Granulocyte-macrophage colony-stimulating factor-based therapies for neurodegenerative or neurological diseases or disorders

Abstract

The present invention relates to the treatment of neurodegenerative or neurological diseases or disorders with granulocyte-macrophage colony-stimulating factor.

Description

[Technical field]

[0001] The present disclosure relates, in part, to the treatment and / or amelioration of neurodegenerative or neurological diseases or disorders, as well as diagnostic, prognostic, and patient selection methods.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 309,220, filed February 11, 2022, the entire contents of which are incorporated herein by reference in their entirety.

[0003] Description of electronically submitted text files This application contains a Sequence Listing in XML format that was submitted electronically via the Patent Center. The contents of the XML copy created on February 9, 2023 is named "PNR-008PC127114-5008.xml" and is 8,192 bytes in size. This Sequence Listing is incorporated herein by reference in its entirety. [Background technology]

[0004] Neurodegenerative or neurological diseases or disorders are increasingly recognized as leading causes of death and disability (including disability-adjusted life years (DALYs; the sum of years of life lost [YLLs] and years lived with disability [YLDs])) worldwide. Globally, in 2016, neurological diseases were the leading cause of DALYs (approximately 276 million) and the second leading cause of death (approximately 9 million). The absolute number of deaths and DALYs for all neurological diseases combined increased between 1990 and 2016 (39% deaths and 15% DALYs), while the age-standardized rates decreased (28% deaths and 27% DALYs). The only neurological diseases that saw a decrease in the proportion and absolute number of deaths and DALYs were tetanus, meningitis, and encephalitis. The four leading causes of neurological DALYs were stroke (42.2%), migraine (16.3%), Alzheimer's disease and other dementias (10.4%), and meningitis (7.9%). These neurological disorders include, but are not limited to, tetanus, meningitis, encephalitis, stroke, brain and other CNS cancers, traumatic brain injury, spinal cord injury, Alzheimer's disease (AD) and other dementias, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), which is a typical neuroinflammatory disease, Huntington's disease (HD) or Huntington's chorea, motor neuron disease, idiopathic epilepsy, migraine, tension headache, and other less common residual categories of neurological disorders. See Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Lancet Neurol 2019;18:459-80.

[0005] Neurodegenerative or neurological diseases or disorders can be broadly classified according to their clinical symptoms, with extrapyramidal and pyramidal motor disorders, cognitive disorders, or behavioral disorders being the most common. Few patients have pure syndromes, and most patients have mixed clinical symptoms. Although neurodegenerative or neurological diseases or disorders are generally defined by the accumulation of specific proteins and anatomical vulnerabilities, these neurodegenerative or neurological diseases or disorders share many fundamental processes related to progressive neuronal dysfunction and neuronal cell death, such as proteotoxic stress and associated abnormalities in the ubiquitin-proteasome and autophagosomal / lysosomal systems, oxidative stress, programmed cell death, and neuroinflammation. See Dugger BN and Dickson DW. Cold Spring Harb Perspect Biol.2017.9(7):a028035.

[0006] There is growing recognition that inflammation may play an important role in neurodegenerative or neurological diseases or disorders of the CNS. Adaptive and innate immune responses have been observed at various stages of neurodegenerative or neurological diseases or disorders. These distinct immune responses may not only drive the disease process but also serve as therapeutic targets. Ongoing research into the specific inflammatory mechanisms that play a role in disease pathogenesis and progression is revealing lessons about inflammation-driven neurodegeneration, understanding the emergence of these diseases, and therapies to treat them. More immune therapeutic strategies that have been successful in MS are now being applied to other neurodegenerative or neurological diseases or disorders. While some approaches suppress CNS immune mechanisms, others harness the immune system to remove harmful products and cells. See Mamun AA and Liu F. Neurol Neurother.2017.2(1);Chitnas T and Weiner HL. J Clin Invest.2017.127(10):3577-3587. Not all immune responses in the CNS are harmful, and in many cases they actually support repair and regeneration. For example, microglia clear debris after myelin injury, which, when inhibited, results in delayed regeneration. Immune activation is also important to limit neurotropic viral infection and to clear necrotic cells after ischemia. Thus, microglia can play a dual role in neurodegeneration, both as inducers of injury and as defenders of brain homeostasis. In addition to microglia, T cells can also assist in the recovery of neurodegenerative or neurological diseases or disorders, although the exact mechanism of this beneficial role of T cells is unclear. Detailed studies of neuroimmune interactions at both cellular and molecular levels have revealed complex interactions, showing that immune cells can secrete both neurotoxic and neuroprotective molecules. Thus, modulation of immune responses in neurological diseases may have therapeutic value.See Neumann H et al. Brain.2009.132:288-95; Schwartz M et al. Neuroscience.2009.158:1133-42; Amor S et al. Immunology.2010.129(2):154-69.

[0007] Because treatment responses can vary based on heterogeneous clinical and molecular phenotypes, a move toward personalized or precision medicine approaches, including the development and validation of biomarkers, has been thought to improve management of many neurodegenerative or neurological diseases or disorders. The field of immune biomarkers has expanded rapidly in recent years, driven by significant advances in molecular immunology and an increasing emphasis on translational research and personalized medicine. Such biomarkers can be used as objective measures of normal and pathogenic processes or as indicators of pharmacological responses to therapeutic inventions. See Biomarkers Definitions Working Group. Clin Pharmacol Ther.2001.69(3):89-95;Willis JCD and Lord GM. Nat Rev Immunol.2015.15:323-329;Renert-Yuval Y et al. J Allergy Clin Immunol.2021.147(4):1174-1190.

[0008] Cluster of differentiation 26 (CD26) is a 110 kD cell surface glycoprotein and a known T cell activation molecule. CD26 has known dipeptidyl peptidase IV (DPP-IV) activity in its extracellular domain. This ectoenzyme can cleave amino-terminal dipeptides from polypeptides that have either L-proline or L-alanine in the penultimate position. In human T cells, CD26 expression appears late in thymic differentiation and is preferentially restricted to CD4+ helper / memory populations, where CD26 can transmit potent costimulatory T cell activation signals. CD26 is also present on epithelial cells of various tissues, including liver, kidney, and intestine. A detailed analysis of human CD4+ lymphocyte subsets reveals that CD26 appears to be more restricted than most other accessory molecules, as it is expressed only in the CD4 memory / helper (CD45RO+CD29+) population. This unique human CD4 cell population is the only one that can recall antigens, induce immunoglobulin G (IgG) synthesis, and activate MHC-restricted cytotoxic T cells. In inflammatory diseases such as rheumatoid arthritis (RA), T cells at the site of inflammation strongly express CD26 molecules on their surface. See Morimoto C and Schlossman SF. Immunol Rev.1998.161:55-70.

[0009] Musashi (MSI) proteins are a family of RNA-binding proteins (RBPs) that are evolutionarily conserved across species. In mammals, two members of this family, Musashi1 (MSI1) and Musashi2 (MSI2), are strongly co-expressed in neural progenitor cells, including CNS stem cells. MSI1 and MSI2 are RNA-binding proteins characterized by two RNP-type RNA recognition motifs (RRMs) and show remarkable similarity to each other, both in their primary structure and their in vitro RNA-binding specificity. In mammals, the expression of MSI1 and MSI2 is developmentally regulated. Both MSI1 and MSI2 are co-expressed primarily in proliferating embryonic multipotent neural progenitor cells, as well as in cell populations thought to be the source of postnatal and adult CNS stem cells. In the cerebral cortex, the expression of MSI1 and MSI2 is rapidly downregulated in newly generated postmitotic neurons, except for some GABAergic interneurons. Although the molecular functions of MSI family members remain unclear, their expression characteristics suggest that they may play similar roles in the development and maintenance of CNS stem cells through post-transcriptional gene regulation. Mammalian MSI1 is expressed in fetal and adult NSCs and mature neurons. The CNS expression pattern of MSI2 is similar to MSI1 in that it is highly expressed in neural stem / progenitor cells, and MSI1 and MSI2 are hypothesized to play overlapping roles with each other, which remain to be elucidated. Nevertheless, MSI2 is continuously expressed in a subset of CNS neurons, particularly GABAergic neurons. Oligomeric assemblies of tau and the RNA-binding protein (RBP), Musashi (MSI), have been reported in Alzheimer's disease (AD). MSI1 protein has been identified in tau inclusion-containing neurons in AD and Pick's disease (PiD). Furthermore, these two RBPs have been shown to exist in soluble aggregates, i.e., oligomeric forms, in human AD brains ex vivo. These oligomers have been detected in mature neurons where they can co-localize with oligomeric tau.Sakakibara S et al. Dev.Biol.1996.176:230–242;Sakakibara S and Okano H.J Neurosci.1997.17:8300–8312;Sakakibara S et al. J Neurosci.2001.21:8091–8107;Keyoung HM et al. Nat.Biotechnol.2001.19:843–850;Okano H et al. J Cell Sci.2002,115:1355–1359; PNAS.2002.99(23):15194-15199;Lovell MA,and Markesbery WR. J Neuropathol Exp Neurol.2005.64:675–680; Acta Neuropathol Commun.2018.6(1):113;Montalbano M et al. Nat Commun.2020.11(1):4305.

[0010] Triggering receptor expressed on myeloid cells 2 (TREM2) belongs to the TREM family of cell surface transmembrane glycoproteins and has a V immunoglobulin extracellular domain and a cytoplasmic tail. The TREM2 gene is expressed in a subpopulation of myeloid cells, including dendritic cells, granulocytes, and tissue-specific macrophages such as osteoclasts, Kuppfer cells, and alveolar macrophages. In the brain, TREM2 is expressed exclusively by microglia. TREM2 expression varies across specific regions of the central nervous system (CNS), with higher expression in the hippocampus, spinal cord, and white matter. Expression of anti-inflammatory molecules has been shown to enhance TREM2 expression, whereas expression of pro-inflammatory molecules such as TNFα, IL1β, or lipopolysaccharide (LPS) has been shown to decrease TREM2 expression in vitro. TREM2 expression is upregulated in pathologies such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury, and AD. In AD, increased expression of TREM2 has been identified in patients, as well as in mouse models of amyloid and tau pathology, and appears to be associated with microglial recruitment to amyloid plaques. Furthermore, age-related increases in TREM2 expression have been shown in both mice and humans. See Gratuze M et al. Mol Neurodegener.2018.13(1):66; Carmona S et al. Lancet Neurol.2018.17(8):721-730.

[0011] Interferon regulatory factor 4 (IRF4) is one of nine IRF family members. All IRF proteins share a similar structure, including an N-terminal DBD, and, except for IRF1 and IRF2, have a C-terminal IRF-associated domain (IAD) that is responsible for interactions with other family members or other transcription factors, including ETS factors and AP1 (activator protein 1) family members. IRF4 is a key regulator of B- and T-cell differentiation, as well as many aspects of cell metabolism. In dendritic cells, Irf4 mediates the upregulation of CD4 +In line with this expression pattern, tissue-resident CD4 + DCs and nearly half of the pDC population express Irf4 - / - is absent in the spleen of mice. IRF-4 is a hematopoietic transcription factor important in regulating microglia / macrophage activation and inflammatory responses. The effects of IRF4 signaling on inflammation are multifaceted and vary across immune cell types and pathological microenvironments regulated by both pro- and anti-inflammatory cytokines. Mechanistically, IRF4 is a typical "context-dependent" transcription factor that controls distinct groups of inflammatory mediators in different ways depending on their activation in different cell types, including phagocytes, T cell subtypes, and neurons. See Seillet C and Belz GT Advances in Immunology.2013.V120:185-210;Mamun AA and Liu F.Neurol Neurother.2017.2(1).

[0012] Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a blood growth factor that controls the production, migration, proliferation, differentiation, and function of hematopoietic cells. It was first identified as a factor capable of inducing in vitro proliferation and differentiation of bone marrow progenitor cells into granulocytes and macrophages. In response to inflammatory stimuli, GM-CSF is released by a variety of cell types, including T lymphocytes, macrophages, fibroblasts, and endothelial cells. GM-CSF then activates and enhances the production and survival of neutrophils, eosinophils, and macrophages. Natural GM-CSF is usually produced near the site of action, where it regulates the in vitro proliferation, differentiation, and survival of hematopoietic progenitor cells, but is present in the circulation at picomolar concentrations (10 -10 ~10 -12There is only one GM-CSF gene, GM-CSF-1. Several studies have shown that GM-CSF has a wide range of functions across various tissues in its action on myeloid cells, and that GM-CSF deletion / depletion approaches may be an important therapeutic target for several inflammatory and autoimmune diseases. See A Metcalf D. Immunol Cell Biology.1987,65:35-43;Gasson JC. Blood.1991,77:1131-1145;Shannon MF et al. Crit Rev Immunol.1997,17:301-323;Alexander WS. Int Rev Immunol.1998,16:651-682;Barreda DR et al. Dev Comp Immunol.2004,28:509-554;Lee KMC et al. Immunotargets Ther.2020.9:225-240.

[0013] Recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) has been approved by the FDA for the treatment of neutropenia, blood disorders, and malignancies such as leukemia in combination with chemotherapy. In clinical practice, GM-CSF is used to treat post-chemotherapy neutropenia and aplastic anemia, and significantly reduces the risk of infection associated with bone marrow transplantation. Its utility in myeloid leukemia therapy and as a vaccine adjuvant is also well established. See Dorr RT. Clin Therapeutics.1993.15(1):19-29;Armitage JO. Blood 1998,92:4491-4508;Kovacic JC et al. J Mol Cell Cardiol.2007,42:19-33;Jacobs PP et al. Microbial Cell Factories 2010,9:93.

[0014] Identification of specific biomarkers can be used for the diagnosis, prognosis, or theranosis of neurodegenerative or neurological diseases or disorders. They can also be used to identify neurodegenerative or neurological diseases or disorders and conditions that do not respond to monotherapy alone and may benefit from combination therapy. Such combination therapy can increase the proportion of patients who respond to treatment. Thus, there remains a need for new and more effective biomarkers and combination therapies for neurodegenerative or neurological diseases or disorders. Summary of the Invention

[0015] Accordingly, in one aspect, the present disclosure relates to a method for treating a neurodegenerative or neurological disease or disorder comprising administering to a patient in need thereof an effective amount of a composition comprising GM-CSF, wherein the patient is characterized by increased or high cluster of differentiation 26 (CD26) expression and / or activity.

[0016] In one aspect, the disclosure relates to a method for treating a neurodegenerative or neurological disease or disorder comprising administering to a patient in need thereof an effective amount of a composition comprising GM-CSF, wherein the patient is characterized by increased or elevated expression and / or activity of one or more of the MSI family proteins, MSI-1 or MSI-2.

[0017] In one aspect, the disclosure relates to a method for treating a neurodegenerative or neurological disease or disorder comprising administering to a patient in need thereof an effective amount of a composition comprising GM-CSF, wherein the patient is characterized by decreased or low expression and / or activity of TREM2.

[0018] In one aspect, the disclosure relates to a method for treating a neurodegenerative or neurological disease or disorder comprising administering to a patient in need thereof an effective amount of a composition comprising GM-CSF, wherein the patient is characterized by reduced or low expression and / or activity of IRF-4.

[0019] In one aspect, the disclosure relates to a method of treating a neurodegenerative or neurological disease or disorder comprising: (a) identifying a patient undergoing or having undergone treatment with an agent for the neurodegenerative or neurological disease or disorder, and described as unsuccessful, intolerant, resistant, or refractory to treatment with the immunomodulatory agent or neurological agent; (b) determining the presence or amount of CD26 and / or one or more MSI proteins and / or TREM2 and / or IRF-4 in a sample from the patient; and (c) administering an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent to the patient exhibiting (i) increased or higher expression and / or activity of CD26 and / or MSI family proteins compared to a pre-treatment and / or non-disease state, and / or (ii) decreased or lower expression and / or activity of TREM2 and / or IRF4 compared to a pre-treatment and / or non-disease state.

[0020] In one aspect, the disclosure provides a method for selecting a patient for treatment with GM-CSF for a neurodegenerative or neurological disease or disorder based on the presence or absence or amount of CD26 and / or one or more MSI proteins and / or TREM2 and / or IRF-4 in a sample from the patient. [Brief description of the drawings]

[0021] [Figure 1] Graph showing the kinetics of CD26 expression induced by Sargramostim (LEUKINE). Monocytes and lymphocytes from multiple human donors (n=3) were treated with Sargramostim (LEUKINE) at various concentrations from 0.001 pM to 10 nM. CD26 expression was assessed in both monocytes and lymphocytes on day 1. For reference, at 10 nM on the X-axis, the upper curve is lymphocytes and the lower curve is monocytes. [Diagram 2]A graph showing the kinetics of Musashi-2 (MSI-2) expression induced by Sargramostim (LEUKINE). Monocytes from human donors were treated with Sargramostim (LEUKINE) at various concentrations ranging from 1 pM to 103 pM. Musashi-2 (MSI-2) expression was assessed in monocytes on day 1 (shown as a curve on the graph). [Figure 3A] A graph showing the kinetics of TREM2 expression induced by sargramostim (LEUKINE). Monocytes and lymphocytes from multiple human donors (n=3) were treated with various concentrations of sargramostim (LEUKINE) from 0.001 nM to 10 nM. TREM2 expression was assessed in both monocytes and lymphocytes on day 1. For reference, at 10 nM on the X-axis, the upper curve is monocytes and the lower curve is lymphocytes. [Figure 3B] Graph showing the kinetics of TREM2 expression induced by sargramostim (LEUKINE). Monocytes from human donors were treated with various concentrations of sargramostim (LEUKINE) from 0.001 nM to 10 nM. TREM2 expression in monocytes was evaluated on days 1, 2, and 3. For reference, at 10 nM on the X-axis, the upper curve is TREM2 expression on day 3, the middle curve is TREM2 expression on day 2, and the lower curve is TREM2 expression on day 1. [Figure 4] Graph showing the kinetics of IRF-4 expression induced by sargramostim (LEUKINE). Monocytes and lymphocytes from multiple human donors (n=3) were treated with various concentrations of sargramostim (LEUKINE) from 0.03 nM to 100 nM. IRF-4 expression was assessed in both monocytes and lymphocytes on day 1. For reference, at 10 nM on the X-axis, the upper curve is monocytes and the lower curve is lymphocytes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The present disclosure relates, in part, to the use of GM-CSF as an effective treatment for certain neurodegenerative or neurological diseases or disorders, selected using CD26 and / or one or more MSI proteins and / or TREM2 and / or IRF-4 as predictive markers of disease sequelae and responsiveness to current treatment, e.g., with agents to treat the neurodegenerative or neurological disease or disorder.

[0023] In certain aspects, the present disclosure relates to improved treatments for neurodegenerative or neurological diseases or disorders in patients who are unsuccessful, intolerant, resistant, or refractory to currently used treatments. For example, in certain embodiments, the presence, level, or activity of CD26, one or more MSI proteins, TREM2, and / or IRF-4 is assessed to inform or predict disease status, and, without limitation, administering GM-CSF converts a patient who is unsuccessful, intolerant, resistant, or refractory to current treatment(s) for a neurological indication into a patient who responds to current treatment(s) for a neurological indication. In certain embodiments, GM-CSF modulates CD26 or cells expressing it to improve the patient's treatment outcome. In certain embodiments, GM-CSF modulates one or more MSI proteins, e.g., MSI-1 or MSI-2, or cells expressing it to improve the patient's treatment outcome. In certain embodiments, GM-CSF modulates TREM-2 or cells expressing it to improve the patient's treatment outcome. In certain embodiments, GM-CSF modulates IRF-4 or cells expressing it to improve the therapeutic outcome of the patient.

[0024] Thus, in some aspects, the disclosure provides a method for treating a neurodegenerative or neurological disease or disorder. In some embodiments, the neurodegenerative or neurological disease or disorder is selected from Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), dementia with Lewy bodies, Parkinson's disease dementia epilepsy, stroke, Huntington's chorea or Huntington's disease (HD), cerebral hypoxia, multiple sclerosis, amyotrophic lateral sclerosis (ALS), neovascular glaucoma, optic neuropathy, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), and peripheral neuropathy.

[0025] Immunomodulatory and / or Neurological Agent Compositions In certain embodiments, the present disclosure relates to compositions, such as pharmaceutical compositions comprising GM-CSF and / or an additional therapeutic agent, for treating a neurodegenerative or neurological disease or disorder.

[0026] In certain embodiments, the additional immunomodulatory or neurological agent is a dopamine precursor such as levodopa, a cholinesterase inhibitor such as donepezil (ARICEPT), rivastigmine (EXELON), galantamine (RAZADYNE), a serotonin dopamine antagonist (SDA), a multiactive receptor targeted antipsychotic (MARTA), and a D 2Atypical antipsychotics / second generation antipsychotics including partial agonists (e.g., ABILIFY / aripiprazole), NMDA receptor antagonists memantine, riluzole (RILUTEK), NSAIDs (nonsteroidal anti-inflammatory drugs), caffeine A2A receptor antagonists and CERE-120 (adeno-associated virus serotype 2-neurturin), deep brain stimulation, TNF-α antagonists such as etanercept, adalimumab, infliximab, IFN-γ inhibitors, The therapeutic agent is selected from TGF-β modulators, IL-33 inhibitors, IL-18 inhibitors, VEGF inhibitors, IL-1 inhibitors, inhibitors of pathological β-amyloid (Aβ) plaques, for example, Aβ-targeting monoclonal antibodies such as aducanumab (ADUHELM), NSAIDs such as methacetamol and aspirin, antidiabetic drugs such as linagliptin, tau activation inhibitors such as liraglutide, miRNAs targeting Aβ plaque formation and tau protein phosphorylation, α-secretase enhancers such as ginkgo biloba and salvia miltiorrhiza, and β-secretase inhibitors such as Coptis Rhizome and Yuanzhi.

[0027] In certain embodiments, the immunomodulatory agent or neurological agent is an antibody or antibody format selected from one or more of a monoclonal antibody, a polyclonal antibody, an antibody fragment, Fab, Fab', Fab'-SH, F(ab')2, Fv, single chain Fv, diabody, linear antibody, bispecific antibody, multispecific antibody, chimeric antibody, humanized antibody, human antibody, and a fusion protein comprising an antigen-binding portion of an antibody.

[0028] Composition of GM-CSF In some embodiments, GM-CSF includes pharma- ceutically safe and effective GM-CSF or its derivatives having the biological activity of GM-CSF. In some embodiments, GM-CSF is rhu GM-CSF, such as sargramostim (LEUKINE). Sargramostim is a recombinant human GM-CSF derived from biosynthetic yeast, which has a single 127 amino acid glycoprotein and differs from endogenous human GM-CSF in that it has a leucine instead of a proline at position 23. In some embodiments, other natural and synthetic GM-CSFs and their derivatives having the biological activity of natural human GM-CSF may be similarly useful.

[0029] In some embodiments, GM-CSF is produced or producible in bacteria, yeast, plants, insect cells, and mammalian cells. In some embodiments, GM-CSF is produced or producible in Escherichia coli cells. In some embodiments, GM-CSF is produced or producible in yeast cells. In some embodiments, GM-CSF is produced or producible in Chinese Hamster Ovary cells (CHO). In some embodiments, GM-CSF is not produced in E. coli cells. In some embodiments, GM-CSF is produced in cells that allow for glycosylation, such as yeast cells or CHO cells.

[0030] In some embodiments, the GM-CSF has the amino acid sequence of SEQ ID NO:1, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto. In some embodiments, the GM-CSF has the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, or a variant having at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98% identity thereto. In some embodiments, the GM-CSF is any of sargramostim, molgramostim, and regramostim. In some embodiments, the GM-CSF is sargramostim.

[0031] Without wishing to be bound by theory, the core of hGM-CSF consists of four helices packed at angles. Crystal structure and mutagenesis analysis of rhGM-CSF (Rozwarski DA et al., Proteins 26:304-13, 1996) showed that in addition to the nonpolar side chains of the protein core, 10 buried hydrogen-bonding residues contain intramolecular hydrogen bonds to main-chain atoms that are better conserved than residues that hydrogen bond to other side-chain atoms, and 24 solvation sites were observed at equivalent positions in the asymmetric units of the two molecules, with the strongest of these located in the cleft between secondary structure elements. Two surface clusters of hydrophobic side chains are located in the vicinity of the predicted receptor-binding region. Mutagenesis of residues in the helix A / helix C face confirmed the importance of specific Glu, Gly, and Gln residues. Thus, these residues are not replaced in functional substitution variants of hGM-CSF for use in this disclosure, and these helices are retained in functional fragment or deletion variants of hGM-CSF for use in this disclosure. Additionally, in certain embodiments, one of skill in the art can refer to UniProtKB entry P04141 for structural information to learn the identity of the variants.

[0032] The N-terminal helix of hGM-CSF is responsible for high affinity binding to its receptor (Shanafelt AB et al.,EMBO J 10:4105-12,1991). Transduction of the biological effects of GM-CSF requires interaction with at least two cell surface receptor components, one of which is shared with the cytokine IL-5. In the above studies, the receptor binding determinants of GM-CSF were identified by locating unique receptor binding domains on a series of human-mouse hybrid GM-CSF cytokines. The interaction of GM-CSF with the shared subunit of their high affinity receptor complex was controlled by a small portion of the peptide chain. The presence of a few key residues in the N-terminal α-helix was sufficient to confer specificity to the interaction.

[0033] In certain embodiments, the amino acid mutations are amino acid substitutions, which can include conservative and / or non-conservative substitutions.

[0034] "Conservative substitutions" may be made, for example, on the basis of similarity in polarity, charge, size, solubility, hydrophobicity, hydrophilicity, and / or amphipathic nature of the amino acid residues involved. The 20 naturally occurring amino acids may be classified into six standard amino acid groups: (1) hydrophobic: Met, Ala, Val, Leu, Ile, (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln, (3) acidic: Asp, Glu, (4) basic: His, Lys, Arg, (5) residues that influence chain orientation: Gly, Pro, and (6) aromatic: Trp, Tyr, Phe.

[0035] As used herein, "conservative substitution" is defined as the exchange of one amino acid for another that is listed in the same group of the six standard amino acid groups. For example, exchange of Asp for Glu results in the modification of the polypeptide to retain one negative charge. Furthermore, glycine and proline can be substituted for each other based on their ability to break alpha helices.

[0036] As used herein, a "non-conservative substitution" is defined as an exchange of one amino acid for another amino acid listed in a different one of the six standard amino acid groups (1) to (6) above.

[0037] In certain embodiments, substitutions may also include non-classical amino acids (e.g., selenocysteine, pyrrolysine, N-formylmethionine, β-alanine, GABA, and δ-aminolevulinic acid, 4-aminobenzoic acid (PABA), D-isomers of common amino acids, 2,4-diaminobutyric acid, α-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-aminobutyric acid, γ-Abu, ε-Ahx, 6-aminohexanoic acid, Aib, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosme, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, β-alanine, fluoroamino acids, designer amino acids such as β-methyl amino acids, Cα-methyl amino acids, Nα-methyl amino acids, and common amino acid analogs).

[0038] Amino acid sequence modifications may be accomplished using techniques known in the art, such as site-directed mutagenesis or PCR-based mutagenesis. Such techniques are described, for example, in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Plainview, NY, 1989, and Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons, New York, NY, 1989. Without wishing to be bound by theory, the degree of glycosylation of biosynthetic GM-CSF is believed to affect half-life, distribution, and excretion (Lieschke and Burgess, N. Engl. J. Med. 327:28-35, 1992; Dorr, RT, Clin. Ther. 15:19-29, 1993; Horgaard et al., Eur. J. Hematol. 50:32-36, 1993). In one embodiment, the GM-CSF molecules of the invention are glycosylated.

[0039] Biomarkers In certain embodiments, the methods of the invention relate to the utility of predictive biomarkers to determine the use of GM-CSF in the treatment of a neurodegenerative or neurological disease or disorder.

[0040] In one aspect, the present disclosure relates to a method of treating a patient in need of treatment, characterized as having failed or being intolerant or refractory to treatment with an immunomodulatory or neurological agent, hi other aspects, evaluating a patient who has failed or being intolerant or refractory to treatment with an immunomodulatory or neurological agent comprises measuring a biomarker in a patient sample.

[0041] In some embodiments, evaluation of patients who have failed or are intolerant or refractory to immunomodulatory or neurological drug treatment includes measuring various patient parameters. In some embodiments, patient samples may be analyzed, for example, using immunohistochemistry or immunofluorescence techniques, which may be used to measure immune infiltration, e.g., CD4 + Th cells (T helper cells), IL-17 producing CD4 + Th cells (Th17 cells), CD8 + Immune subsets such as T cells (cytotoxic T cells) and systemic or circulating intermediate monocytes may be evaluated. In an embodiment, multicolor flow cytometry can be used to measure multiple surface and intracellular markers to characterize cell phenotype and activation state. In an embodiment, whole blood can be used to evaluate changes in cell numbers due to treatment, or changes in cytokine levels, such as IL-1, IL-4, IL-6, IL-10, IL-12, IL-18, IL-33, IFN-γ, IP-10, M-CSF, TGF-β, VEGF, and TNFα. In an embodiment, deep sequencing technology can be used to quantify changes in individual cell clonotypes.

[0042] In one embodiment, evaluation of a patient who has failed or is intolerant or refractory to treatment with an immunomodulatory or neurological agent comprises determining the presence, absence or amount of cluster of differentiation 26 (CD26) isotype in a patient sample.

[0043] In one embodiment, evaluation of a patient who has failed or is intolerant or refractory to treatment with an immunomodulatory or neurological agent comprises determining the presence, absence or amount of one or more MSI family protein isotypes in a patient sample.

[0044] In one embodiment, evaluation of a patient who has failed or is intolerant or refractory to treatment with an immunomodulatory or neurological agent comprises determining the presence, absence or amount of a TREM2 isotype in a patient sample.

[0045] In one embodiment, evaluation of a patient who has failed or is intolerant or refractory to treatment with an immunomodulatory or neurological agent comprises determining the presence, absence or amount of an IRF-4 isotype in a patient sample.

[0046] In one embodiment, the present disclosure relates to methods of treating a neurodegenerative or neurological disease or disorder, using CD26 as a biomarker to predict or determine the need for treatment with GM-CSF.

[0047] In one embodiment, the present disclosure relates to a method for treating a neurodegenerative or neurological disease or disorder, using one or more MSI family proteins as biomarkers to predict or determine the need for treatment with GM-CSF.

[0048] In one embodiment, the present disclosure relates to a method for treating a neurodegenerative or neurological disease or disorder, using TREM2 as a biomarker to predict or determine the need for treatment with GM-CSF.

[0049] In one embodiment, the present disclosure relates to a method for treating a neurodegenerative or neurological disease or disorder, using IRF-4 as a biomarker to predict or determine the need for treatment with GM-CSF.

[0050] In one embodiment, the presence or amount of CD26, one or more MSI proteins, TREM2, and / or IRF-4 is determined by detecting protein and / or nucleic acid in a patient sample.

[0051] In one embodiment, the presence or amount of CD26, one or more MSI proteins, TREM2, and / or IRF-4 in a patient sample is determined by ELISA, immunohistochemical staining, Western blotting, intracellular Western, immunofluorescence staining, or fluorescence activated cell sorting (FACS), etc.

[0052] In one embodiment, the method of determining the presence or amount of CD26, one or more MSI proteins, TREM2, and / or IRF-4 is a method for characterizing a patient or for selecting a patient for a therapy comprising GM-CSF.

[0053] In one embodiment, the method for measuring the level of CD26, an MSI family protein, TREM2, and / or IRF4 comprises analyzing the level of CD26, an MSI family protein, TREM2, and / or IRF4 in a biological sample from a patient.

[0054] In one embodiment, the methods of the invention, e.g., methods of determining the presence, level, or activity of CD26, one or more MSI proteins, TREM2, and / or IRF-4 for patient selection purposes, use a sample selected from blood, a skin sample or tissue sample, plasma, serum, pus, urine, sweat, tears, mucus, sputum, saliva, cerebrospinal fluid (CSF), and / or other bodily fluids.

[0055] In one embodiment, the patient selection method is performed using a patient sample, where the sample is selected from blood, a skin or tissue sample, a tissue biopsy, a formalin-fixed or paraffin-embedded tissue specimen, a cytological sample, cultured cells, plasma, serum, pus, urine, sweat, tears, mucus, sputum, saliva, cerebrospinal fluid (CSF), and / or other bodily fluids.

[0056] In an embodiment, the method of the invention directs treatment decisions for a patient. For example, in an embodiment, the method includes monitoring expression and / or activity of CD26 and / or one or more MSI proteins during the course of treatment. In an embodiment, the method detects high or increased expression or activity of CD26 and / or one or more MSI proteins, which correlates with the patient failing or being intolerant or refractory to treatment with an immunomodulatory or neurological agent. In such an embodiment, without limitation, this directs treatment of the patient with a GM-CSF agent. In an embodiment, a patient with increased expression and / or activity of CD26 and / or one or more MSI proteins is directed to continue administration of GM-CSF. In an embodiment, a patient with increased or high expression or activity of CD26 and / or one or more MSI proteins is directed to receive, for example, a higher dose of GM-CSF and / or additional neurological treatment. In an embodiment, a patient with decreased expression and / or activity of CD26 and / or one or more MSI proteins is directed to discontinue administration of GM-CSF.

[0057] In an embodiment, the method includes monitoring TREM2 and / or IRF-4 expression and / or activity during the course of treatment. In an embodiment, the method detects low or decreased TREM2 and / or IRF-4 expression or activity, which correlates with the patient failing or being intolerant or refractory to treatment with an immunomodulatory or neurological agent. In such an embodiment, without limitation, this indicates treatment of the patient with a GM-CSF agent. In an embodiment, a patient with decreased TREM2 and / or IRF-4 expression and / or activity is instructed to continue administering GM-CSF. In an embodiment, a patient with decreased or low TREM2 and / or IRF-4 expression or activity is instructed to receive, for example, a higher dose of GM-CSF and / or additional neurological therapy. In an embodiment, a patient with increased TREM2 and / or IRF-4 expression and / or activity is instructed to discontinue administration of GM-CSF.

[0058] In some embodiments, the GM-CSF agents described herein enhance treatment with an immunomodulatory or neurological agent, hi some embodiments, the GM-CSF agents described herein are used to modulate a patient's immune system, for example, by decreasing or increasing the expression and / or activity of CD26, one or more MSI proteins, TREM2, and / or IRF-4.

[0059] Treatment method In one aspect, the disclosure relates to a method of treating a neurodegenerative or neurological disease or disorder comprising administering to a patient in need thereof an effective amount of the composition GM-CSF.

[0060] In another aspect, the disclosure relates to a method of treating a neurodegenerative or neurological disease or disorder comprising administering to a patient in need thereof an effective amount of a composition comprising GM-CSF in combination with an immunomodulatory or neurological agent, wherein the patient is characterized by the presence or absence or amount of CD26, one or more MSI proteins, TREM2, and / or IRF-4 in a patient sample.

[0061] In certain aspects, the disclosure relates to a method of treating a neurodegenerative or neurological disease or disorder, comprising: (a) identifying a patient who is or has been treated with a drug for a neurological problem and who is described as unsuccessful, intolerant, resistant, or refractory to treatment with an immunomodulatory or neurological drug; (b) determining the presence, absence, or amount of CD26, one or more MSI proteins, TREM2, and / or IRF-4 in a sample from the patient; and (c)(i) administering an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent to the patient who has increased or higher expression and / or activity of CD26 and / or one or more MSI proteins compared to a pre-treatment and / or non-disease state, or (c)(ii) administering an effective amount of a granulocyte-macrophage colony-stimulating factor (GM-CSF) agent to the patient who has decreased or lower expression and / or activity of TREM2 and / or IRF-4 compared to a pre-treatment and / or non-disease state.

[0062] In certain aspects, the disclosure relates to a method of treating a neurodegenerative or neurological disease or disorder, comprising: (a) selecting a patient having a neurodegenerative or neurological disease or disorder and having one or more of: (i) increased expression and / or activity of CD26 compared to a non-disease state; (ii) increased expression and / or activity of one or more MSI proteins compared to a non-disease state; (iii) decreased expression and / or activity of TREM2 compared to a non-disease state; and (iv) decreased expression and / or activity of IRF-4 compared to a non-disease state; and (b) administering to the patient an effective amount of a composition comprising GM-CSF.

[0063] In certain embodiments, the present disclosure relates to a method for treating a neurodegenerative or neurological disease or disorder comprising administering to a patient in need thereof an effective amount of a composition comprising GM-CSF, alone or in combination with an immunomodulatory or neurological agent, wherein the patient is characterized as a partial or non-responder to the neurological treatment.

[0064] In certain embodiments, the present disclosure relates to a method of treating cancer comprising administering an effective amount of a composition comprising GM-CSF, alone or in combination with an immunomodulatory or neurological agent, wherein the patient has failed or is characterized as being intolerant or refractory to treatment with the immunomodulatory or neurological agent.

[0065] In one embodiment, the method of treatment reduces the expression and / or activity of CD26. In one embodiment, the method of treatment reduces the expression and / or activity of one or more MSI proteins.

[0066] In certain embodiments, the method of treatment increases the expression and / or activity of TREM2, hi certain embodiments, the method of treatment increases the expression and / or activity of IRF-4.

[0067] In certain embodiments, the method of treatment prevents, treats, and / or ameliorates the progression and / or onset of a neurodegenerative or neurological disease or disorder in a patient. In certain embodiments, the method of treatment ameliorates a neurodegenerative or neurological disease or disorder in a patient. In certain embodiments, the method of treatment causes a disease-modifying response in a patient. In other embodiments, the method of treatment slows cognitive decline in a patient, either temporarily or permanently. In yet other embodiments, the method of treatment causes an improvement in the symptoms of a neurodegenerative or neurological disease or disorder. In still other embodiments, the method of treatment slows the onset and / or progression of a neurodegenerative or neurological disease or disorder.

[0068] In some embodiments, the method of treatment reduces or alleviates, reverses, or prevents chronic inflammation in the central nervous system (CNS). In some embodiments, the method of treatment reduces or alleviates dysfunction of endogenous or exogenous CNS immune cells. In some embodiments, the method reduces or alleviates activation of CNS astrocytes and mononuclear phagocytes, such as perivascular macrophages and microglial cells.

[0069] In certain embodiments, the treatment reduces or alleviates or reverses astrogliosis. In certain embodiments, the treatment modulates the expression of one or more cytokines and / or proteins.

[0070] In some embodiments, the treatment modulates or maintains or supports glutamine-glutamate balance in the CNS. In some embodiments, the treatment reduces or alleviates or reverses chronic microglial cell activation. In some embodiments, the treatment reduces or reverses axonal injury.

[0071] In certain embodiments, the treatment reduces or prevents amyloid pathology. In certain embodiments, the treatment reduces or prevents tauopathy.

[0072] In certain embodiments, the method of treatment reduces the sequelae of the neurodegenerative or neurological disease or disorder in the patient compared to before treatment.

[0073] In certain embodiments, the treatment methods reverse or prevent excessive production and / or signaling of one or more inflammatory cytokines, such as IL-1, IL-4, IL-6, IL-10, IL-12, IL-18, IL-33, IFN-g, IP-10, M-CSF, TGF-b, VEGF, and TNFα.

[0074] In certain embodiments, the methods of treatment reduce or prevent amyloid pathology, hi certain embodiments, the methods of treatment reduce or prevent tauopathy.

[0075] In certain embodiments, the agent that stimulates survival, proliferation, and activation of neutrophils, macrophages, and / or dendritic cells is administered at a time selected from: (i) concurrently with an immunomodulatory agent or neurological agent; (ii) within about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, or about 96 hours, or within about 1 week or about 2 weeks, after administration of the neurological agent; (iii) at least about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 36 hours, about 72 hours, or about 96 hours, or about 1 week or about 2 weeks prior to administration of the neurological agent; and / or (iv) after expression of extracellular markers, such as CD86, CD109, and / or CD122, has been reduced by at least about 10%, about 20%, about 30%, about 40%, or about 50%.

[0076] In some embodiments, the neurodegenerative or neurological disease or disorder is selected from one or more of Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), dementia with Lewy bodies, Parkinson's disease dementia epilepsy, stroke, Huntington's chorea or Huntington's disease (HD), cerebral hypoxia, multiple sclerosis, amyotrophic lateral sclerosis (ALS), neovascular glaucoma, optic neuropathy, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), and peripheral neuropathy. In some embodiments, the patient is suffering from Alzheimer's disease or Parkinson's disease.

[0077] In certain embodiments, the patient suffers from a chronic progressive disorder of the nervous system.

[0078] In one embodiment, patients are characterized by having oxidative stress, loss of neurite integrity, apoptosis, neuronal loss and / or inflammatory responses, cognitive impairment, decline in cognitive function, behavioral and personality changes, tremors, bradykinesia, rigidity, impaired posture and balance, loss of automatic movements, decreased motor coordination, changes in speech, photophobia, difficulty controlling eye muscles, slowed eye movements, dysphagia, blepharospasm, fainting or lightheadedness due to orthostatic hypotension, dizziness, impaired bladder control, distinct visual hallucinations and delusions, changes in memory, concentration and judgment, memory loss, depression, irritability, anxiety, rapid eye movement (REM) sleep disorder, seizures, paresthesia, numbness or tingling, spasticity, difficulty chewing or swallowing, muscle spasms and weakness in the limbs, and / or tingling or tingling in the hands and feet.

[0079] In certain embodiments, the method includes administering to the patient a dopamine precursor such as levodopa, a cholinesterase inhibitor such as donepezil (ARICEPT), rivastigmine (EXELON), galantamine (RAZADYNE), a serotonin dopamine antagonist (SDA), a multiactive receptor targeted antipsychotic (MARTA), and a D 2Atypical antipsychotics / second generation antipsychotics including partial agonists (e.g., ABILIFY / aripiprazole), NMDA receptor antagonists memantine, riluzole (RILUTEK), NSAIDs (nonsteroidal anti-inflammatory drugs), caffeine A2A receptor antagonists and CERE-120 (adeno-associated virus serotype 2-neurturin), deep brain stimulation, TNF-α antagonists such as etanercept, adalimumab, infliximab, IFN-γ inhibitors, The method further comprises administering one or more additional therapeutic agents selected from a TGF-β modulator, an IL-33 inhibitor, an IL-18 inhibitor, a VEGF inhibitor, an IL-1 inhibitor, an inhibitor of pathological beta amyloid (Aβ) plaques, e.g., an Aβ targeting monoclonal antibody such as aducanumab (ADUHELM), an NSAID such as methacetamol and aspirin, an antidiabetic drug such as linagliptin, a tau activation inhibitor such as liraglutide, an miRNA targeting Aβ plaque formation and tau protein phosphorylation, an alpha secretase enhancer such as ginkgo biloba and salvia miltiorrhiza, and a beta secretase inhibitor such as Coptis Rhizome and Yuanzhi.

[0080] Pharmaceutically acceptable salts and excipients The compositions described herein may have a sufficiently basic functional group that can react with inorganic or organic acids to form pharma- ceutically acceptable salts, or a carboxyl group that can react with inorganic or organic bases to form pharma- ceutically acceptable salts. Pharmaceutically acceptable acid addition salts are formed from pharma- ceutically acceptable acids as is well known in the art. Such salts include, for example, the pharma- ceutically acceptable salts described in Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P.H. Stahl and C.G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are incorporated herein by reference in their entirety.

[0081] Pharmaceutically acceptable salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, Examples of suitable salts include benzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, glycolate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, xylenesulfonate, and tartrate.

[0082] The term "pharmaceutically acceptable salt" also refers to a salt of a composition of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium, hydroxides of alkaline earth metals such as calcium and magnesium, hydroxides of other metals such as aluminum and zinc, ammonia, and organic amines such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine, tributylamine, pyridine, N-methyl,N-ethylamine, diethylamine, triethylamine, mono-, bis-, or tris-(2-OH-lower alkylamines) such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)amines such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine, N-methyl-D-glucamine, and amino acids such as arginine, lysine, and the like.

[0083] In certain embodiments, the compositions described herein are in the form of a pharma- ceutically acceptable salt.

[0084] Pharmaceutical Compositions and Formulations In certain embodiments, the disclosure relates to compositions, eg, pharmaceutical compositions, comprising GM-CSF and / or an additional therapeutic agent, eg, a therapeutic agent described herein, and a pharma- ceutically acceptable carrier or excipient.

[0085] In certain embodiments, the additional therapeutic agent is a dopamine precursor such as levodopa, a cholinesterase inhibitor such as donepezil (ARICEPT), rivastigmine (EXELON), galantamine (RAZADYNE), a serotonin dopamine antagonist (SDA), a multiactive receptor targeted antipsychotic (MARTA), and a D 2Atypical antipsychotics / second generation antipsychotics including partial agonists (e.g., ABILIFY / aripiprazole), NMDA receptor antagonists memantine, riluzole (RILUTEK), NSAIDs (nonsteroidal anti-inflammatory drugs), caffeine A2A receptor antagonists and CERE-120 (adeno-associated virus serotype 2-neurturin), deep brain stimulation, TNF-α antagonists such as etanercept, adalimumab, infliximab, IFN-γ inhibitors, and / or are selected from TGF-β modulators, IL-33 inhibitors, IL-18 inhibitors, VEGF inhibitors, IL-1 inhibitors, inhibitors of pathological beta amyloid (Aβ) plaques, e.g., Aβ targeting monoclonal antibodies such as aducanumab (ADUHELM), NSAIDs such as methacetamol and aspirin, antidiabetic drugs such as linagliptin, tau activation inhibitors such as liraglutide, miRNAs targeting Aβ plaque formation and tau protein phosphorylation, alpha secretase enhancers such as ginkgo biloba and salvia miltiorrhiza, beta secretase inhibitors such as Coptis Rhizome and Enzhi Rhizome, and pharmacokinetically acceptable salts, acids, or derivatives of any of the above.

[0086] Any of the pharmaceutical compositions described herein can be administered to a patient as a component of a composition that includes a pharma- ceutically acceptable carrier or vehicle. Such compositions can optionally include a suitable amount of a pharma- ceutically acceptable excipient to provide the form for proper administration.

[0087] In some embodiments, the pharmaceutical excipients may be liquids, such as water and oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Pharmaceutical excipients may be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents may be used. In one embodiment, the pharma- ceutically acceptable excipients are sterile when administered to a patient. When any of the agents described herein are administered intravenously, water is a useful excipient. Saline, aqueous dextrose, and glycerol solutions may also be used as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol, water, ethanol, etc. The agents described herein can also contain small amounts of wetting or emulsifying agents, or pH buffering agents, if desired. Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), which is incorporated herein by reference.

[0088] The present disclosure includes the described pharmaceutical compositions (and / or additional therapeutic agents) in various formulations. Any of the inventive pharmaceutical compositions (and / or additional therapeutic agents) described herein can be in the form of a solution, suspension, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquid, gelatin capsules, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, lyophilized powders, freeze suspensions, dry powders, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule. In another embodiment, the composition is in the form of a tablet. In yet another embodiment, the pharmaceutical composition is formulated in the form of a soft gel capsule. In an embodiment, the pharmaceutical composition is formulated in the form of a gelatin capsule. In yet another embodiment, the pharmaceutical composition is formulated as a liquid.

[0089] If necessary, the pharmaceutical compositions of the present invention (and / or additional therapeutic agents) can also include solubilizing agents. The agents can also be delivered in a suitable vehicle or delivery device known in the art. The combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device.

[0090] The formulations of the present disclosure, including the pharmaceutical composition of the present invention (and / or additional therapeutic agent), may be conveniently provided in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Such methods generally include the step of combining the therapeutic agent with a carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately combining the therapeutic agent with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation (e.g., wet or dry granulation, powder blending, etc., followed by tableting using conventional methods known in the art).

[0091] In certain embodiments, any pharmaceutical composition described herein (and / or additional therapeutic agents) is formulated in accordance with routine procedures into compositions suitable for the administration methods described herein.

[0092] Routes of administration include, for example, topical, oral, intradermal, transdermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intranasal, epidural, sublingual, intranasal, intracerebral, intravaginal, rectal, or inhalation. Administration can be local or systemic. In some embodiments, administration is by intravenous route. The method of administration can be left to the discretion of the physician and depends in part on the site of the pathology. In most instances, administration releases any agent described herein onto or into the affected area.

[0093] In certain embodiments, GM-CSF (and / or additional therapeutic agents) are administered by intravenous route.

[0094] In one embodiment, the pharmaceutical compositions (and / or additional therapeutic agents) described herein are formulated into compositions suitable for administration according to conventional procedures. For intravenous administration, suitable carriers include saline, sterile water, Cremophor ELTM (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). The carrier must be stable under the conditions of manufacture and storage and must be preserved against microorganisms. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.

[0095] Dosage forms suitable for parenteral administration (e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, and intraarticular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may be prepared in the form of sterile solid compositions (e.g., lyophilized compositions) that can be dissolved or suspended in a sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art. Formulation components suitable for parenteral administration include sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents, antibacterial agents such as benzyl alcohol or methylparabens, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as EDTA, buffers such as acetates, citrates, or phosphates, and tonicity adjusters such as sodium chloride or dextrose.

[0096] The composition for oral delivery can be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs.In order to provide a medicament that is medicamentically palatable, the composition for oral administration can contain one or more agents, for example, sweeteners such as fructose, aspartame, or saccharin, flavors such as peppermint, wintergreen oil, or cherry, colorants, and preservatives.

[0097] The topical delivery composition may be in the form of, for example, a cream, gel, ointment, lotion, spray, aqueous or oily suspension, powder, or emulsion. Enhanced skin permeability and penetration may be achieved by non-invasive methods, such as, for example, the use of any of the nanocarriers in combination with any of the pharmaceutical compositions (and / or additional therapeutic agents) described herein. The skin can act as a reservoir and be used to deliver the compositions (and / or additional therapeutic agents) described herein in a sustained manner over a longer period of time.

[0098] Any of the pharmaceutical compositions of the invention (and / or additional therapeutic agents) described herein can be administered by controlled or sustained release means or by delivery devices known to those of skill in the art, including, but not limited to, those described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms may be useful for providing controlled or sustained release of one or more active ingredients, for example, using hydropropyl cellulose, hydropropyl methyl cellulose, polyvinylpyrrolidone, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide desired release profiles at various rates. Suitable controlled or sustained release formulations known to those skilled in the art, including those described herein, can be easily selected for use with the active ingredients of the medicaments described herein. Thus, the present disclosure provides single unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps, and caplets adapted for controlled or sustained release.

[0099] Controlled or sustained release of an active ingredient can be stimulated by various conditions including, but not limited to, changes in pH, changes in temperature, stimulation with light of appropriate wavelengths, enzyme concentration or availability, water concentration or availability, or other physiological conditions or compounds.

[0100] In another embodiment, a controlled release system can be placed near the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled release systems discussed in the review by Langer, 1990, Science 249:1527-1533 may also be used.

[0101] The pharmaceutical preparation is preferably sterile. Sterility can be achieved, for example, by filtration through sterile filtration membranes. If the composition is lyophilized, filter sterilization can be performed prior to or after lyophilization and reconstitution.

[0102] Administration and Dosage It will be understood that the actual dosage of the composition administered according to the present disclosure will vary depending on the specific dosage form and administration method. Many factors that may change the action of the composition (e.g., body weight, sex, diet, administration time, administration route, excretion rate, patient condition, drug combination, genetic predisposition and reaction sensitivity) can be taken into consideration by those skilled in the art. Administration can be performed continuously or in one or more individual doses within the maximum tolerated dose. The optimal administration rate for a given set of conditions can be confirmed by those skilled in the art using conventional dose administration tests.

[0103] In some embodiments, GM-CSF is administered at a total dose of about 125 μg, about 150 μg, or about 200 μg, or about 250 μg, or about 300 μg, or about 350 μg. In some embodiments, GM-CSF is administered at a total dose of about 250 μg.

[0104] In certain embodiments, GM-CSF is administered at a dose of about 125 μg, about 150 μg, or about 200 μg, or about 250 μg, or about 300 μg, or about 350 μg.

[0105] In some embodiments, GM-CSF is administered on a monthly or twice monthly, weekly or twice weekly, daily or twice daily dosing schedule, hi some embodiments, GM-CSF is administered weekly.

[0106] In one embodiment, the GM-CSF is sargramostim and is administered at a dose of about 125 μg once a week.

[0107] Combination Therapies and Additional Therapeutic Agents In certain embodiments, the pharmaceutical compositions of the present disclosure are administered in combination with an additional agent(s), for example, an immunomodulatory agent such as a checkpoint inhibitor or a neurological agent. The combination administration can be simultaneous or sequential.

[0108] In one embodiment, the additional immunomodulatory agent or neurological agent and the GM-CSF of the present disclosure are administered to the patient simultaneously. As used herein, the term "simultaneously" refers to administering the immunomodulatory agent or neurological agent and the GM-CSF within a time interval of about 60 minutes, for example, within about 30 minutes, within about 20 minutes, within about 10 minutes, within about 5 minutes, or within about 1 minute. The administration of the immunomodulatory agent or neurological agent and the GM-CSF can be performed by simultaneous administration of a single formulation (e.g., a formulation including an additional therapeutic agent and a GM-CSF composition) or separate formulations (e.g., a first formulation including an immunomodulatory agent or neurological agent and a second formulation including a GM-CSF composition).

[0109] Co-administration of the therapeutic agents is not required when the timing of administration of the therapeutic agents is such that the pharmacological activity of the immunomodulatory agent or neurological agent and GM-CSF overlaps in time, thereby providing a combined therapeutic effect. For example, the immunomodulatory agent or neurological agent and the target site, the GM-CSF composition, can be administered sequentially. As used herein, the term "sequentially" means that the immunomodulatory agent or neurological agent and GM-CSF are administered at a time interval of about 60 minutes or more. For example, the time between the sequential administration of the immunomodulatory agent or neurological agent and GM-CSF can be about 60 minutes or more, about 2 hours or more, about 5 hours or more, about 10 hours or more, about 1 day or more, about 2 days or more, about 3 days or more, about 1 week or more, about 2 weeks or more, or about 1 month or more. The optimal administration time depends on the rate of metabolism, excretion, and / or pharmacodynamic activity of the additional therapeutic agent and GM-CSF administered. Either the immunomodulatory agent or neurological agent or the GM-CSF composition can be administered first.

[0110] Co-administration also does not require that the therapeutic agents be administered to a patient by the same route of administration. Rather, each therapeutic agent can be administered by any suitable route, e.g., orally or parenterally.

[0111] In certain embodiments, GM-CSF as described herein acts synergistically when co-administered with an immunomodulatory or neurological agent, In such embodiments, the targeting moiety, GM-CSF composition, and immunomodulatory or neurological agent may be administered at lower doses than would be used when these agents are used in a monotherapy setting.

[0112] sample In certain embodiments, the sample is selected from a biopsy, a tissue, and / or a bodily fluid.

[0113] In certain embodiments, the sample is selected from blood, a skin or tissue sample, a tissue biopsy, a formalin-fixed or paraffin-embedded tissue specimen, a cytological sample, cultured cells, plasma, serum, pus, urine, sweat, tears, mucus, sputum, saliva, and / or other bodily fluids.

[0114] array SEQ ID NO:1 is wild type GM-CSF:

[0115] APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFDCWEPVQE.

[0116] SEQ ID NO:2 is sargramostim:

[0117] APARSPSPSTQPWEHVNAIQEALRLLNLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFDCWEPVQE.

[0118] SEQ ID NO:3 is molgramostim:

[0119] APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQIITFESFKENLKDFLLVIPFDCWEPVQE.

[0120] SEQ ID NO:4 is regramostim:

[0121] APARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEMNETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHCPPTPETSCATQTTFESFKENLKDFLLVIPFDCWEPVQE.

[0122] definition In connection with the invention disclosed herein, the following definitions are used: Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0123] When used in relation to an agent effective to treat a coronavirus infection, an "effective amount" is an amount effective to treat or alleviate the coronavirus infection.

[0124] As used herein, "a", "an" or "the" can mean one or more than one. Additionally, the term "about", when used in connection with a referenced numerical indication, means the referenced numerical indication ± up to 10% of the referenced numerical indication. For example, the term "about 50" covers the range of 45 to 55.

[0125] As referred to herein, all composition percentages are by weight of the total composition unless otherwise specified. As used herein, the term "comprises" and variations thereof are intended to be non-limiting, and the recitation of items in a list does not exclude other similar items that may also be useful in the materials, compositions, devices, and methods of this technology. Similarly, the terms "can" and "may" and variations thereof are intended to be non-limiting, and a statement that an embodiment can or may include certain elements or features does not exclude other embodiments of this technology that do not include those elements or features.

[0126] Although the open-ended term "comprising" is used herein to describe and claim the present invention as a synonym for terms such as including, containing, or having, the present invention or embodiments thereof may alternatively be described using alternative terms such as "consisting of" or "consisting essentially of." EXAMPLES

[0127] Example 1: Expression and dynamics of CD26, MSI proteins, TREM2, and IRF-4 in human monocytes Peripheral blood mononuclear cells from healthy volunteers were cultured overnight in the presence of various concentrations of sargramostim (LEUKINE) ranging from 0.001 nM to 100 nM. At the end of the culture period, cells were harvested and stained for expression of CD26, Musashi-2 (MSI-2), or IRF-4 on monocytes and lymphocytes on day 1. Expression of TREM2 on monocytes and lymphocytes was also measured on days 1, 2, and 3 after treatment. Cells were co-stained for CD14 expression for differentiation of monocytes. Expression of various surface receptors was normalized to levels without added LEUKINE and plotted against various concentrations of LEUKINE. This procedure was replicated in separate donors (n=3) and error bars for expression levels are shown. Treatment with sargramostim (LEUKINE) reduced expression of CD26 (Figure 1) and Musashi-2 (MSI-2) (Figure 2). However, treatment with sargramostim (LEUKINE) increased the expression of TREM2 (FIGS. 3A and 3B) and IRF-4 (FIG. 4) on monocytes, but not lymphocytes.

[0128] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed within the scope of the following claims.

[0129] All patents and publications referenced herein are hereby incorporated by reference in their entirety.

[0130] As used herein, all headings are for organizational purposes only and are not intended to limit the disclosure in any way. Contents of individual sections may be equally applicable to all sections.

Claims

1. A pharmaceutical composition comprising an effective amount of granulocyte-macrophage colony-stimulating factor (GM-CSF) for use in a method for treating or preventing a neurodegenerative or neurological disease or disorder, said method comprising: (a) determining the presence or absence or amount of one or more of (i)-(iv) in a sample from a patient: (i) Group of differentiation antigens 26 (CD26); (ii) one or more Musashi (MSI) family proteins (optionally selected from Musashi-1 (MSI-1) and Musashi-2 (MSI-2)); (iii) Triggering receptor expressed on myeloid cells 2 (TREM2); and (iv) interferon regulatory factor 4 (IRF4); and (b) administering said pharmaceutical composition to said patient. A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition of claim 1, wherein the presence or amount of CD26, one or more MSI family proteins, TREM2, and / or IRF4 is determined by ELISA, immunohistochemical staining, Western blotting, intracellular Western, immunofluorescence staining, or fluorescence-activated cell sorting (FACS).

3. A pharmaceutical composition comprising an effective amount of granulocyte-macrophage colony-stimulating factor (GM-CSF) for use in a method for treating a neurodegenerative or neurological disease or disorder, said method comprising: (a) selecting a patient having a neurodegenerative or neurological disease or disorder and having one or more of (i)-(iv) in a sample derived from the patient; (i) Increased expression and / or activity of CD26 compared to a non-disease state or before treatment (ii) increased expression and / or activity of one or more MSI family proteins (wherein the MSI family proteins are optionally selected from Musashi-1 (MSI-1) and Musashi-2 (MSI-2)) compared to a non-disease state or before treatment; (iii) TREM2 expression and / or activity is reduced compared to a non-disease state or before treatment. (iv) IRF4 expression and / or activity is reduced compared to a non-disease state or before treatment; and (b) administering said pharmaceutical composition to said patient. A pharmaceutical composition comprising:

4. A pharmaceutical composition described in claim 1 or 3, wherein the method further comprises one or more of the following (a) to (d): (a) monitoring CD26 expression and / or activity during said course of treatment, wherein an increase in CD26 expression and / or activity indicates continued administration of GM-CSF and a decrease in CD26 expression and / or activity indicates discontinuation of administration of GM-CSF; (b) monitoring the expression and / or activity of one or more Musashi (MSI) family proteins, including Musashi-1 and / or Musashi-2, during said course of treatment, wherein an increase in expression and / or activity of the one or more MSI family proteins indicates continued administration of GM-CSF, and a decrease in expression and / or activity of the one or more MSI family proteins indicates discontinuation of administration of GM-CSF; (c) monitoring TREM2 expression and / or activity during said course of treatment, wherein a decrease in TREM2 expression and / or activity indicates continued administration of GM-CSF and an increase in TREM2 expression and / or activity indicates discontinuation of administration of GM-CSF; (d) monitoring IRF4 expression and / or activity during said course of treatment, wherein a decrease in IRF4 expression and / or activity indicates continued administration of GM-CSF and an increase in IRF4 expression and / or activity indicates discontinuation of administration of GM-CSF.

5. A pharmaceutical composition as described in claim 1 or 3, wherein the dose of GM-CSF used to treat a neurodegenerative or neurological disease or disorder depends on the expression and / or activity of CD26, one or more MSI family proteins, TREM2, and / or IRF4.

6. 4. The pharmaceutical composition of claim 1 or 3, wherein the sample comprises blood, a tissue sample, plasma, serum, pus, urine, sweat, tears, mucus, sputum, saliva, cerebrospinal fluid (CSF), and / or other bodily fluids.

7. 4. The pharmaceutical composition of claim 1 or 3, wherein the neurodegenerative or neurological disease or disorder is one or more of Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), dementia with Lewy bodies, Parkinson's dementia, epilepsy, stroke, Huntington's chorea or Huntington's disease (HD), cerebral hypoxia, multiple sclerosis, amyotrophic lateral sclerosis (ALS), neovascular glaucoma, optic neuropathy, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA), and peripheral neuropathy.

8. the patient is suffering from Alzheimer's disease or Parkinson's disease, and / or the patient is characterized by oxidative stress, loss of neurite integrity, apoptosis, neuronal loss and / or inflammatory response, cognitive impairment, cognitive decline, behavioral and personality changes, tremor, bradykinesia, rigidity, impaired posture and balance, loss of automatic movements, decreased motor coordination, changes in speech, photophobia, difficulty controlling eye muscles, slowed saccadic eye movements, dysphagia, blepharospasm, fainting or lightheadedness due to orthostatic hypotension, dizziness, impaired bladder control, distinct visual hallucinations and delusions, changes in memory, concentration and judgment, memory loss, depression, irritability, anxiety, rapid eye movement (REM) sleep disorder, seizures, paresthesia, numbness or tingling, spasticity, difficulty chewing or swallowing, muscle spasms and weakness in the limbs, and / or tingling or tingling in the hands and feet, The pharmaceutical composition according to claim 1 or 3.

9. The method comprises: (a) preventing, treating, and / or mitigating the progression and / or onset of said neurodegenerative or neurological disease or disorder; (b) ameliorates said neurodegenerative or neurological disease or disorder in said patient; (c) modulating the expression of one or more cytokines and / or proteins, optionally wherein the cytokines and / or proteins are one or more of IL-1, IL-4, IL-6, IL-10, IL-12, IL-18, IL-33, IFN-γ, IP-10, M-CSF, TGF-β, VEGF, and TNFα; and / or (d) reducing the sequelae of said neurodegenerative or neurological disease or disorder in said patient compared to before treatment; The pharmaceutical composition according to claim 1 or 3.

10. 4. The pharmaceutical composition of claim 1 or 3, wherein the GM-CSF has the amino acid sequence of SEQ ID NO: 1, or a variant thereof having about 90%, about 93%, about 95%, about 97%, or about 98% identity thereto.

11. 4. The pharmaceutical composition of claim 1, wherein the GM-CSF has an amino acid sequence of one of SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4, or a variant thereof having about 90%, about 93%, about 95%, about 97%, or about 98% identity thereto.

12. 4. The pharmaceutical composition of claim 1, wherein the GM-CSF is one of molgramostim, sargramostim, and regramostim.

13. The pharmaceutical composition of claim 1 or 3, wherein the method comprises administering the GM-CSF at a total dose of about 125 μg, about 150 μg, or about 200 μg, or about 250 μg, or about 300 μg, or about 350 μg.

14. The pharmaceutical composition of claim 1 or 3, wherein the method comprises administering the GM-CSF on a monthly, twice-monthly, weekly, twice-weekly, daily, or twice-daily dosing schedule.

15. A pharmaceutical composition described in claim 1 or 3, wherein the method comprises administering sargramostim at a dose of approximately 125 μg once a week.

16. The pharmaceutical composition of claim 1 or 3, wherein the method comprises administering the GM-CSF intravenously.

17. The method may involve the use of dopamine precursors such as levodopa, cholinesterase inhibitors such as donepezil (ARICEPT), rivastigmine (EXELON), galantamine (RAZADYNE), serotonin dopamine antagonists (SDAs), multi-active receptor-targeted antipsychotics (MARTAs), and D ２ atypical antipsychotics / second generation antipsychotics including partial agonists (e.g., ABILIFY / aripiprazole), NMDA receptor antagonists memantine, riluzole (RILUTEK), NSAIDs (nonsteroidal anti-inflammatory drugs), caffeine A2A receptor antagonists and CERE-120 (adeno-associated virus serotype 2-neurturin), deep brain stimulation, TNF-α antagonists such as etanercept, adalimumab, infliximab, IFN-γ inhibitors, 4. The pharmaceutical composition of claim 1 or 3, further comprising administering one or more additional therapeutic agents selected from a TGF-β modulator, an IL-33 inhibitor, an IL-18 inhibitor, a VEGF inhibitor, an IL-1 inhibitor, an inhibitor of pathological beta amyloid (Aβ) plaques, for example, an Aβ-targeting monoclonal antibody such as aducanumab (ADUHELM), an NSAID such as metacetamol and aspirin, an antidiabetic drug such as linagliptin, an inhibitor of tau activation such as liraglutide, an miRNA targeting Aβ plaque formation and tau protein phosphorylation, an alpha-secretase enhancer such as ginkgo biloba and salvia miltiorrhiza, and a beta-secretase inhibitor such as Coptis Rhizome and Yuanzhi.

18. The GM-CSF is (a) temporarily or permanently slowing cognitive decline; (b) causing an amelioration of the symptoms of said neurodegenerative or neurological disease or disorder; and / or (c) delaying the onset and / or development of said neurodegenerative or neurological disease or disorder; The pharmaceutical composition according to claim 1 or 3.

19. The method comprising: (a) reverse or prevent chronic inflammation within the central nervous system (CNS); (b) reducing or alleviating dysfunction of endogenous or exogenous CNS immune cells; (c) reducing or attenuating the activation of CNS astrocytes and mononuclear phagocytes, optionally wherein the mononuclear phagocytes include perivascular macrophages and microglial cells; (d) reducing, alleviating, or reversing astrogliosis; (e) regulating, maintaining, or supporting glutamine-glutamate balance within the CNS; (f) reducing, alleviating, or reversing chronic microglial cell activation; (g) reversing axonal injury; (h) reducing or preventing excessive production and / or signaling of one or more inflammatory cytokines and / or proteins; (i) reducing or preventing amyloid pathology; and / or (j) reducing or preventing taupathies; The pharmaceutical composition according to claim 1 or 3.

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