, the packing can comprise co-formulated HD ACi and antiviral agent. In certain embodiments, the packing can comprise co-formulated nanatinostat and valganciclovir. When such packaging is utilized with the schedules disclosed herein, a day when both HD ACi and antiviral agent are to be administered the packing comprise a single oral dosage form that comprises both HD ACi and antiviral agent; and a day when only an antiviral agent is to be administered the packing can comprise antiviral agent without HD ACi. When such packaging is utilized with the schedules disclosed herein, a day when both nanatinostat and valganciclovir are to be administered the packing comprise a single oral dosage f orm that comprises both nanatinostat and valganciclovir; and a day when only valganciclovir is to be administered the packing can comprise valganciclovir without nanatinostat. [0075] The schedules described herein can also be administered to certain patients with HDACi or antiviral side effects. In certain embodiments, the methods described herein encompass selecting a patent with thrombocytopenia. In certain embodiments, the methods and HDACi compositions described herein are for use in a patent with thrombocytopenia. Thrombocytopenia is generally defined as a platelet countbelow 150,000 platelets per microliter. In certain embodiments, the patient can be selected for treatment by the methods herein with a platelet count of below about 50,000; 75,000; 100,000, or 125,000 platelets per microliter. In certain embodiments, the methods do not encompass a set schedule of HDACi administration, but further monitoring for resolution of thrombocytopenia before retreatment with HDACi. In certain embodiments, if a patient has one or more dose interruptions for HDACi toxicity or has had to interrupt for more than 14 days, the methods described herein include a dose reduction for the HDACi inhibitor. In certain embodiments with a dose reduction, the HDACi will comprise nanatinostat and the dose reduction will be in 5 mg increments. In certain embodiments, the HDACi dose is re-escalated.

[0076] The schedules described herein can also be administered to certain patients with HDACi or antiviral side effects. In certain embodiments, the methods described herein encompass selecting a patent with high creatinine levels or another marker of impaired kidney function. In certain embodiments, the methods and HDACi compositions described herein are for use in a patent with high creatinine levels or another marker of impaired kidney function. A serum creatinine level that exceeds 1 .1 mg/dL for a woman or 1.3 mg/dL for a man is generally considered elevated. In certain embodiments, an individual is selected to receive HDACi and antiviral according to the schedule described herein if they possess a serum creatinine level that exceeds 1. 1 mg/dL for a woman or 1 .3 mg/dL for a man. In certain embodiments, a patient can be selected to receive HDACi and antiviral according to the schedule described herein if they possess a blood urea nitrogen level in excess of the normal range. In certain embodiments, 20 milligrams per deciliter BUN exceeds the normal range.

[0077] The dosing schedules of HDACi and antivirals described herein can also be deployed prospectively to prevent certain side-effects in at risk individuals. In certain embodiments, a patient can be selected to receive HDACi and antiviral according to a schedule described herein if they possess a risk factor for compromised kidney function or thrombocytopenia. Risk factors for compromised kidney function comprise preexisting kidney disease, receipt of a kidney transplant, diabetes, high blood pressure, family history of kidney disease, advanced age, or African-American, Asian, Native American, or Hispanic ethnicity. Risk factors for thrombocytopenia comprise previous treatment with chemotherapy or radiation therapy, a history of anemia or thrombocytopenia.

[0078] In certain embodiments, the individual selected to be treated by the methodsand schedules described herein is positive for the human immunodeficiency virus (HIV).

FORMULATIONS, ROUTES OF ADMINISTRATION, AND EFFECTIVE DOSES [0079] Another aspect of the present invention relates to formulations, routes of administration and effective doses for pharmaceutical compositions comprising an agent or combination of agents. Such pharmaceutical compositions can be used to treat a virus-induced autoimmune disease such as MS as described above. A pharmaceutical composition can comprise a viral inducing agent. A pharmaceutical composition can comprise a viral inducing agent and one or more additional agents. A pharmaceutical composition can comprise an antiviral agent. A pharmaceutical composition can comprise an antiviral agent and one or more additional agents. A pharmaceutical composition can comprise a viral inducing agent and an antiviral agent. A pharmaceutical composition can comprise a viral inducing agent, an antiviral agent, and one or more additional agents.

[0080] The agents or their pharmaceutically acceptable salts can be provided alone or in combination with one or more other agents or with one or more other forms. For example, a formulation can comprise one or more agents in particular proportions, depending on the relative potencies of each agent and the intended indication. For example, in compositions for targeting two different targets and where potencies are similar, about a 1 :1 ratio of agents can be used. The two forms can be formulated together, in the same dosage unit, e.g., in one cream, suppository, tablet, capsule, enteric coated tablet or capsule, aerosol spray, or packet of powder to be dissolved in a beverage; or each form may be formulated in a separate unit, e.g., two creams, two suppositories, two tablets, two capsules, a tablet and a liquid for dissolving the tablet, two aerosol sprays, or a packet of powder and a liquid for dissolving the powder, etc. [0081] A “pharmaceutically acceptable salt” can be a salt that retains the biological effectiveness and properties of one or more agents, and which are not biologically or otherwise undesirable. For example, a pharmaceutically acceptable salt does not interfere with the beneficial effect of a viral inducing agent or an antiviral agent.

[0082] Salts can include those of the inorganic ions, for example, sodium, potassium, calcium, magnesium ions, and the like. Salts can include salts with inorganic or organic acids, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p -toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid. If one or more agents contain a carboxy group or other acidic group, it can be converted into a pharmaceutically acceptable addition salt with inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclo hexyl-amine, ethanolamine, diethanolamine, triethanolamine, and the like.

[0083] A pharmaceutically acceptable ester or amide can be an ester or amide that retains biological effectiveness and properties of one or more agents, and which are not biologically or otherwise undesirable. For example, the ester or amide does not interfere with the beneficial effect of a viral inducing agent, an antiviral agent, or an additional agent. Esters can include, for example, ethyl, methyl, isobutyl, ethylene glycol, and the like. Amides include can include, for example, unsubstituted amides, alkyl amides, dialkyl amides, and the like.

[0084] One or more agents and/or combinations of agents can be administered with still other agents. The choice of agents that can be co-administered with the agents and/or combinations of agents can depend, at least in part, on the condition being treated. Agents of particular use in the formulations of the present invention include, for example, any agent having a therapeutic effect for MS, including, e.g., drugs used to treat inflammatory conditions. For example, formulations of the instant invention can additionally contain one or more conventional anti-inflammatory drugs, such as an NSAID, e.g., ibuprofen, naproxen, acetominophen, ketoprofen, or aspirin. In some alternative embodiments, for the treatment of a virus-induced inflammatory condition can additionally contain one or more conventional influenza antiviral agents, such as amantadine, rimantadine, zanamivir, and oseltamivir. In treatments for retroviral infections, such as HIV, formulations of the instant invention may additionally contain one or more conventional antiviral drug, such as protease inhibitors (lopinavir/ritonavir {Kaletra™}, indinavir {Crixivan™}, ritonavir {Norvir™}, nelfinavir {Viracept™}, saquinavir hard gel capsules {Invirase™}, atazanavir {Reyataz™}, amprenavir {Agenerase™}, fosamprenavir {Telzir™}, tipranavir{Aptivus™}), reverse transcriptase inhibitors, includingnon-Nucleoside and Nucleoside/nucleotide inhibitors(AZT {zidovudine, Retrovir™ },ddl {didanosine, Videx™}, 3TC {lamivudine, Epivir™}, d4T {stavudine, Zerit™}, abacavir {Ziagen™}, FTC {emtricitabine, Emtriva™}, tenofovir {Viread™}, efavirenz {Sustiva™} and nevirapine {Viramune™}), fusion inhibitors T20 {enfuvirtide, Fuzeon™}, integrase inhibitors (MK-0518 and GS-9137), and maturation inhibitors (PA-457 {Bevirimat™}). As another example, formulations can additionally contain one or more supplements, such as vitamin C, E or other anti-oxidants. [0085] One or more agents (or pharmaceutically acceptable salts, esters or amides thereof) can be administered per se or in the form of a pharmaceutical composition wherein the one or more active agent(s) is in an admixture or mixture with one or more pharmaceutically acceptable carriers. A pharmaceutical composition, as used herein, can be any composition prepared for administration to a subject. Pharmaceutical compositions can be formulated in conventional manner using one or more physiologically acceptable carriers, comprising excipients, diluents, and/or auxiliaries, e.g., that facilitate processing of the active agents into preparations that can be administered. Proper formulation can depend at least in part upon the route of administration chosen. One or more agents, or pharmaceutically acceptable salts, esters, or amides thereof, can be delivered to a patient using a number of routes or modes of administration, including oral, buccal, topical, rectal, transdermal, transmucosal, subcutaneous, intravenous, and intramuscular applications, as well as by inhalation.

[0086] For oral administration, one or more agents can be formulated readily by combining the one or more active agents with pharmaceutically acceptable carriers well known in the art. Such carriers can enable the one or more agents to be formulated as tablets, including chewable tablets, pills, dragees, capsules, lozenges, hard candy, liquids, gels, syrups, slurries, powders, suspensions, elixirs, wafers, and the like, for oral ingestion by a patient to be treated. Such formulations can comprise pharmaceutically acceptable carriers including solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Generally, the agents of the invention can be included at concentration levels ranging from about 0.5%, about 5%, about 10%, about 20%, or about 30% to about 50%, about 60%, about 70%, about 80% or about 90% by weight of the total composition of oral dosage forms, in an amount sufficient to provide a desired unit of dosage.

[0087] Aqueous suspensions for oral use can contain one or more agents with pharmaceutically acceptable excipients, such as a suspending agent (e.g., methyl cellulose), a wetting agent (e.g., lecithin, lysolecithin and/or a long-chain fatty alcohol), as well as coloring agents, preservatives, flavoring agents, and the like.

[0088] Oils or non-aqueous solvents can be required to bring one or more agents into solution, due to, for example, the presence of large lipophilic moieties. Alternatively, emulsions, suspensions, or other preparations, for example, liposomal preparations, can be used. With respect to liposomal preparations, any known methods for preparing liposomes for treatment of a condition can be used. See, for example, Bangham et al., J. Mol. Biol. 23 : 238-252 (1965) and Szoka et al., Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein by reference. Ligands can also be attached to the liposomes to direct these compositions to particular sites of action. One or more agents can also be integrated into foodstuffs, e.g, cream cheese, butter, salad dressing, or ice cream to facilitate solubilization, administration, and/or compliance in certain patient populations.

[0089] Pharmaceutical preparations for oral use can be obtained as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; flavoring elements, cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or poly vinyl pyrrolidone (PVP). Disintegrating agents can be added, for example, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. One or more agents can also be formulated as a sustained release preparation.

[0090] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of one or more active agents.

[0091] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active agents can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration canbe in dosages suitable for administration.

[0092] For injection, one or more agents can be formulated in aqueous solutions, including but not limited to physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. Such compositions can also include one or more excipients, for example, preservatives, solubilizers, fillers, lubricants, stabilizers, albumin, and the like. Methods of formulation are known in the art, for example, as disclosed in Remington’s Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton P.

[0093] One or more agents can also be formulated as a depot preparation. Such long acting formulations canbe administered by implantation or transcutaneous delivery (for example subcutaneously or intramuscularly), intramuscular injection or use of a transdermal patch. Thus, for example, one or more agents can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0094] Pharmaceutical compositions comprising one or more agents can exert local and regional effects when administered topically or injected at or near particular sites of infection. Direct topical application, e.g., of a viscous liquid, gel,jelly, cream, lotion, ointment, suppository, foam, or aerosol spray, can be used for local administration, to produce, for example local and/or regional effects. Pharmaceutically appropriate vehicles for such formulation include, for example, lower aliphatic alcohols, polyglycols (e.g., glycerol or polyethylene glycol), esters of fatty acids, oils, fats, silicones, and the like. Such preparations may also include preservatives (e.g., p-hydroxybenzoic acid esters) and/or antioxidants (e.g., ascorbic acid and tocopherol). See also Dermatological Formulations: Percutaneous absorption, Barry (Ed.), Marcel Dekker Incl, 1983. In some embodiments, local/topical formulations comprising a viral inducing agent and or antiviral agent are used to treat epidermal or mucosal viral -induced inflammatory condition. [0095] Pharmaceutical compositions can contain a cosmetically or dermatologically acceptable carrier. Such carriers can be compatible with skin, nails, mucous membranes, tissues and/or hair, and can include any conventionally used cosmetic or dermatological carrier meeting these requirements. Such carriers canbe readily selected by one of ordinary skill in the art. In formulating skin ointments, an agent or combination of agents canbe formulated in an oleaginous hydrocarbon base, an anhydrous absorption base, a water-in-oil absorption base, an oil-in-water water-removable base and/or a water-soluble base.

[0096] The compositions according to the present invention canbe in any form suitable for topical application, including aqueous, aqueous -alcoholic or oily solutions, lotion or serum dispersions, aqueous, anhydrous or oily gels, emulsions obtainedby dispersion of a fatty phase in an aqueous phase (O/W or oil in water) or, conversely, (W/O or water in oil), microemulsions or alternatively microcapsules, microparticles or lipid vesicle dispersions of ionic and/or nonionic type. These compositions can be prepared according to conventional methods. The amounts of the various constituents of the compositions according to the invention can be those conventionally used in the art. These compositions constitute protection, treatment or care creams, milks, lotions, gels or foams for the face, for the hands, for the body and/or for the mucous membranes, or for cleansing the skin. The compositions can also consist of solid preparations constituting soaps or cleansing bars.

[0097] A pharmaceutical composition can also contain adjuvants common to the cosmetic and dermatological fields, for example, hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preserving agents, antioxidants, solvents, fragrances, fillers, sunscreens, odor-absorbers and dyestuffs. The amounts of these various adjuvants can be those conventionally used in the fields considered and, for example, are from about 0.01% to about 20% of the total weight of the composition. Depending on their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase and/or into the lipid vesicles.

[0098] Ocular viral infections can be effectively treated with ophthalmic solutions, suspensions, ointments or inserts comprising an agent or combination of agents of the present invention. [0099] In some embodiments, viral infections of the ear can be effectively treated with otic solutions, suspensions, ointments or inserts comprising an agent or combination of agents of the present invention.

[00100] One or more agents can be delivered in soluble rather than suspension form, which can allow for more rapid and quantitative absorption to the sites of action. In general, formulations such as jellies, creams, lotions, suppositories and ointments can provide an area with more extended exposure to the agents of the present invention, while formulations in solution, e.g., sprays, provide more immediate, short-term exposure.

[00101] Relating to topical/local application, a pharmaceutical composition can include one or more penetration enhancers. For example, the formulations can comprise suitable solid or gel phase carriers or excipients that increase penetration or help delivery of agents or combinations of agents of the invention across a permeability barrier, e.g., the skin. Many of these penetrationenhancing compounds are known in the art of topical formulation, and include, e.g., water, alcohols (e.g., terpenes like methanol, ethanol, 2-propanol), sulfoxides (e.g., dimethyl sulfoxide, decylmethyl sulfoxide, tetradecylmethyl sulfoxide), pyrrolidones (e.g., 2 -pyrrolidone, N-methyl- 2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone), laurocapram, acetone, dimethylacetamide, dimethylformamide, tetrahydrofurfuryl alcohol, L-a-amino acids, anionic, cationic, amphoteric or nonionic surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), fatty acids, fatty alcohols (e.g., oleic acid), amines, amides, clofibric acid amides, hexamethylene lauramide, proteolytic enzymes, a-bisabolol, d-limonene, urea andN,N-diethyl-m-toluamide, and the like. Additional examples include humectants (e.g., urea), glycols (e.g., propylene glycol and polyethylene glycol), glycerol monolaurate, alkanes, alkanols, ORGELASE, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and/or other polymers. A pharmaceutical composition can include one or more such penetration enhancers. [00102] A pharmaceutical composition for local/topical application can include one or more antimicrobial preservatives, for example, quaternary ammonium compounds, organic mercurials, p -hydroxy benzoates, aromatic alcohols, chlorobutanol, and the like.

[00103] Gastrointestinal viral infections can be effectively treated with orally - or rectally delivered solutions, suspensions, ointments, enemas and/or suppositories comprising an agent or combination of agents of the present invention.

[00104] Respiratory viral infections can be effectively treated with aerosol solutions, suspensions or dry powders comprising an agent or combination of agents of the present invention. Administration by inhalation is particularly useful in treating viral infections of the lung, such as influenza. The aerosol can be administered through the respiratory system or nasal passages. For example, one skilled in the art will recognize that a composition of the present invention can be suspended or dissolved in an appropriate carrier, e.g., a pharmaceutically acceptable propellant, and administered directly into the lungs using a nasal spray or inhalant. For example, an aerosol formulation comprising a viral inducing agent and/or antiviral agent can be dissolved, suspended or emulsified in a propellant or a mixture of solvent and propellant, e.g, for administration as a nasal spray or inhalant. Aerosol formulations may contain any acceptable propellant under pressure, such as a cosmetically or dermatologically or pharmaceutically acceptable propellant, as conventionally used in the art.

[00105] An aerosol formulation for nasal administration is generally an aqueous solution designed to be administered to the nasal passages in drops or sprays. Nasal solutions can be similar to nasal secretions in that they are generally isotonic and slightly buffered to maintain a pH of about 5.5 to about 6.5, although pH values outside of this range can additionally be used. Antimicrobial agents or preservatives can also be included in the formulation.

[00106] An aerosol formulation for inhalations and inhalants can be designed so that an agent or combination of agents can be carried into the respiratory tree of the subject when administered by the nasal or oral respiratory route. Inhalation solutions can be administered, for example, by a nebulizer. Inhalations or insufflations, comprising finely powdered or liquid drugs, can be delivered to the respiratory system as a pharmaceutical aerosol of a solution or suspension of the agent or combination of agents in a propellant, e.g., to aid in disbursement. Propellants can be liquefied gases, including halocarbons, for example, fluorocarbons such as fluorinated chlorinated hydrocarbons, hydrochlorofluorocarbons, and hydrochlorocarbons, as well as hydrocarbons and hydrocarbon ethers.

[00107] Halocarbon propellants can include fluorocarbon propellants in which all hydrogens are replaced with fluorine, chlorofluorocarbon propellants in which all hydrogens are replaced with chlorine and at least one fluorine, hydrogen-containing fluorocarbon propellants, and hydrogen-containing chlorofluorocarbon propellants. Halocarbon propellants are describedin Johnson, U.S. Pat. No. 5,376,359, issued Dec. 27, 1994; Byron et al., U.S. Pat. No. 5, 190,029, issued Mar. 2, 1993; and Purewal et al., U.S. Pat. No. 5,776,434, issued Jul. 7, 1998.

Hydrocarbon propellants useful in the invention include, for example, propane, isobutane, n- butane, pentane, isopentane and neopentane. A blend of hydrocarbons can also be used as a propellant. Ether propellants include, for example, dimethyl ether as well as the ethers. An aerosol formulation of the invention can also comprise more than one propellant. For example, an aerosol formulation can comprise more than one propellant from the same class, such as two or more fluorocarbons; or more than one, more than two, more than three propellants from different classes, such as a fluorohydrocarbon and a hydrocarbon. Pharmaceutical compositions of the present invention can also be dispensed with a compressed gas, e.g., an inert gas such as carbon dioxide, nitrous oxide or nitrogen.

[00108] Aerosol formulations can also include other components, for example, ethanol, isopropanol, propylene glycol, as well as surfactants or other components such as oils and detergents. These components can serve to stabilize the formulation and/or lubricate valve components.

[00109] The aerosol formulation can be packaged under pressure and can be formulated as an aerosol using solutions, suspensions, emulsions, powders and semisolid preparations. For example, a solution aerosol formulation can comprise a solution of an agent, such as a viral inducing agent and/or antiviral agent in (substantially) pure propellant or as a mixture of propellant and solvent. The solvent can be used to dissolve the agent and/or retard the evaporation of the propellant. Solvents useful in the invention include, for example, water, ethanol and glycols. Any combination of suitable solvents can be used, optionally combined with preservatives, antioxidants, and/or other aerosol components.

[00110] An aerosol formulation can also be a dispersion or suspension. A suspension aerosol formulation may comprise a suspension of an agent or combination of agents of the instant invention, e.g., a viral inducing agent and/or antiviral agent, and a dispersing agent. Dispersing agents useful in the invention include, for example, sorbitan trioleate, oleyl alcohol, oleic acid, lecithin and corn oil. A suspension aerosol formulation can also include lubricants, preservatives, antioxidant, and/or other aerosol components.

[00111] An aerosol formulation can be formulated as an emulsion. An emulsion aerosol formulation can include, for example, an alcohol such as ethanol, a surfactant, water and a propellant, as well as an agent or combination of agents, e.g., a viral inducing agent and/or an antiviral agent. The surfactant used can be nonionic, anionic or cationic. One example of an emulsion aerosol formulation comprises, for example, ethanol, surfactant, water and propellant. Another example of an emulsion aerosol formulation comprises, for example, vegetable oil, glyceryl monostearate and propane.

[00112] Pharmaceutical compositions suitable for use in the present invention can include compositions wherein the active ingredients are present in an effective amount, i.e., in an amount effective to achieve therapeutic and/or prophylactic benefit in a host with at least one virus-induced inflammatory condition. The actual amount effective for a particular application will depend on the condition or conditions being treated, the condition of the subject, the formulation, and the route of administration, as well as other factors known to those of skill in the art. Determination of an effective amount of a viral inducing agent and/or antiviral agent is well within the capabilities of those skilled in the art, in light of the disclosure herein, and can be determined using routine optimization techniques.

[00113] An effective amount for use in humans can be determined from animal models. For example, a dose for humans can be formulated to achieve circulating, liver, topical and/or gastrointestinal concentrations that have been found to be effective in animals. One skilled in the art can determine the effective amount for human use, especially in light of the animal model experimental data described herein. Based on animal data, and other types of similar data, those skilled in the art can determine an effective amount of a composition appropriate for humans. [00114] An effective amount when referring to an agent or combination of agents of the invention can generally mean the dose ranges, modes of administration, formulations, etc., that have been recommended or approved by any of the various regulatory or advisory organizations in the medical or pharmaceutical arts (e.g., FDA, AMA) or by the manufacturer or supplier.

[00115] Further, appropriate doses for a viral inducing agent and/or antiviral agent can be determined based on in vitro experimental results.

[00116] A person of skill in the art would be able to monitor in a patient the effect of administration of a particular agent. For example, HIV or EBV viral load levels can be determined by techniques standard in the art, such as measuring CD4 cell counts, and/or viral levels as detected by PCR. Other techniques would be apparent to one of skill in the art.

[00117] This disclosure provides for a kit, the kits can comprise one or more containers, the kit can comprise any combination of HD AC inhibitors, antivirals or additional agents mentioned in the methods of this disclosure in suitable packaging. The kit may contain instructions for use. The HD AC inhibitor or antiviral can be present in any concentration disclosed herein, can be packaged for administration by any route disclosed herein, or in any formulation disclosed herein. In some embodiments, the HD AC inhibitor and antiviral agent are packaged together, in a suitable package or container, in a kit. The kit may be for convenient administration or dosing, and management thereof. In some further embodiments, the HD AC inhibitor and antiviral are formulated together as a pharmaceutical composition in a single dose. In some alternative embodiments, the HD AC inhibitor and antiviral are formulated as separate pharmaceutical compositions. In some embodiments, the pharmaceutical composition of the HD AC inhibitor is packaged for once a week, twice a week, thrice a week, four times a week or more, once a month, twice a month, thrice a month, four times a month or more dosing; and the pharmaceutical composition of the antiviral is packaged for daily, twice daily, thrice daily, four times a day or more dosing. In some embodiments, the antiviral is administered or taken without the HD AC inhibitor. In some embodiments, the treatment course of the HD AC inhibitor and antiviral can be as follows: the HD AC inhibitor and the antiviral are taken or administered together in the same pharmaceutical composition on any of the first, second, third, fourth, fifth or more days of treatment; and the antiviral is taken or administered by itself on any of days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more. In some further embodiments, the treatment course can be as follows: the HD AC inhibitor and antiviral are taken or administered separately in different pharmaceutical composition on any of the first, second, third, fourth, fifth or more days of treatment, either at the same time ortemporally separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more hours; and the antiviral is taken or administered by itself on any of days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or more. In some embodiments, the HD AC inhibitor packagedin the kit is nanatinostat. In some embodiments, the antiviral is ganciclovir, in other embodiments, it is valganciclovir. In some embodiments, the treatment course is repeated for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more iterations.

[00118] The kits described herein may comprise a plurality of oral dosage forms, wherein the oral dosage form comprises an HDACi and an antiviral. In certain embodiments, the plurality comprises seven or a multiple thereof. In certain embodiments, the kit comprisesone oral dosage form comprising HD ACi and antiviral co-formulatedinto a single form, and six oral dosage forms comprising an antiviral and no or a reduced amount of HD ACi. In certain embodiments, the kit comprises two oral dosage forms comprising HD ACi and antiviral co- formulated into a single form, and five oral dosage forms comprising an antiviral and no or a reduced amount of HD ACi. In certain embodiments, the kit comprises three oral dosage forms comprising HD ACi and antiviral co-formulated into a single form, and four oral dosage forms comprising an antiviral and no or a reduced amount of HD ACi. In certain embodiments, the kit comprises four oral dosage forms comprising HD ACi and antiviral co-formulated into a single form, and three oral dosage forms comprising an antiviral and no or a reduced amount of HD ACi. In certain embodiments, the kit comprises five oral dosage forms comprising HD ACi and antiviral co-formulatedinto a single form, and two oral dosage forms comprising an antiviral and no or a reduced amount of HD ACi. In certain embodiments, the kit comprises six oral dosage forms comprising HD ACi and antiviral co-formulated into a single form, and one oral dosage form comprising an antiviral and no or a reduced amount of HD ACi. The package may suitably comprise a multiple of seven of any of these amounts (e.g., kits providing one, two, or three-months’ worth of dosage). The oral dosage forms may be compounded for dosing once a day, twice a day, or three times daily. In certain embodiments, the HD ACi comprises nanatinostat. In certain embodiments, the amount of nanatinostat incorporated into the oral dosage form comprises 5 milligrams, 10 milligrams, 15 milligrams, 20 milligrams, 25 milligrams, 30 milligrams. In certain embodiments, the antiviral comprises valganciclovir. In certain embodiments, the amount of valganciclovir incorporated into the oral dosage form comprises 450 milligrams, 900 milligrams, or 1,800 milligrams.

[00119] The kits described herein may comprise a plurality of oral dosage forms, wherein the oral dosage form comprises an HD ACi and an antiviral formulated separately. In certain embodiments, the kit comprises at least two oral dosage form comprising HD ACi and antiviral formulated separately, and six oral dosage forms comprising an antiviral and no or a reduced amount of HD ACi. In certain embodiments, the kit comprises four oral dosage forms comprising HD ACi and antiviral formulated separately, and five oral dosage forms comprising an antiviral and no or a reduced amount of HD ACi. In certain embodiments, the kit comprises six oral dosage forms comprising HD ACi and antiviral formulated separately, and four oral dosage forms comprising an antiviral and no or a reduced amount of HD ACi. In certain embodiments, the kit comprises eight oral dosage forms comprising HD ACi and antiviral formulated separately, and three oral dosage forms comprising an antiviral and no or a reduced amount of HDACi. In certain embodiments, the kit comprises ten oral dosage forms comprising HD ACi and antiviral formulated separately, and two oral dosage forms comprising an antiviral and no or a reduced amount of HDACi. In certain embodiments, the kit comprises twelve oral dosage forms comprising HDACi and antiviral formulated separately, and one oral dosage form comprising an antiviral and no or a reduced amount of HDACi. The package may suitably comprise a multiple of seven of any of these amounts (e.g., kits providing one, two, or three - months’ worth of dosage). The oral dosage forms may be compounded for dosing once a day, twice a day, or three times daily. In certain embodiments, the HDACi comprises nanatinostat. In certain embodiments, the amount of nanatinostat incorporated into the oral dosage form comprises 5 milligrams, 10 milligrams, 15 milligrams, 20 milligrams, 25 milligrams, 30 milligrams. In certain embodiments, the antiviral comprises valganciclovir. In certain embodiments, the amount of valganciclovir incorporated into the oral dosage form comprises 450 milligrams, 900 milligrams, or 1,800 milligrams.

[00120] The kits of this invention are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar, blister packs, plastic bags), and the like. Also contemplated are packages for use in combination with a specific device, such as an inhaler, nasal administration device (e.g., an atomizer) or an infu sion device such as a minipump. A kit may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is an HD AC inhibitor. The HD AC inhibitor can be nanatinostat. The container may further comprise a second pharmaceutically active agent. This second pharmaceutically active agent can be an antiviral. The antiviral can be ganciclovir or valganciclovir.

NUMBERED EMBODIMENTS

[00121] Embodiment 1. A method of inducing expression of a viral kinase in an individual with a latent viral infection comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby inducing expression of the viral kinase.

[00122] Embodiment 2. The method of embodiment 1, wherein the individual is not afflicted with a cancer or a tumor.

[00123] Embodiment 3. The method of embodiment 1 or 2, wherein the latent viral infection is a cytomegalovirus or Epstein -Barr virus infection.

[00124] Embodiment4. The method of embodiment 1 or 2, wherein the latentviral infection is an Epstein-Barr virus infection.

[00125] Embodiment s. The method of embodiment 4, wherein the viral kinase is BGLF4.

[00126] Embodiment 6. The method of embodiment 1 or 2, wherein the latentviral infection is a cytomegalovirus infection.

[00127] Embodiment?. The method of embodiment 6, wherein the viral kinase is UL97.

[00128] Embodiment 8. The method of any one of embodiments 1 to 7, wherein expression of the viral kinase is induced in a B cell of the individual.

[00129] Embodiment 9. The method of embodiment s, wherein the B cell is non-cancerous. [00130] Embodiment 10. The method of embodiment 8 or 9, wherein the B cell is not mitotic. [00131] Embodiment 11. The method of any one of embodiments 8 to 10, wherein the B cell is in the central nervous system of the individual.

[00132] Embodiment 12. The method of any one of embodiments 1 to 11, wherein the HDACi is selected from vorinostat, romidepsin, mocetinostat, belinostat, pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide, domatinostat, entinostat, nanatinostat and combinations thereof.

[00133] Embodiment 13. The method of any one of embodiments 1 to 11 , wherein the HDACi is nanatinostat.

[00134] Embodiment 14. The method of any one of embodiments 1 to 13, wherein the HDACi is administered at a dose of about 5 milligrams per day to about 40 milligrams per day.

[00135] Embodiment 15. The method of any one of embodiments 1 to 13, wherein the HDACi is administered at a dose of about 10 milligrams per day to about 30 milligrams per day.

[00136] Embodiment 16. The method of any one of embodiments 1 to 13, wherein the HDACi is administered at a dose of about 10 milligrams per day to about 20 milligrams per day. [00137] Embodiment 17. The method of any one of embodiments 1 to 13, wherein the HDACi is administered at a dose of about 10 milligrams per day.

[00138] Embodiment 18. The method of any one of embodiments 1 to 13, wherein the HDACi is administered at a dose of about 20 milligrams per day.

[00139] Embodiment 19. The method of any one of embodiments 1 to 13, wherein the HDACi is administered at a dose of about 30 milligrams per day.

[00140] Embodiment 20. The method of any one of embodiments 1 to 13, wherein the HDACi is administered at a dose of about 40 milligrams per day.

[00141] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 3 days of the 7 day schedule.

[00142] Embodiment 22. The method of any one of embodiments 1 to 20, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 4 days of the 7 day schedule.

[00143] Embodiment 23. The method of any one of embodiments 1 to 20, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 5 days of the 7 day schedule.

[00144] Embodiment 24. The method of any one of embodiments 21 to 23, wherein the schedule is repeated.

[00145] Embodiment 25. The method of any one of embodiments 1 to 20, wherein the HDACi is administered q.d., b.i.d., ort.i.d.

[00146] Embodiment 26. The method of any one of embodiments 1 to 25, wherein the antiviral is a nucleoside analog or nucleotide analog.

[00147] Embodiment 27. The method of any one of embodiments 1 to 25, wherein the antiviral is selected from the list consisting of aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof.

[00148] Embodiment 28. The method of any one of embodiments 1 to 25, wherein the antiviral is valganciclovir.

[00149] Embodiment 29. The method of any one of embodiments 1 to 28, wherein the antiviral is administered at a total daily dose of 1 ,800 milligrams.

[00150] Embodiment 30. The method of any one of embodiments 1 to 28, wherein the antiviral is administered at a total daily dose of 900 milligrams. [00151] Embodiment 31. The method of any one of embodiments 1 to 28, wherein the antiviral is administered at a total daily dose of 450 milligrams.

[00152] Embodiment 32. The method of any one of embodiments 1 to 28, wherein the antiviral is administered according to a 7 day schedule, wherein the antiviral is administered every day of the treatment schedule.

[00153] Embodiment 33. The method of any one of embodiments 1 to 28, wherein the antiviral is administered according to a 7 day schedule, wherein the antiviral is not administered on one or more days of the treatment schedule.

[00154] Embodiment 34. The method of any one of embodiments 1 to 33, wherein the individual is afflicted with an autoimmune disease of the central nervous system.

[00155] Embodiment35. The method of embodiment 34, wherein the autoimmune diseaseof the central nervous system comprises multiple sclerosis.

[00156] Embodiment 36. The method of embodiment 35, wherein the multiple sclerosis is active multiple sclerosis.

[00157] Embodiment 37. The method of embodiment 35 or 36, wherein the multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary -progressive MS (MS).

[00158] Embodiment 38. The method of embodiment 35 or 36, wherein the multiple sclerosis is relap sing-remitting MS (RRMS).

[00159] Embodiment 39. The method of embodiment 35 or 36, wherein the multiple sclerosis is primary -progressive MS (MS).

[00160] Embodiment 40. The method of embodiment 35 or 36, wherein the multiple sclerosis is secondary -progressive MS (SPMS).

[00161] Embodiment 41. A method of inducing expression of a viral kinase in a non -cancerous B cell of the central nervous system of an individual, the method comprising admini stering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby inducing expression of the viral kinase in the non-cancerous B cell of the central nervous system.

[00162] Embodiment 42. The method of embodiment 41, wherein the individual is not afflicted with a cancer or a tumor.

[00163] Embodiment 43. The method of embodiment 41 or 42, wherein the viral kinase is a cytomegalovirus or Epstein -Barr virus kinase. [00164] Embodiment 44. The method of embodiment 41 or 42, wherein the viral kinase is an Epstein-Barr virus kinase.

[00165] Embodiment 45. The method of embodiment 44, wherein the viral kinase is BGLF4.

[00166] Embodiment 46. The method of embodiment 41 or 42, wherein the viral kinase is a cytomegalovirus kinase.

[00167] Embodiment 47. The method of embodiment 46, wherein the viral kinase is UL97.

[00168] Embodiment 48. The method of any one of embodiments 41 to 47, wherein the B cell is not mitotic.

[00169] Embodiment 49. The method of any one of embodiments 41 to 48, wherein the HDACi is selected from vorinostat, romidepsin, mocetinostat, belinostat, pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide, domatinostat, entinostat, nanatinostat and combinations thereof.

[00170] Embodiment 50. The method of any one of embodiments 41 to 48, wherein the HDACi is nanatinostat.

[00171] Embodiment 51. The method of any one of embodiments 41 to 50, wherein the HDACi is administered ata dose of about 5 milligrams per day to about 40 milligrams per day.

[00172] Embodiment 52. The method of any one of embodiments 41 to 50, wherein the HDACi is administered at a dose of about 10 milligrams per day to about 30 milligrams per day.

[00173] Embodiment 53. The method of any one of embodiments 41 to 50, wherein the HDACi is administered at a dose of about 10 milligrams per day to about 20 milligrams per day.

[00174] Embodiment 54. The method of any one of embodiments 41 to 50, wherein the HDACi is administered at a dose of about 10 milligrams per day.

[00175] Embodiment 55. The method of any one of embodiments 41 to 50, wherein the HDACi is administered at a dose of about 20 milligrams per day.

[00176] Embodiment 56. The method of any one of embodiments 41 to 50, wherein the HDACi is administered at a dose of about 30 milligrams per day.

[00177] Embodiment 57. The method of any one of embodiments 41 to 50, wherein the HDACi is administered at a dose of about 40 milligrams per day.

[00178] Embodiment 58. The method of any one of embodiments 41 to 57, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 3 days of the 7 day schedule. [00179] Embodiment 59. The method of any one of embodiments 41 to 57, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 4 days of the 7 day schedule.

[00180] Embodiment 60. The method of any one of embodiments 41 to 57, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 5 days of the 7 day schedule.

[00181] Embodiment 61. The method of any one of embodiments 58 to 60, wherein the schedule is repeated.

[00182] Embodiment 62. The method of any one of embodiments 41 to 61 , wherein the HDACi is administered q.d., b.i.d., ort.i.d.

[00183] Embodiment 63. The method of any one of embodiments 41 to 62, wherein the antiviral is a nucleoside analog or nucleotide analog.

[00184] Embodiment 64. The method of any one of embodiments 41 to 62, wherein the antiviral is selected from the list consisting of aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof.

[00185] Embodiment 65. The method of any one of embodiments 41 to 62, wherein the antiviral is valganciclovir.

[00186] Embodiment 66. The method of any one of embodiments 41 to 65, wherein the antiviral is administered at a total daily dose of 1 ,800 milligrams.

[00187] Embodiment 67. The method of any one of embodiments 41 to 65, wherein the antiviral is administered at a total daily dose of 900 milligrams.

[00188] Embodiment 68. The method of any one of embodiments 41 to 65, wherein the antiviral is administered at a total daily dose of 450 milligrams.

[00189] Embodiment 69. The method of any one of embodiments 41 to 68, wherein the antiviral is administered according to a 7 day schedule, wherein the antiviral is administered every day of the treatment schedule.

[00190] Embodiment 70. The method of any one of embodiments 41 to 68, wherein the antiviral is administered according to a 7 day schedule, wherein the antiviral is not administered on one or more days of the treatment schedule.

[00191] Embodiment 71. The method of any one of embodiments 41 to 70, wherein the individual is afflicted with an autoimmune disease of the central nervous system.

[00192] Embodiment 72. The method of embodiment 71, wherein the autoimmune disease of the central nervous system comprises multiple sclerosis. [00193] Embodiment 73. The method of embodiment 72, wherein the multiple sclerosis is active multiple sclerosis.

[00194] Embodiment 74. The method of embodiment 72 or 73, wherein the multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary -progressive MS (MS).

[00195] Embodiment 75. The method of embodiment 72 or 73, wherein the multiple sclerosis is relap sing-remitting MS (RRMS).

[00196] Embodiment 76. The method of embodiment 72 or 73, wherein the multiple sclerosis is primary -progressive MS (MS).

[00197] Embodiment 77. The method of embodiment 72 or 73, wherein the multiple sclerosis is secondary -progressive MS (SPMS).

[00198] Embodiment 78. A method of treating an autoimmune disease of the central nervous system in an individual, the method comprising administering to the individual a histone deacetylase inhibitor (HDACi) and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby treating the autoimmune disease of the central nervous system.

[00199] Embodiment 79. The method of embodiment 78, wherein the individual is not afflicted with a cancer or a tumor.

[00200] Embodiment 80. The method of embodiment 78 or 79, wherein the individual has a latent cytomegalovirus or Ep stein -Barr virus infection.

[00201] Embodiment 81. The method of embodiment 78 or 79, wherein the individual has a latent Epstein-Barr virus infection.

[00202] Embodiment 82. The method of embodiment 78 or 79, wherein the individual has a latent cytomegalovirus virus infection.

[00203] Embodiment 83. The method of any one of embodiments 78to 82, wherein the HDACi is selected from vorinostat, romidepsin, mocetinostat, belinostat, pracinostat, givinostat, panobinostat, CUDC-101, CDX101, chidamide, domatinostat, entinostat, nanatinostat and combinations thereof.

[00204] Embodiment 84. The method of any one of embodiments 78 to 83, wherein the HDACi is nanatinostat.

[00205] Embodiment 85. The method of any one of embodiments 78 to 84, wherein the HDACi is administered ata dose of about 5 milligrams per day to about 40 milligrams per day. [00206] Embodiment 86. The method of any one of embodiments 78 to 84, wherein the HDACi is administered at a dose of about 10 milligrams per day to about 30 milligrams per day.

[00207] Embodiment 87. The method of any one of embodiments 78 to 84, wherein the HDACi is administered at a dose of about 10 milligrams per day to about 20 milligrams per day.

[00208] Embodiment 88. The method of any one of embodiments 78 to 84, wherein the HDACi is administered at a dose of about 10 milligrams per day.

[00209] Embodiment 89. The method of any one of embodiments 78 to 84, wherein the HDACi is administered at a dose of about20 milligrams per day.

[00210] Embodiment 90. The method of any one of embodiments 78 to 84, wherein the HDACi is administered at a dose of about 30 milligrams per day.

[00211] Embodiment 91. The method of any one of embodiments 78 to 84, wherein the HDACi is administered at a dose of about 40 milligrams per day.

[00212] Embodiment92. The method of any one of embodiments 78to 91, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 3 days of the 7 day schedule.

[00213] Embodiment93. The method of any one of embodiments 78to 91, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 4 days of the 7 day schedule.

[00214] Embodiment94. The method of any one of embodiments 78to 91, wherein the HDACi is administered according to a 7 day schedule, wherein the HDACi is administered on 5 days of the 7 day schedule.

[00215] Embodiment 95. The method of any one of embodiments 92 to 94, wherein the schedule is repeated.

[00216] Embodiment 96. The method of any one of embodiments 78 to 95, wherein the HDACi is administered q.d., b.i.d., ort.i.d.

[00217] Embodiment 97. The method of any one of embodiments 78 to 96, wherein the antiviral is a nucleoside analog or nucleotide analog.

[00218] Embodiment 98. The method of any one of embodiments 78 to 97, wherein the antiviral is selected from the list consisting of aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof.

[00219] Embodiment 99. The method of any one of embodiments 78 to 98, wherein the antiviral is valganciclovir. [00220] Embodiment 100. The method of any one of embodiments 78 to 98, wherein the antiviral is administered at a total daily dose of 1 ,800 milligrams.

[00221] Embodiment 101. The method of any one of embodiments 78 to 98, wherein the antiviral is administered at a total daily dose of 900 milligrams.

[00222] Embodiment 102. The method of any one of embodiments 78 to 98, wherein the antiviral is administered at a total daily dose of 450 milligrams.

[00223] Embodiment 103. The method of any one of embodiments 78 to 102, wherein the antiviral is administered according to a 7 day schedule, wherein the antiviral is administered every day of the treatment schedule.

[00224] Embodiment 104. The method of any oneof embodiments 78 to 103, wherein the antiviral is administered according to a 7 day schedule, wherein the antiviral is not administered on one or more days of the treatment schedule.

[00225] Embodiment 105. The method of any oneof embodiments 78 to 104, wherein the autoimmune disease of the central nervous system comprises multiple sclerosis.

[00226] Embodiment 106. The method of embodiment 105, wherein the multiple sclerosis is active multiple sclerosis.

[00227] Embodiment 107. The method of embodiment 105 or 106, wherein the multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primaryprogressive MS (MS).

[00228] Embodiment 108. The method of embodiment 105 or 106, wherein the multiple sclerosis is relap sing-remitting MS (RRMS).

[00229] Embodiment 109. The method of embodiment 105 or 106, wherein the multiple sclerosis is primary -progressive MS (MS).

[00230] Embodiment 110. The method of embodiment 105 or 106, wherein the multiple sclerosis is secondary -progressive MS (SPMS).

EXAMPLES

Example 1 -Nanatinostat crosses the blood brain barrier

[00231] The goal of the experiment in this example was to study the capacity of nanatinostat to penetrate the blood brain barrier (BBB) in a murine model. A direct comparison was performed to assess the biodistribution of nanatinostat in plasma and brain of BALB/c mice following a single dose. Five male mice CRL BALB/c strain 028 with average body weight 25 -30 g were studied. Nanatinostat (5mg/ml in 5% DMSO/95% sterile saline) was administered orally at a concentration of 25 mg/kg/dose. Plasma and brain samples were collected from each mice one- hour post-treatment and the level of nanatinostat was determined using LC-MS/MS following the procedure of the analytical facility (Basi). As shown in FIG. 1 Nanatinostat was detected in the brain and plasma of BALB/c mice one hour after administering the drug. The mean concentration of nanatinostat in the brain was 11.8 ng/ml and ranged from 7.97 ng/ml to 14.9 ng/ml. The average plasma concentration of nanatinostat was 45.5 ng/ml and ranged from 28.8 ng/ml to 64.5 ng/ml. As a small molecule, nanatinostat successfully penetrated the blood brain barrier and reached a brain distribution that was only 3.85 -fold less than its distribution in plasma.

Example 2 - Nanatinostat triggers the EBV lytic cycle in an EBV-transformed lymphoblastoid cell line

[00232] EBV infection was recently shown to be an etiological factor in multiple sclerosis. Elimination of EBV-infectedB-cells could serve as a therapy for multiple sclerosis using a“kick and kill” approach to eliminate latently infected EBV positive B cells in MS patients. The approach employs nanatinostat (the kick), a potent class I specific HD AC inhibitor, and the antiviral prodrug ganciclovir (the kill). Treatment with nanatinostat activates expression of the master lytic cycle switch protein, BZLF1 (aka ZEBRA, Z fragment of Epstein Barr virus Replication Activator). BZLF1 is a transcription factor that activates expression of downstream target viral genes, including the viral protein kinase, BGLF4, which phosphorylates ganciclovir into its active (cytotoxic) form. Phosphorylated ganciclovir becomes incorporated into cellular and viral DNA causing apoptosis. The kick and kill approach has been studied using different in vitro and in vivo systems that were derived from EBV positive cancer tissue. However, MS is not a malignant condition, therefore, the objective of this experiment was to determine the capacity of nanatinostat to activate the lytic cycle in EBV infected B -cell lines derived from healthy individuals with no cancer. [00233] We studied expression of the EBV lytic cycle activator, BZLF1, in a lymphoblastoid cell line (LCL) derived from a healthy individual. Treatments with the indicated HD AC inhibitors and concentrations were used: 3 mM sodium butyrate (NaB), 50, 100 and 200 nM Nanatinostat free base (NStat-FB), and 50, 100 and 200 nMNanatinostat mesylate salt(NStat- Mesylate). Cells were incubated with the HD AC inhibitors for 24h then harvested. Two methods were used to assess the expression of BZLF1 , Western blotting of the overall expression of the BZLF1 protein FIG. 2A and FACS analysis assessing the percent of cells expressing BZLF1, FIG. 2B. The experiment showed that nanatinostat in its two formulations (free base and mesylate salt) activated expression of BZLF1, a bona fide marker of EBV lytic cycle induction, to an extent higher than that observed with sodium butyrate and VRx-3531, an HD AC inhibitor related to nanatinostat. These results demonstrate that nanatinostat is competent to induce the EBV lytic phase, the most critical and rate limiting step in the kick and kill approach, in non- cancer derived EBV positive

Example 3 - Evaluation of Combination of Nanatinostat and Valganciclovir in a Mouse Model

[00234] Methods: 3 experiments with 5 mice per experimental groups and 8 groups: (1) PBS, (2) PBS plus nanatinostat, (3) PBS plus ganciclovir, (4) PBS plus nanatinostat and ganciclovir, (5) EBV, (6) EBV plus nanatinostat, (7) EBV plus valganciclovir, and (8) EBV plus nanatinostat and valganciclovir. Mice: 3 x 40 BALB/c Rag2'^/_ f- hSIRPatg HLA-A*020 lhe knock-in hp2m knock-in HLA-DRA*0101 knock-in HLA-DRB1*15O1 knock-in (BRGS-A2DR15) mice reconstituted with HLA typed and HLA-DRBl *1501 matched human CD34+ hematopoietic progenitor (HPC) cells. Attenuated immune control of Ep stein -Barr virus in the humanized mouse model has been shown to be associated with MS risk factors. See Zdimerovaet al., Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15 , 51 EUR. J. IMMUNOL. 64-75(2021). Daily i.p. injections of ganciclovir and daily oral gavage for nanatinostat, starts from weektwo after i.p. infection with 10⁵Raji infectious units (RIU) of firefly luciferase transgenic B95-8 EBV. Experiment terminates at 5 to 6 weeks after infection, according to plan illustrated in FIG. 3. [00235] After the experiment terminates, sacrifice mice and analyze blood, spleen, and brain for viral load and EBV encoded luciferase signal by an in vivo imaging system (IVIS). Perform flow cytometry from these various organs to assess CD8+ T cell expansion that usually follows viral loads, and assess changes in leucocyte compartments due to pharmacological treatments. Use neurofilament light chain (NfL) concentrations to characterize subclinical neuroaxonal damage. Using immunohistochemistry, characterize brain areas of EBV encoded luciferase activity for leucocyte infiltrates, demyelination and the phenotype of EBV infected B cells.

Example 4 — Investigation of the Presence of EBV positive B cells in Cervical Lymph Nodes of Multiple Sclerosis Patients and the Capacity ofNanatinostatto Reactivate the Virus in these Cells

[00236] Summary: Detection of EBV (latent/lytic products and viral genome) in the cervical lymph nodes of MS patients supports an immunopathologic role for EBV in disease development or progression. Treatment with Nanatinostat is expected to enhance virus detection by inducing viral gene expression and viral genome amplification.

[00237] Methods: HH514-16, a subclone of the P3 J-HRIK EBV infected Burkitt lymphoma cell line will be used and cultured under these conditions: cell lines are cultured in RPM1 1640 supplemented with 8% fetal bovine serum; cell cultures are maintained in the presence of penicillin (50 U/ml), streptomycin (50 U/ml), and amphotericin B (1 pg/ml); cells are grown at 37°C under 5% CO2.

[00238] Prepare nanatinostat solution (nstat) with nstat mesylate salt, soluble up to 3 mg/mL in 0.0001 NHC1 (pH3) or4.1 mM.

[00239] Induce EBV lytic cycle. Fortissue culture: Ensure cells are in a logarithmic-phase growth not to exceed 105/cells/ml, typically 48 h after last subculture. Count cells and resuspend at a concentration equal to 106/ml in fresh medium. For biopsy samples, an extra step of B -cell enrichment/isolation can be employed. Treat cells with varying concentrations of nstat. For tissue culture: 50 nM, 100 nM, 200 nM, 400 nM, 800nM. For biopsies: 400 nM and 800 nM NStat. Include a control, no treatment, condition. Incubate cells for 48h at 37°C under 5% CO?. Harvest and count cells.

[00240] Analysis: Activation of the EBV lytic cycle will be assessed in cell culture using flow cell cytometry for the EBV BZLF1 protein. Alternatively, activation of the EBV lytic cycle will be assessed in human tissue samples using immunohistochemistry for the EBV BZLF1 protein. Example 5 — kick and kill treatment of Epstein-Barr virus infection in a preclinical humanized mouse model of multiple sclerosis

[00241] Two pilot experiments (exemplified in FIG. 4 A and FIG. 4B, respectively) will be performed prior to the main experiment (exemplified in FIG. 4C) to optimize donor PBMC superinfection andNanotinostat-ganciclovir (Nano-GCV) treatment in HuPBMC mice. Utilizing the parameters determined in the two pilot experiments, HuPBMC mice (n = 12 - 20 mice/donor) will be generated using untreated or Akata-GFP tagged EB V superinfected PBMCs derived from either relap sing-remitting MS (RRMS) diagnosed or unaffected healthy control donors (HD), that are all EB V seropositive by serum ELISA (FIG. 4C). Experimental autoimmune encephalomyelitis (EAE) will be induced in HuPBMC mice using recombinant human myelin oligodendrocyte glycoprotein (rhMOG) emulsified in complete Freund’s adjuvant and co-administered with pertussis toxin (PTx). Nano-GCV treatment will be initiated at one of three timepoints: prior to EAE induction (2 weeks post-engraftment), post-EAE induction but pre-symptom onset (day 5 post-induction), or post-symptom onset (day 15 post-induction). During the experiment, HuPBMC EAE mice will be assessed for clinical EAE scores, weight loss, and overall health condition. At EAE endpoint (day 25 post-induction), all mice will be evaluated for the presence of any macroscopically visible tumors in the abdominal cavity, then peripheral and CNS tissues will be processed for immunological and viral assays. Endpoint measurements will include serum neurofilament light chain quantification and anti -MOG IgM by ELISA (marker of axonal damage), analysis of EBV GFP⁺ human B cells and T cell infiltration and cytokine production in the brain, spinal cord, liver, and spleen (polarization, immune reconstitution, and treatment efficacy) by flow cytometric analysis, and immune cell mediated demyelination of the CNS by immunohistochemistry (IHC). From the liver and spleen (and potentially the CNS tissues if EBV can be detected within these tissues by flow cytometric or histological analyses), DNA and RNA samples will be collected for RT-qPCR analysis of viral load and gene expression indicative of any remaining lytic and latent infection (e.g.

BALF5, EBNA-1, BZLF1, and BGLF4). Uninduced control HuPBMC mice will also be included for CNS specific effects.

[00242] The experimental design may be repeated with larger numbers of mice for any effective initiating timepoints to evaluate additional genetically distinct donors (e.g., enrollment is 3 HD and 3 RRMS donors total over 6 experiments).

[00243] Donor history of Epstein-Barr virus (EBV) infection exacerbates disease severity by skewing the balance of effector and regulatory T cells in the brain and spinal cord in the humanized multiple sclerosis mouse model. See Allanach et al., Epstein-Barr virus promotes T cell dysregulation in a humanized mouse model of multiple sclerosis, bioRxiv (January 4, 2023 ), doi: https://d0i.0rg/l 0.1101 /2022.02.23.481716.

[00244] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[00245] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Claims

CLAIMS What is claimed is:

1. A method of treating active multiple sclerosis in an individual, the method comprising administering to the individual nanatinostat and an antiviral, wherein the individual is not afflicted with a leukemia or a lymphoma, thereby treating the active multiple sclerosis.

2. The method of claim 1 , wherein the individual is not afflicted with a cancer or a tumor.

3. The method of claim 1 or 2, wherein the individual has a latent cytomegalovirus or Epstein-Barr virus infection.

4. The method of claim 1 or 2, wherein the individual has a latent Epstein -Barr virus infection.

5. The method of claim 1 or 2, wherein the individual has a latent cytomegalovirus virus infection.

6. The method of any one of claims 1 to 5, wherein the HDACi is administered at a dose of about 5 milligrams per day to about 40 milligrams per day.

7. The method of any one of claims 1 to 5, wherein the HDACi is administered at a dose of about 10 milligrams per day to about 30 milligrams per day.

8. The method of any one of claims 1 to 5, wherein the HDACi is administered at a dose of about 10 milligrams per day to about 20 milligrams per day.

9. The method of any one of claims 1 to 5, wherein the HDACi is administered at a dose of about 10 milligrams per day.

10. The method of any one of claims 1 to 5, wherein the HDACi is administered at a dose of about 20 milligrams per day.

11. The method of any one of claims 1 to 5, wherein the HDACi is administered at a dose of about 30 milligrams per day.

12. The method of any one of claims 1 to 5, wherein the HDACi is administered at a dose of about 40 milligrams per day.

13. The method of any one of claims 1 to 12, wherein the HD ACi is administered according to a 7 day schedule, wherein the HD ACi is administered on 3 days of the 7 day schedule.

14. The method of any one of claims 1 to 12, wherein the HD ACi is administered according to a 7 day schedule, wherein the HD ACi is administered on 4 days of the 7 day schedule.

15. The method of any one of claims 1 to 12, wherein the HD ACi is administered according to a 7 day schedule, wherein the HD ACi is administered on 5 days of the 7 day schedule.

16. The method of any one of claims 1 to 15, wherein the schedule is repeated.

17. The method of any one of claims 1 to 16, wherein the HD ACi is administered q.d., b.i.d., ort.i.d.

18. The method of any one of claims 1 to 16, wherein the antiviral is a nucleoside analog or nucleotide analog.

19. The method of any one of claims 1 to 18, wherein the antiviral is selected from the list consisting of aciclovir, ganciclovir, valaciclovir, valganciclovir, famciclovir, and combinations thereof.

20. The method of any one of claims 1 to 19, wherein the antiviral is valganciclovir.

21. The method of any one of claims 1 to 19, wherein the antiviral is administered at a total daily dose of 1,800 milligrams.

22. The method of any one of claims 1 to 19, wherein the antiviral is administered at a total daily dose of 900 milligrams.

23. The method of any one of claims 1 to 19, wherein the antiviral is administered at a total daily dose of 450 milligrams.

24. The method of any one of claims 1 to 23, wherein the antiviral is administered according to a 7 day schedule, wherein the antiviral is administered every day of the treatment schedule.

25. The method of any one of claims 1 to 23, wherein the antiviral is administered according to a 7 day schedule, wherein the antiviral is not administered on one or more days of the treatment schedule.

26. The method of any one of claims 1 or 25, wherein the active multiple sclerosis is relap sing-remitting MS (RRMS), secondary -progressive MS (SPMS), or primary-progressive MS (MS).

27. The method of claim 26, wherein the multiple sclerosis is relap sing-remitting MS (RRMS).

28. The method of claim 26, wherein the multiple sclerosis is prim ary -progressive MS (MS).

29. The method of claim 26, wherein the multiple sclerosis is secondary-progressive MS (SPMS).