Use of JAK inhibitors in managing inflammation-related depression and central nervous system (CNS) lesions

Abstract

The present disclosure relates to methods of treating, preventing, or reversing inflammation-associated central nervous system (CNS) disorders or conditions comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib. In certain embodiments, the CNS-related inflammatory disorder is depression, refractory depression, fatigue, or cognitive dysfunction.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 351,456, filed on June 13, 2022. The entire text of this application is hereby incorporated by reference for all purposes.

[0003] background

[0004] Depression is a major health problem. The effectiveness of antidepressants varies widely, and many patients try several treatment options without improvement. Signs of treatment-resistant depression (TRD) include more frequent, more severe, and longer-lasting episodes of depression, transient improvements followed by the return of depressive symptoms, anxiety, or anxiety disorders. Therefore, there is a need to find improved treatments for depression and TRD. Both depression and TRD, as well as other CNS pathologies, are associated with inflammatory markers in the blood and brain.

[0005] Janus kinases (JAKs) are cytoplasmic tyrosine kinases that include JAK1, JAK2, JAK3, and TYK2. JAKs signal through biological pathways that regulate the transcription of several genes involved in inflammation and cancer. An overview of JAK inhibitors approved worldwide is reported by Shawky et al. Pharmaceutics, 2022, 14, 1001.

[0006] Thyssen et al. reported improvements in symptoms of anxiety and depression in patients with atopic dermatitis treated with baricitinib. J Eur Acad Dermatol Venereol, 2022, 36(2): e147-e150.

[0007] See also International PCT Publication No. WO 2022 / 251434 to Gavegnano and Ribeiro.

[0008] Citation of references herein is not an admission that prior art.

[0009] Overview

[0010] The present disclosure relates to methods for treating, preventing or reversing inflammation-related central nervous system (CNS) disorders or conditions, comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib. In certain embodiments, the inflammation-related CNS disorder is depression, refractory depression, and depressive symptoms associated with apathy, suicidal ideology, fatigue, or cognitive dysfunction.

[0011] In certain embodiments, the disclosure relates to methods of treating depression associated with inflammation, comprising administering to a patient in need thereof an effective amount of a JAK inhibitor, such as baricitinib. In certain embodiments, the disclosure relates to methods of treating depression, comprising administering to a patient in need thereof an effective amount of a JAK inhibitor, such as baricitinib. In certain embodiments, the methods reported herein are intended to exclude patients with atopic dermatitis, rheumatoid arthritis, or alopecia.

[0012] In certain embodiments, the patient has been on an antidepressant prior to administration of the JAK inhibitor / baricitinib and has not responded or has become unresponsive to antidepressant treatment. In certain embodiments, the patient has previously been on an antidepressant and continues to present with clinical depression. In certain embodiments, the patient has previously been on two different antidepressants and continues to present with clinical depression. In certain embodiments, baricitinib is administered in combination with another antidepressant.

[0013] In certain embodiments, the disclosure relates to methods of treating inflammation-associated depressive symptoms, including fatigue and cognitive dysfunction, comprising administering to a patient in need thereof an effective amount of a JAK inhibitor, such as baricitinib.

[0014] In certain embodiments, the disclosure relates to methods of treating inflammation-associated schizophrenia comprising administering to a patient in need thereof an effective amount of a JAK inhibitor, such as baricitinib.

[0015] In certain embodiments, the disclosure relates to methods of treating inflammation-associated dopamine disorders to improve memory / cognition, motivation, motor activity, (treat or prevent) psychomotor retardation, prevent fatigue, improve anhedonia, improve memory, improve attention, improve cognition, prevent (reduce) sleep disruption, and prevent suicide, comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0016] In certain embodiments, for any of the methods disclosed herein, a JAK inhibitor can be administered in combination with another drug, an antidepressant, an antipsychotic, or an anti-inflammatory drug.

[0017] Brief description of the attached pictures from multiple perspectives

[0018] Figures 1A-1F The data presented indicate that 1 μM baricitinib significantly reduced inflammation in primary monocytes and myeloid cells, a key driver of treatment-resistant depression and other inflammatory disorders.

[0019] Figure 1A Data for CD69 cells are shown.

[0020] Figure 1BData for TCF-1 cells are shown.

[0021] Figure 1C Data for parental cell frequencies are shown.

[0022] Figure 1D Data for CD69 cells are shown.

[0023] Figure 1E Data for GzB cells are shown.

[0024] Figure 1F Data for TCF-1 cells are shown.

[0025] Figure 1G-1H The data presented indicate that IL-6 induces molecular signatures of depression (dopaminergic neurons) and that baricitinib significantly reverses these signatures of depression.Molecular signatures associated with IL-6 treatment in human DA neurons.

[0026] Figure 1G Gene Ontology (GO) analyses showing biological pathways, cellular compartments, and molecular functions enriched in the specific upregulated gene sets of IL-6-treated DA neurons are shown.

[0027] Figure 1H Downregulated genes in DA neurons treated with IL-6 + baricitinib are shown. This data indicates that baricitinib can reverse key features of depression in primary human neuronal cells.

[0028] Figure 2A-2G The data shown indicate that baricitinib reversed depressive behavior and associated inflammatory markers in a refractory rat model. Baricitinib significantly reversed depressive behavior in a refractory depression rat model. These data demonstrate that baricitinib reversed depressive behavior in depressed rats and simultaneously increased non-depressive behavior. TNFa levels were measured by the Meso Scale Discovery platform in the plasma of depressed rats treated intraperitoneally (IP) with vehicle (saline) or baricitinib (25 mg). Immobility time (depression index—less immobility = less depression; more activity less depression), time to immobility (longer time to immobility = less depression) and active / climbing + swimming were evaluated, and these were associated with TNFa levels.

[0029] Figure 2A The data shown indicate that baricitinib significantly reversed depressive behavior (measured as depression rate) compared to depressed controls. At both physiological concentrations tested, baricitinib significantly reversed depressive behavior (measured as depression rate) compared to depressed controls.

[0030] Figure 2BThe data shown indicate that baricitinib significantly reverses depressed animal behavior toward non-depressed behavior. At both physiological concentrations tested, baricitinib also significantly reverses depressed animal behavior toward non-depressed behavior.

[0031] Figure 2C The data presented indicate that baricitinib significantly improved short-term memory in depressed rats (to that of non-depressed rats).

[0032] Figure 2D The data presented indicate that baricitinib reverses treatment-resistant depression by reducing inflammation.Baricitinib reverses treatment-resistant depression by reducing inflammation (TNF-α).

[0033] Figure 2E The data presented indicate that baricitinib reverses refractory depressive behaviors as measured by immobility.

[0034] Figure 2F The data presented indicate that baricitinib reverses refractory depressive behaviors as measured by time to immobility.

[0035] Figure 2G The data presented indicate that baricitinib reverses refractory depressive behaviors as measured by active / climbing time.

[0036] Figures 3A-3I The data shown indicate that baricitinib significantly reduced immune activation and inflammation in an in vitro primary microglia model that mimics the human depressive behavioral phenotype in vitro. The data indicate that baricitinib significantly reduced immune activation and inflammation in an in vitro primary microglia model that mimics the human depressive behavioral phenotype as indicated by primary in vitro microglia model cell markers of microglial activation; baricitinib significantly reduced LPS-induced global activation that mimics the immune dysregulation and inflammation that control the depressive behavioral phenotype (h-gating strategy for activated cells).

[0037] Figure 3A The data presented indicate that baricitinib significantly reversed key markers of CNS inflammation and refractory depression as measured by CD206.

[0038] Figure 3B The data presented indicate that baricitinib significantly reversed key markers of CNS inflammation and refractory depression as measured by CD40.

[0039] Figure 3C The data presented indicate that baricitinib significantly reversed key markers of CNS inflammation and refractory depression as measured by CD32.

[0040] Figure 3DThe data presented indicate that baricitinib significantly reversed key markers of CNS inflammation and refractory depression as measured by CD86.

[0041] Figure 3E The data presented indicate that baricitinib significantly reversed key markers of CNS inflammation and refractory depression as measured by CD163.

[0042] Figure 3F The data presented indicate that baricitinib significantly reversed key markers of CNS inflammation and refractory depression as measured by CD16.

[0043] Figure 3G The data presented indicate that baricitinib significantly reversed key markers of CNS inflammation and refractory depression as measured by HLA-DR.

[0044] Figure 3H The gating strategy for measuring activated and non-activated microglia is shown.

[0045] Fig. 3I The data shown indicate that baricitinib significantly reversed the total population of activated microglia. DETAILED DESCRIPTION

[0046] Before describing the present disclosure in more detail, it should be understood that the present disclosure is not limited to the particular embodiments described, as such may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, as the scope of the present disclosure will be limited only by the appended claims.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used to implement or test this disclosure, preferred methods and materials are now described.

[0048] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with the cited publication.

[0049] The "embodiments" of the present disclosure refer to examples, but are not necessarily limited to such examples. As will be apparent to those skilled in the art upon reading the present disclosure, each of the individual embodiments described and illustrated herein has discrete components and features that can be readily separated or combined with the features of any other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method may be performed in the order of events recited or in any other order that is logically possible.

[0050] Unless otherwise indicated, the embodiments of the present disclosure will employ techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art and are fully explained in the literature.

[0051] It must be noted that, as used in the specification and the appended claims, the singular forms "a / an" and "the" include plural referents unless the context clearly dictates otherwise. In this specification and the following claims, reference will be made to a number of terms which shall be defined to have the following meanings unless a contrary intention is evident.

[0052] As used in this disclosure and in one or more claims, the words “comprising” (and any forms of comprising, such as “comprise” and “comprises”), “having” (and any forms of having, such as “have” and “has”), “including” (and any forms of including, such as “includes” and “include”), or “containing” (and any forms of containing, such as “contains” and “contain”) have the meanings ascribed to them under U.S. patent law, in that they are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0053] When applied to the methods and compositions covered by the present disclosure, "consisting essentially of" or "consisting of" and the like refer to those compositions as disclosed herein, which exclude certain prior art elements to provide the claimed inventive features, but which may contain additional composition components or method steps, etc. that do not materially affect one or more basic and novel characteristics of the composition or method.

[0054] The term "JAK inhibitor" or "Janus kinase inhibitor" refers to any class of compounds (small molecules, biomolecules, anti-JAK antibodies, interfering RNA, shRNA, nucleic acids / vectors encoding proteins, CRISPR-Cas mediated systems, etc.) that specifically bind to Janus kinases that alter the JAK-STAT signaling pathway when in contact with Janus kinases (JAK1, JAK2, JAK3, TYK2). Examples include baricitinib, tofacitinib, upadacitinib, serotoninib, gandotinib, lestaurtinib, molotinib, pactinib, ruxolitinib, oclacitinib, pegfitinib, fidartinib, filgotinib, dicartinib, abrocitinib, all of which are contemplated for use as disclosed herein.

[0055] As used herein, the term "small molecule" refers to any type of covalently bound molecule with a molecular weight of less than 900 or 1000 Da. Typically, most atoms include carbon, hydrogen, oxygen, nitrogen, and to a lesser extent sulfur and / or halogens. Examples include steroids, short peptides, monocyclic or polycyclic aromatic or non-aromatic heterocyclic compounds.

[0056] As used herein, the term "subject" refers to any animal, preferably a human patient.

[0057] As used herein, the term "treatment (treat and treating)" is not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. On the contrary, embodiments of the present disclosure also contemplate treatments that only alleviate symptoms, reverse and / or delay disease progression.

[0058] As used herein, the terms "prevent and preventing" include prevention of recurrence, spread, or onset. It is not intended to limit the present disclosure to complete prevention. In some embodiments, onset is delayed, or the severity of the disease is reduced.

[0059] As used herein, the term "in combination with" when used to describe administration of an agent with an additional therapy means that the agent may be administered before, with, or after the additional therapy, or a combination thereof, such that the multiple agents are available at some overlapping time.

[0060] The term "effective amount" refers to the amount of the compound or pharmaceutical composition described herein that is sufficient to achieve the intended application (including but not limited to the treatment of diseases as shown below). With regard to combination therapy, an "effective amount" indicates that the combination of agents results in a synergistic or additive effect when compared to a single agent. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition treated (e.g., the subject's weight and age, the severity of the disease condition), the mode of administration, etc. (which can be easily determined by one of ordinary skill in the art). The specific dose will vary depending on, for example, the specific compound selected, the dosing regimen followed, whether to be administered in combination with other agents, the time of administration, the tissue administered, and the physical delivery system carried.

[0061] The terms "drug", "pharmaceutical", "pharmaceutical preparation" and similar terms are used interchangeably herein and mean and include a medicament, drug, compound, composition of matter or mixtures thereof, including formulations thereof, which provide some therapeutic effect, usually a beneficial effect. This includes any physiologically or pharmacologically active substance that produces a local or systemic effect. Examples include chemotherapeutic drugs, analgesics, steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, antidepressants, statins, antibiotics, antibacterial drugs, antineoplastic drugs, antispasmodics, cell-extracellular matrix interaction modulators, proteins, hormones, enzymes and enzyme inhibitors, anticoagulants and / or antithrombins, and vasodilators.

[0062] The term "antidepressant" refers to a pharmacological agent that, when present in a therapeutically effective amount, is generally considered useful for treating depression. Non-limiting examples include duloxetine, paroxetine, fluoxetine, levomilnacipran, escitalopram, citalopram, desvenlafaxine, doxepin, desipramine, imipramine, clomipramine, trimipramine, sertraline, trazodone, vilazodone, venlafaxine, amitriptyline, nortriptyline, protriptyline, isocarboxazid, phenelzine, tranylcypromine, bupropion, selegiline, mirtazapine, mianserin, and dextromethorphan.

[0063] The term "antipsychotic" refers to a pharmacological agent that, when present in a therapeutically effective amount, is generally considered useful for treating psychotic symptoms such as delusions (false beliefs) and hallucinations (seeing or hearing things that are not there). Non-limiting examples include risperidone, quetiapine, olanzapine, ziprasidone, paliperidone, aripiprazole, clozapine, chlorpromazine, triflupentixol, fluphenazine, haloperidol, loxapine, perphenazine, pimozide, trifluoperazine, thiothixene, and zuclopenthixol.

[0064] The terms "anti-inflammatory" and "anti-inflammatory drug" are also used interchangeably herein and mean and include "pharmacological agents" and / or "active agent formulations" that, when present in a therapeutically effective amount, prevent or treat inflammation of body tissues, i.e., the protective tissue response to tissue injury or destruction that serves to destroy, dilute, or isolate both the injurious agent and the damaged tissue. Examples include alclofenac, alclometasone dipropionate, alpha amylase, ancifar, amfenac sodium, anakinra, aniroic acid, balsalazide disodium, bendazolic acid, benoxaprofen, bromelain, bropimol, budesonide, carprofen, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cortodoxone, decanoate, deflazacort, testosterone cypionate, desonide, desoximetasone, dexamethasone dipropionate, diclofenac Potassium phosphate, diclofenac sodium, diflorasone diacetate, diflumizone sodium, diflunisal, difluprednate, dimethyl sulfoxide, inoricon sodium, etodolac, felbinac, fenamox, fenbufen, fenclorac, fendosal, fenpipalon, fentiazolic, flurazadone, flufenamic acid, flunisolide acetate, flunixin, flunixin meglumine, fluorometholone acetate, flurbiprofen, fluticasone propionate, furanprofen, halcinonide, halobeta propionate Ibuprofen, ibuprofen aluminum, picoprofen, indomethacin, indomethacin sodium, indoprofen, isoxacic acid, isoxicam, ketoprofen, lofemazole hydrochloride, loteprednol etabonate, meclofenamic acid sodium, meclofenamic acid, mefenamic acid, aminosalicylic acid, methenolone, methenolone acetate, nabumetone, nandrolone, naproxen, naproxen sodium, naproxen, olsalazine sodium, oxaprozin, hydroxyphenylbutazone, anadrol, pyrimethamine nicardipine, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, proquinezone, proxazole, proxazole citrate, disalicylate, stanozolol, sudoxicam, sulindac, suprofen, talniflumate, tenidap, tenidap sodium, tenoxicam, testosterone, testosterone blend, tiopine, tixocortol pivalate, tolmetin, tolmetin sodium, triclosanone, trifluramide, zidometacin and zomepirate sodium.

[0065] How to use

[0066] The present disclosure relates to methods for treating, preventing or reversing inflammation-related central nervous system (CNS) disorders or conditions, comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib. In certain embodiments, the inflammation-related CNS disorder is depression or refractory depression, and includes symptoms such as fatigue and cognitive dysfunction.

[0067] In certain embodiments, the disclosure relates to methods of treating depression associated with inflammation, comprising administering to a patient in need thereof an effective amount of a JAK inhibitor, such as baricitinib. In certain embodiments, the disclosure relates to methods of treating depression, comprising administering to a patient in need thereof an effective amount of a JAK inhibitor, such as baricitinib. In certain embodiments, the methods reported herein are intended to exclude patients with atopic dermatitis, rheumatoid arthritis, or alopecia.

[0068] In certain embodiments, the patient has been treated with an antidepressant and has not responded or has become unresponsive to treatment. In certain embodiments, the patient has been previously treated with an antidepressant and continues to exhibit clinical depression. In certain embodiments, the patient has been previously treated with two different antidepressants and continues to exhibit clinical depression. In certain embodiments, baricitinib is administered in combination with another antidepressant.

[0069] In certain embodiments, the disclosure relates to methods of treating inflammation-associated dopamine disorders to improve memory / cognition, motivation, motor activity, (treat or prevent) psychomotor retardation, prevent fatigue, improve anhedonia, improve memory, improve attention, improve cognition, prevent (reduce) sleep disruption, and prevent suicide, comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0070] In certain embodiments, the inflammation-related CNS disorder or condition is schizophrenia. In certain embodiments, the disclosure relates to methods for treating or preventing schizophrenia, comprising administering an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib, to a patient in need thereof. In certain embodiments, a JAK inhibitor is administered in combination with an antipsychotic.

[0071] In certain embodiments, the inflammation-related CNS disorder or condition is post-traumatic stress disorder (PTSD). In certain embodiments, the disclosure relates to methods of treating or preventing post-traumatic stress disorder (PTSD), comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0072] In certain embodiments, the inflammation-related CNS disorder or condition is anxiety.In certain embodiments, the disclosure relates to methods of treating or preventing anxiety comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0073] In certain embodiments, the inflammation-related CNS disorder or condition is bipolar disorder.In certain embodiments, the disclosure relates to methods of treating or preventing bipolar disorder comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0074] In certain embodiments, the inflammation-related CNS disorder or condition is dementia.In certain embodiments, the disclosure relates to methods of treating or preventing dementia comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0075] In certain embodiments, the disclosure relates to methods of improving memory comprising administering an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib, to a patient in need thereof.

[0076] In certain embodiments, the disclosure relates to methods of treating chronic fatigue syndrome comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0077] In certain embodiments, the disclosure relates to methods of treating infection-related depression and depressive symptoms comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0078] In certain embodiments, the disclosure relates to methods of treating viral-induced or related infectious depression comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0079] In certain embodiments, the disclosure relates to methods of treating HIV depression and depressive symptoms comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0080] In certain embodiments, the disclosure relates to methods of treating bacterial-induced or -related infection-related depression comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0081] In certain embodiments, the disclosure relates to methods of treating depression caused by Lyme disease / post-Lyme disease treatment syndrome, comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0082] In certain embodiments, the disclosure relates to methods for treating or preventing chronic depression or acute depression, comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib. In certain embodiments, the subject is diagnosed with chronic depression, i.e., persistent depressive disorder or dysthymia, for example, wherein the symptoms must have been present for at least one or two years.

[0083] In certain embodiments, the disclosure relates to methods for treating or preventing intense sadness, hopelessness, or feelings of emptiness, decreased speech, decreased movement, decreased thinking speed, anxiety, restlessness, anhedonia, significant changes in sleep, significant changes in eating habits, weakness, persistent fatigue, feelings of low self-esteem, misplaced guilt, exaggerated guilt, fixation on past failures, social isolation, difficulty thinking, concentration, difficulty making decisions, pain, headache, muscle pain, stomach pain, suicidal thoughts, or suicidal behavior, comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0084] In certain embodiments, the disclosure relates to methods of treating post-treatment Lyme disease syndrome comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0085] In certain embodiments, the disclosure relates to methods of treating a Jarisch–Herxheimer reaction, comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib. In certain embodiments, the Jarisch–Herxheimer reaction is associated with syphilis, louse-borne relapsing fever, leptospirosis, and tick-borne relapsing fever.

[0086] In certain embodiments, the disclosure relates to methods of treating Lyme arthritis comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0087] In certain embodiments, the disclosure relates to methods of treating neurological Lyme disease / neuroborreliosis comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0088] In certain embodiments, the disclosure relates to methods of treating acute CNS inflammatory disorders comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0089] In certain embodiments, the disclosure relates to methods of treating stroke comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0090] In certain embodiments, the disclosure relates to methods of treating traumatic brain injury (TBI) comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0091] In certain embodiments, the disclosure relates to methods of treating spinal cord injury comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0092] In certain embodiments, the disclosure relates to methods of treating rare and orphan inflammatory diseases comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0093] In certain embodiments, the disclosure relates to methods of treating prion disease comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0094] In certain embodiments, the disclosure relates to methods of treating inflammation-associated neuropsychiatric and neurodegenerative disorders and CNS pathologies comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor, such as baricitinib.

[0095] In certain embodiments, the inflammation-related CNS disorder or condition is Alzheimer's disease or Parkinson's disease.

[0096] In certain embodiments, for any of the methods disclosed herein, a JAK inhibitor can be administered in combination with another drug, an antidepressant, an antipsychotic, or an anti-inflammatory drug.

[0097] In certain embodiments, the JAK inhibitor is a small molecule. In certain embodiments, the JAK inhibitor is selected from baricitinib, abrocitinib, dicartinib, fidartinib, filgotinib, oclacitinib, paculitinib, pemfitinib, ruxolitinib, tofacitinib, and upadacitinib.

[0098] Treatment or reversal of inflammation-related depression, refractory depression, and related central nervous system (CNS) inflammatory disorders with the JAK inhibitor baricitinib

[0099] The prevalence of major depressive disorder is high, and many seek therapeutic intervention, but one-third of depressed patients are ineffective. Patients with treatment-resistant depression (TRD) experience a chronic depressive state that fails to resolve after treatment with at least two antidepressants. Experiments indicate that inflammation is strongly associated with depression and TRD in humans and animal models. Inflammation confers dysfunction in key mechanistic pathways that drive depression and TRD and related disorders (including but not limited to schizophrenia, post-traumatic stress disorder, anxiety disorders, Alzheimer's disease, Parkinson's disease, and / or other neuropsychiatric and neurodegenerative disorders with CNS inflammatory lesions).

[0100] The present disclosure contemplates the use of JAK inhibitors such as baricitinib, alone or in combination, to treat, prevent, or reverse disease in people suffering from depression, refractory depression, and related disorders, including but not limited to schizophrenia, post-traumatic stress disorder, anxiety disorders, Alzheimer's disease, Parkinson's disease, and / or other neuropsychiatric and neurodegenerative disorders with CNS inflammatory lesions.

[0101] In certain embodiments, the subject with depression or treatment-resistant depression suffers from or is diagnosed with chronic inflammation, including myeloid cell activation and impaired dopamine (DA) neurotransmission, motivational deficits (including anhedonia), psychomotor deficits, fatigue, and / or other neuropsychiatric and neurodegenerative disorders.

[0102] In certain embodiments, the subject for the treatment or prevention of a disease or condition reported herein has or is diagnosed with abnormal and / or elevated inflammatory markers such as C-reactive protein (CRP), interferon (IFN)-α or interleukin (IL)-6, decreased DA release in the ventral striatum (e.g., associated with anhedonia, psychomotor retardation, cognitive dysfunction and fatigue).

[0103] In certain embodiments, the subject for treating or preventing a disease or condition reported herein suffers from or is diagnosed with stress, inflammation, IL-6-related striatal DA neuron dysfunction, or inflammation-induced blood-brain barrier disruption.

[0104] Baricitinib for depression and refractory depression

[0105] The experiments indicate that baricitinib at physiologically relevant concentrations can block key inflammatory and dysregulatory events in vitro that mimic the inflammatory dysregulation observed in humans in depression and treatment-resistant depression. These data were collected in primary human macrophage- and microglia-like cells from healthy volunteers (Table 1), primary monocytes, and DA neurons derived from human induced pluripotent stem cells (hiPSCs).

[0106] Table 1 - Therapeutic concentrations of baricitinib demonstrate efficacy in reversing inflammatory and immune dysregulation in key CNS cells that contribute to treatment-resistant depression and associated CNS inflammatory pathologies.

[0107]

[0108] The data presented in Table 1 indicate that baricitinib significantly reduced inflammation in primary monocytes and myeloid cells, which is a key driver of pathology and symptoms in depression, refractory depression, and other inflammatory disorders. Table 1 summarizes the effective concentrations 50 (EC50) for blocking neuropathological and inflammatory hallmarks of depression in microglia and activated monocytes. 50 ).

[0109] These data indicate that baricitinib can be used for inflammation-related depression, refractory depression and other CNS disorders (including but not limited to schizophrenia, post-traumatic stress disorder, anxiety disorders, Alzheimer's disease, Parkinson's disease, and / or other neuropsychiatric and neurodegenerative disorders with CNS inflammatory lesions). This embodiment includes the use of Jak inhibitors (such as baricitinib) to treat or reverse inflammation-related depression, refractory depression and / or related CNS lesions.

[0110] Baricitinib-induced depressive behavior was reduced compared with untreated rats

[0111] In a behavioral model of refractory depression in rats, rats treated with baricitinib had significantly reduced depressive behavior compared to untreated rats. This indicates that baricitinib reversed depression. Measurements of immune dysregulated cytokines in this model indicate that baricitinib reduced these markers and was associated with a reversal of depressive behavior. Microglial dysregulation drives the depressive phenotype. In a human model of activated microglia, baricitinib reversed key markers that drive human depression. Dysfunction of dopaminergic neurons drives depression. In a primary human dopaminergic neuron model, baricitinib reversed the inflammatory dopaminergic phenotype and restored neurons to normal dopamine function. Measurements showed that the reversal of depressive behavior by baricitinib was associated with restoration of neuronal function and microglial activity.

[0112] Activation of primary human microglia

[0113] Experiments were performed to determine the effect of baricitinib on primary human microglia activation (a key driver of depressive behavioral phenotypes). Microglia were derived from CD14-isolated monocytes from healthy donors and differentiated into microglia using a GM-CSF and IL-34-based culture medium. LPS was added to simulate immune dysregulation and inflammation that drive CNS depressive behavioral phenotypes, including the immune dysregulation phenotype of depression, as indicated by elevated microglial activation surface markers. The data show that baricitinib significantly reversed LPS-activated (depressive phenotype simulation) in primary human microglia.

[0114] Baricitinib reverses chronic fatigue syndrome

[0115] Interferon alpha drives chronic fatigue syndrome, and baricitinib blocks these type 1 interferons; therefore, baricitinib is considered for the treatment of chronic fatigue syndrome.

Claims

1. A method for treating, preventing or reversing an inflammation-related central nervous system (CNS) disorder or condition, the method comprising administering to a patient in need thereof an effective amount of a Janus kinase (JAK) inhibitor.

2. The method of claim 1, wherein the inhibitor is selected from baricitinib, abrocitinib, dicartinib, fidartinib, filgotinib, oclacitinib, paclitinib, pemfitinib, ruxolitinib, tofacitinib, and upadacitinib.

3. The method of claim 1, wherein the inflammation-related CNS disorder or condition is depression, except in patients suffering from atopic dermatitis.

4. The method of claim 1, wherein the inflammation-related CNS disorder or condition is schizophrenia.

5. The method of claim 1, wherein the inflammation-related CNS disorder or condition is post-traumatic stress disorder (PTSD).

6. The method of claim 1, wherein the inflammation-related CNS disorder or condition is anxiety.

7. The method of claim 1, wherein the inflammation-related CNS disorder or condition is Alzheimer's disease.

8. The method of claim 1, wherein the inflammation-related CNS disorder or condition is Parkinson's disease.

9. A method of treating depression including, but not limited to, acute suicidal ideation or behavior, apathy, or a related neurodegenerative disorder, comprising administering an effective amount of baricitinib to a patient in need thereof, except for a patient suffering from atopic dermatitis.

10. The method of claim 9, wherein the patient has been previously treated with an antidepressant and has not responded.

11. The method of claim 9, wherein the patient was previously administered an antidepressant and continues to present with clinical depression.

12. The method of claim 9, wherein the patient has been previously administered two different antidepressant medications and continues to present with clinical depression.

13. The method of claim 9, wherein baricitinib is administered in combination with another drug, an anti-inflammatory drug, an antidepressant drug, or an antipsychotic drug.

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