Methods of treating neurodegenerative diseases

Abstract

The present disclosure provides methods of treating neurodegenerative diseases through depletion of soluble biomolecules (e.g., soluble TNF, soluble TNFR1, and soluble TNFR2).

Description

[0001] Attorney Docket No. NIH-01625 METHODS OF TREATING NEURODEGENERATIVE DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 683,900, filed on August 16, 2024, and U.S. Provisional Application No.63 / 860,460, filed on August 8, 2025, each of which is incorporated by reference herein in its entirety. BACKGROUND TNF-α has been implicated in the etiology of neurodegenerative diseases (e.g., multiple sclerosis, MS). However, the use of conventional TNF-inhibiting drugs has not been successful. Recent studies have clarified that soluble TNF (sTNF) signaling through the TNF receptor 1 (TNFR1) drives the pathogenic role of TNF in MS, while membrane TNF (mTNF) signaling through TNFR2 plays a profound neurorestorative role, counterbalancing the effect of sTNF. Treatment of neurodegenerative diseases would be greatly benefited by methods that influence soluble TNF signaling and membrane TNF signaling. SUMMARY The present disclosure provides, among other things, methods of treatment of neurodegenerative diseases or disorders (e.g., multiple sclerosis) through selective depletion of sTNF, sTNFR1, and / or sTNFR2. In some aspects, the disclosure provides methods of treating a neurodegenerative disease or disorder in a subject in need thereof, comprising depleting one or more depletion targets selected from soluble tumor necrosis factor receptor 1 (sTNFR1), soluble tumor necrosis factor receptor 2 (sTNFR2), and soluble tumor necrosis factor (sTNF) from a body fluid of the subject. In other aspects, the disclosure provides methods of promoting neuron myelination in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In certain aspects, the disclosure provides methods of inhibiting neuron demyelination in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In certain aspects, the disclosure provides methods of enhancing the generation of oligodendrocytes in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. 1 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some aspects, the disclosure provides methods of increasing oligodendrocyte precursor cell proliferation in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In certain aspects, the disclosure provides methods of increasing oligodendrocyte precursor cell differentiation to form oligodendrocytes in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In certain aspects, the disclosure provides methods of maintaining or increasing the number of oligodendrocytes and / or oligodendrocyte precursor cells in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, depleting one or more depletion targets comprises administering to the subject a composition comprising a depletion particle. In some embodiments, depleting one or more depletion targets comprises administering to the subject a composition comprising a first depletion particle and a second depletion particle. In some embodiments, depleting one or more depletion targets comprises administering to the subject a composition comprising a first depletion particle, a second depletion particle, and a third depletion particle. In some embodiments, depleting one or more depletion targets comprises administering to the subject a depletion particle that comprises a first depletion agent. In some embodiments, depleting one or more depletion targets comprises administering to the subject a depletion particle that comprises a first depletion agent, and a second depletion agent. In some embodiments, depleting one or more depletion targets comprises administering to the subject a depletion particle that comprises a first depletion agent, a second depletion agent, and a third depletion agent. In some embodiments, the methods further comprise administering a selective sTNF antagonist, wherein the sTNF antagonist comprises an antibody or a TNF mutein. In some aspects, the present disclosure provides one or more depletion particle(s) for use in the treatment of a neurodegenerative disease or disorder in a subject in need thereof. In some aspects, the present disclosure provides one or more depletion particle(s) for use in promoting neuron myelination in a subject in need thereof. In some aspects, the present disclosure provides one or more depletion particle(s) for use in inhibiting neuron demyelination in a subject in need thereof. 2 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some aspects, the present disclosure provides one or more depletion particle(s) for use in enhancing the generation of oligodendrocytes in a subject in need thereof. In some aspects, the present disclosure provides one or more depletion particle(s) for use in increasing oligodendrocyte precursor cell proliferation in a subject in need thereof. In some aspects, the present disclosure provides one or more depletion particle(s) for use in increasing oligodendrocyte precursor cell differentiation to form oligodendrocytes in a subject in need thereof. In some aspects, the present disclosure provides one or more depletion particle(s) for use in maintaining or increasing the number of oligodendrocytes and / or oligodendrocyte precursor cells in a subject in need thereof. In certain aspects, the present disclosure provides use of one or more depletion particle(s) for the manufacture of a medicament for the treatment of a neurodegenerative disease or disorder in a subject in need thereof. In some aspects, the present disclosure provides use of one or more depletion particle(s) for the manufacture of a medicament for promoting neuron myelination in a subject in need thereof. In some aspects, the present disclosure provides use of one or more depletion particle(s) for the manufacture of a medicament for inhibiting neuron demyelination in a subject in need thereof. In some aspects, the present disclosure provides use of one or more depletion particle(s) for the manufacture of a medicament for enhancing the generation of oligodendrocytes in a subject in need thereof. In some aspects, the present disclosure provides use of one or more depletion particle(s) for the manufacture of a medicament for increasing oligodendrocyte precursor cell proliferation in a subject in need thereof. In some aspects, the present disclosure provides use of one or more depletion particle(s) for the manufacture of a medicament for increasing oligodendrocyte precursor cell differentiation to form oligodendrocytes in a subject in need thereof. In some aspects, the present disclosure provides use of one or more depletion particle(s) for the manufacture of a medicament for maintaining or increasing the number of oligodendrocytes and / or oligodendrocyte precursor cells in a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS The Drawings included herein, which are composed of the following Figures, are for illustration purposes only and not for limitation. 3 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 FIG.1 is a schematic diagram showing counterbalancing effects of soluble tumor necrosis factor (sTNF) and membrane TNF (mTNF) that contribute to homeostasis and healthy conditions of the CNS. FIG.2 is a schematic diagram showing elevation of sTNF causing disruption of the blood- brain barrier (BBB) and driving demyelination of neuronal axons. FIG.3 is a schematic diagram showing effects of untreated multiple sclerosis including elevation of sTNF causing disruption of the blood-brain barrier (BBB), driving demyelination of neuronal axons, and elevation of sTNFR1, causing suppression of mTNF / TNFR2 signaling needed for restoring myelination of neuronal axons. FIG.4 is a schematic diagram showing therapeutic effects of intervention with anti-sTNF particles. The term “NaNot” denotes a depletion particle as described herein. FIG.5 is a schematic diagram showing therapeutic effects of intervention with anti-sTNF particles and anti-sTNFR1 particles. The term “NaNot” denotes a depletion particle as described herein. FIGs.6A-6B are schematic diagrams showing the impact of sTNFR1 binding on mTNFR1 (FIG.6A) and mTNFR2 (FIG.6B) signaling as described in Example 1. FIGs.7A-7D show example clusters of TNF trimers each complexed with either two or three TNF receptors, with a TNF trimer at each vertex: FIG.7A: a single hexagonal cluster with TNF trimers numbered 1 to 6; FIG.7B: a linear array of 6 trimers; FIG.7C: a linear array of 4 trimers with 2 branched trimers; FIG.7D: a hexagonal ring with a single branched trimer. FIG.8 is a plot showing the fold change in the ratio of mTNFR1 to mTNFR2 signaling on moving from healthy control (HC), with CSF sTNFR1 concentration = 40 pM to MS with elevated CSF sTNFR1 (on the x-axis), for a corresponding elevation of TNF of 7.7x over HC, as described in Example 1. FIG.9 shows the fold change increase in the beneficial mTNFR2 / mTNFR1 signaling ratio (note this is the inverse of the deleterious mTNFR1 / mTNFR2 ratio shown in FIG.8) in MS treatment as sTNFR1 is depleted from the CSF from an initial concentration of 200 pM, as described in Example 1. FIG.10 shows the effect of the presence of sTNFR2 on the mTNFR2 / mTNFR1 signaling ratio as a function of sTNR1 concentration, for (i) Kd(TNF-sTNFR2) = 0.4 nM; (ii) Kd(TNF- sTNFR2) = 1.0 nM, as described in Example 1. FIG.11 shows a robustness analysis and the effect of different choice of parameters used in Example 1. 4 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 FIG.12 shows a particle according to Example 10 with PLGA-10% PEG NP shielding showing front and rear sides. FIGs.13A-13B show capture from solution of sTNFR1 (FIG.13A) and sTNFR2 (FIG. 13B) by particles as described in Example 11. FIG.14 shows the viability of L929 mouse fibroblast cells at various effective TNF-α concentrations, either in solution or on a shielded particle as described in Example 12. FIG.15 shows the viability of L929 mouse fibroblast cells at various effective TNF-α concentrations, either in solution or on a shielded particle as described in Example 12. FIGs.16A-16B show the difference in binding of particles with anti-sTNFR1 antibodies immobilized on their surface with (FIG.16A) or without (FIG.16B) PEG coating molecules on the surface of the particles, to a test particle with TNFR1 on its surface as described in Example 13. FIG.17 shows the depletion of sTNFR1 and sTNFR2 from mouse serum in vivo by a mixture of anti-sTNFR1 and anti-sTNFR2 particles as described in Example 13. FIG.18 shows the EAE score measuring paralysis in the EAE mouse model of MS described in Example 2. FIG.19A shows inflammatory endpoints measured in the EAE mouse model of MS described in Example 2. FIG.19B shows neurodegenerative endpoints measured in the EAE mouse model of MS described in Example 2. FIG.20A shows the inflammatory composite score derived from the inflammatory endpoints in FIG.19A, described in Example 2. FIG.20B shows the neurodegenerative composite score derived from the neurodegenerative endpoints in FIG.19B, described in Example 2. FIG.21A shows the density of oligodendrocyte precursor cells measured in the spinal cord of mice in the EAE model, described in Example 2. FIG.21B shows the density of oligodendrocyte cells measured in the spinal cord of mice in the EAE model, described in Example 2. DETAILED DESCRIPTION The disclosure features methods of treating a neurodegenerative disease or disorder through sequestering a biomolecule (e.g., sTNF, sTNFR1, and / or sTNFR2) associated with exacerbation of the disease or disorder away from its natural environment, e.g., to thereby inhibit the biological activity of the soluble biomolecule. For example, the disclosure provides methods of treating a neurodegenerative disease, such as multiple sclerosis (MS) by administering a particle, or a 5 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 plurality of particles, comprising an agent (e.g., immobilized on a surface of the particle) that selectively binds to a soluble biomolecule. Once the soluble biomolecule is bound by the agent, it is sequestered by the particle such that the soluble biomolecule has a reduced ability (e.g., substantially reduced ability or no ability) to interact with other natural binding partners of the soluble biomolecule. Thus, the soluble biomolecule becomes inert. The disclosure also features particles and compositions comprising particles suitable for depleting a biomolecule (e.g. sTNF, sTNFR1 and / or sTNFR2) or a combination of more than one biomolecule from a body fluid of a subject. In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification. The publications and other reference materials referenced herein to describe the background of the disclosure and to provide additional detail regarding its practice are hereby incorporated by reference. In this application, unless otherwise clear from context, (i) the terms “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising” and "including" may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) where ranges are provided, endpoints are included. The soluble biomolecule is, generally, a first member of a specific binding pair. As used herein, a “binding partner,” “specific binding partner,” or a “member of a specific binding pair,” generally comprises any member of a pair of binding members that bind to each other with substantial affinity and specificity. A pair of binding partners may bind to one another to the substantial exclusion of at least most or at least substantially all other components of a sample, and / or may have a dissociation constant of less than about 10-4, 10-5, 10-6, 10-7, or 10-8M, among others. A pair of binding partners may “fit” together in a predefined manner that relies on a plurality of atomic interactions to cooperatively increase specificity and affinity. Binding partners may be derived from biological systems (e.g., receptor-ligand interactions), chemical interactions, and / or by molecular imprinting technology, among others. The term “biomolecule” as used herein, refers to any molecule that may exert an effect on a living organism. In some embodiments, the biomolecule is an atom, such as lithium or lead (e.g., the biomolecule may be a metal cation). In some embodiments, the biomolecule is not an atom or metal ion. For example, the biomolecule may be a molecule, such as an organic compound or inorganic compound. In some embodiments, the biomolecule is a drug, such as warfarin or 6 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 dabigatran. The biomolecule may be a biologic drug, for example, comprising a protein or peptide, for example, comprising an antibody or an antigen-binding portion thereof. The biomolecule may be a psychoactive drug, such as diacetylmorphine. The biomolecule may be a poison, toxin, or venom. The biomolecule may be an allergen. The biomolecule may be a carcinogen. The biomolecule may be the agent of a chemical weapon, such as a nerve agent. The biomolecule may be a molecule that is endogenous to the organism, such as a hormone, cytokine, neurotransmitter, soluble extracellular receptor, antibody, or soluble matrix protein. The biomolecule may be a peptide, polypeptide, protein, nucleic acid, carbohydrate, or sugar. The biomolecule may comprise a peptide, polypeptide, protein, nucleic acid, carbohydrate, or sugar. The biomolecule may be a misfolded protein. The biomolecule may be an amyloid or the soluble precursor of an amyloid. “Polypeptide,” “peptide,” and “protein” are used interchangeably and mean any peptide-linked chain of amino acids, regardless of length or post-translational modification. The biomolecule may be a lipid, a steroid, or cholesterol. The biomolecule may comprise a lipid, a steroid, or cholesterol. The biomolecule may be a circulating, cell-free nucleic acid, such as a circulating, cell-free RNA. The biomolecule may be a micro RNA (miRNA). The terms “specific binding,” “specifically binds,” “selective binding,” “selectively binds,” and like grammatical terms, as used herein, refer to two molecules forming a complex that is relatively stable under physiologic conditions. Typically, binding is considered specific or selective when the association constant or on-rate (ka) is higher than 106M-1s-1. Thus, a first member of a specific binding pair can specifically bind to the second member of the binding pair with a kaof at least (or greater than) 106M-1s-1(e.g., at least or greater than 107, 108, 109, 1010, 1011, 1012, 1013, 1014, or 1015M-1s-1or higher). In some embodiments, a specific or selective interaction has a dissociation rate constant or off-rate (kd) of less than or equal to 10-3s-1(e.g., 8 x 10-4, 5 x 10-4, 2 x 10-4, 10-4, or 10-5s-1). The dissociation constant KDis the ratio of the kinetic rate constants – kd / ka. In some embodiments, a specific or selective interaction has a KD of less than 10-8, 10-9, 10-10, 10-11, or 10-12M. In some embodiments, a specific or selective interaction has a KD of less than 1 x 10-9M. As used herein, the term “interaction,” when referring to an interaction between two molecules, refers to the physical contact (e.g., binding) of the molecules with one another. Generally, such an interaction results in an activity (which produces a biological effect) of one or both of said molecules. To inhibit such an interaction results in the disruption of the activity of one or more molecules involved in the interaction. 7 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 As used herein, the term “inhibiting” and grammatical equivalents thereof refer to a decrease, limiting, and / or blocking of a particular action, function, or interaction. In one embodiment, the term refers to reducing the level of a given output or parameter to a quantity (e.g., the background level of the interaction between two members of a specific binding pair) which is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% less than the quantity in a corresponding control. A reduced level of a given output or parameter need not, although it may, mean an absolute absence of the output or parameter. The present disclosure does not require, and is not limited to, methods that wholly eliminate the output or parameter. Substantial inhibition can be, e.g., at least 50% (e.g., 55, 60, 65, 70, 75, 80, 85, 90, or 95% or greater) inhibition of an interaction between two biomolecules (e.g., the first and second members of a binding pair). Herein the terms “target” and “depletion target” are used interchangeably to refer to a biomolecule that is depleted from its environment, such as from a body fluid, for example the circulation, according to the present disclosure. A target is a selective binding partner of an agent provided on a particle for use according to the present disclosure. The target may be depleted from a body fluid of a subject by being bound selectively by the agent, and so sequestered from a body fluid. The target may be depleted from a body fluid other than the circulation of the subject by way of depletion from the circulation. For example, the target may be depleted from the body fluid by passing from the body fluid to the circulation. For example, a target may be depleted from the cerebrospinal fluid (CSF) of a subject by way of depletion from the circulation, where the target may pass between the CSF and the circulation. Once a target has bound to an agent on a particle in the circulation, the particle may then be cleared from circulation, for example by phagocytosis by immune cells such as macrophages (Kupffer cells) in the liver, along with the target, resulting in clearance of the target from the body. In some embodiments, the “depletion target” or “target” has a soluble form and a cell membrane-bound form. The “depletion target” or “target” may be a soluble form of a biomolecule that is a binding partner of the agent(s) provided on a particle for use according to the present disclosure. A target may be a soluble form of a protein that is present on the surface of a cell, such as a variant comprising a modified amino acid sequence or a portion of the protein present on the surface of the cell. A target may have a membrane form, for example bound to the membrane, such as a transmembrane protein. A target may comprise a portion of, or substantially all of, the extracellular region of a membrane-bound protein. A target may be shed from the membrane- bound protein by the action of an enzyme such as a sheddase, e.g. ADAM10 or ADAM17. A target 8 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 may be a splice variant of a transmembrane protein that is secreted from a cell in soluble form. A target may comprise a similar or identical binding site for ligands, such as endogenous ligands, to that on the membrane form. A target may be a soluble form of a cell surface protein, such as of a cell surface receptor protein, for example a cytokine receptor protein such as sTNFR1 or sTNFR2. A target may be a soluble form of a cell surface cytokine, for example sTNF. As used herein, the term “particle” refers to a small mass that can comprise any material, such as alumina, metal (e.g., gold or platinum), glass, silica, latex, plastic, a sugar, a lipid or any polymeric material, and be of any size and shape. The particle may be a nanoparticle, and may be configured to circulate within the vasculature of a subject, such as a human subject. The particle may be substantially solid or may comprise one or more pores or voids. The particle may comprise a polymer or may comprise a mixture of more than one polymer. The particle may comprise a polymer known in the art for use in particles intended for use in drug delivery (see for example Swider et al. Acta Biomaterialia 73, 38-51 (2018); Hu et al., Biomaterials 2002, 23:3193-3201; Mitchell, M.J., et al., Nat Rev Drug Discov 20, 101–124 (2021), herein incorporated by reference in their entireties). In some embodiments, the particle comprises a biocompatible polymer. Non- limiting examples of biocompatible polymers that may be useful in various embodiments of the present disclosure include polydioxanone (PDO), polyhydroxyalkanoate, polyhydroxybutyrate, poly(glycerol sebacate), polyglycolide, polylactide, polycaprolactone, or copolymers or derivatives including these and / or other polymers. The particle may be biodegradable, e.g., it may comprise a biodegradable polymer. Examples of biodegradable polymers include, but are not limited to, poly(lactide) (or polylactic acid)), poly-ε-caprolactone, poly(α-glutamic acid) (α-PGA), poly(glycolide) (or poly(glycolic acid)), poly(orthoesters), poly(caprolactones), polylysine, poly(ethylene imine), poly(acrylic acid), poly(urethanes), poly(anhydrides), poly(esters), poly(trimethylene carbonate), poly(ethyleneimine), poly(acrylic acid), poly(urethane), poly(beta amino esters) or the like, and copolymers or derivatives of these and / or other polymers, for example, poly(lactide-co-glycolide) (PLGA). The particle may be a lipid nanoparticle. In some embodiments the particle or particles comprise silica, for example silica formed by the Stober process (Stober 1968) or the Hartlen process (Hartlen 2008). Particles may comprise a hollow core or a core formed from a different material, for example a metal that may be used to trace the particles by analysis of the metal or to render them magnetic. In some embodiments, the particle or particles comprise silicon. (See, e.g., International Patent Application Publication Nos. WO 2013 / 011764, WO 2013 / 029278, and WO 2014 / 151381, and U.S. Patent Application Publication No.2014 / 0271886, the disclosures of each of which are incorporated by reference in their entirety). 9 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the particle or particles comprise or consist of nucleic acid (e.g., naturally- occurring or non-naturally occurring nucleic acid). Methods for making such nucleic acid-based microscopic structures are known in the art and are described in, e.g., Douglas et al., Nucl Acids Res 37(15):5001-5006 (2009); Douglas et al., Nature 459(7245):414-428 (2009); Voigt et al., Nat Nanotechnol 5(3):200-203 (2010); and Endo et al., Curr Protoc Nucleic Acid Chem Chapter 12(Unit 12.8) (2011). In some embodiments the particles comprise more than one material, for example in a core-shell configuration in which the core comprises a first material and the shell a second material, different from the first. Examples of core-shell particles are particles comprising a metallic or metal-oxide core and a shell surrounding the core. The shell may comprise for example silica, a polymer, a lipid or components from a cell membrane. The particles may be magnetic, such as paramagnetic or super-paramagnetic, for example having a magnetic core comprising iron or an iron-containing compound such as an oxide of iron. The particles may be adapted to be captured from a fluid, such as from a body fluid of a subject, using magnetic force, for example as disclosed by Herrmann et al., Nephrol. Dialysis Transplant 26(9) 2948-2954 (2011). As used herein, the term “depletion particle” refers to a particle configured to deplete a target, such as a biomolecule, from a fluid, for example from a body fluid of a subject, such as from a body fluid. A depletion particle against a specific target comprises a capture agent or “depletion agent” that binds to that target. The terms “depletion”, “deplete”, “depleting”, and grammatical variations thereof, as used herein, refer to inactivation, neutralization, capturing, binding, and / or reduction of the levels of a target in a subject (e.g., in a body fluid of a subject). In some embodiments, depletion of a biomolecule refers to reduction in the ability of the biomolecule to interact with its natural ligand. In some embodiments, depletion of a biomolecule refers to the decrease in the concentration of the biomolecule in a body fluid of a subject. No particular timescale for the depletion is implied except by the context of its use. For example, depletion does not require immediate or even prompt physical removal of a biomolecule from the subject or the body fluid in question. Also, a biomolecule may be, e.g., inactivated or neutralized through a suitable process (and thus will have been depleted) while remaining physically within the bodily fluid in inactivated form. That inactivated form may then eliminated from the bodily fluid by normal processes over a longer timescale. As used herein, the terms “capture agent”, “depletion agent” and “agent” are used interchangeably and refer to an agent that binds selectively to a target, such as a target biomolecule. An agent is typically selected to bind selectively to a target with a value of 10 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 association constant ka, dissociation constant kdand / or equilibrium constant KDas described herein. Examples of agents include antibodies; antibody fragments; protein binding partners of the target, which may be natural or mutein variants of natural proteins; nucleic acid constructs, such as aptamers, with binding affinity for non-nucleic acid binding partners; and scaffold proteins. Agents may be coupled to particles through coupling groups formed from reaction of reactive groups on the particle with functional groups linked to the agent, for example as disclosed in U.S. Patent No.: 10,653,790 and references therein. Agents may be immobilized on the surface of the particles by reacting a functionalized agent comprising a functional group with a plurality of reactive groups present on the surface of the particle. In some embodiments the particle or particles are configured to deplete a target from a body fluid, such as from a body fluid. Such particles may be sized and shaped to circulate within the vasculature of a subject, such as a human. Particles may have a longest dimension of 1 micron, 500 nm, 250 nm, 200 nm, 150 nm, 100 nm, 75 nm or 50 nm. Such particles may comprise a plurality of agents and a coating, wherein the coating is configured to reduce clearance of the particle from circulation, as known in the art for particles used for drug delivery. In some embodiments, the particle comprises a depletion agent that is shielded from interaction with a molecule on the surface of a cell. Herein, the term “shielded particle” means a particle comprising shielded depletion agents. In some embodiments, the shielded depletion agent on the particle has a reduced ability to interact with a molecule on the surface of a cell, compared with a depletion agent that is not shielded. In some embodiments, the particle comprises one or more depletion agents that are sterically hindered from binding to a molecule on the surface of a cell, such as a membrane-bound form of the target. In some embodiments, the particle comprises one or more shielding moieties configured to shield the agent from interaction with a molecule on the surface of a cell, such as a membrane-bound form of the target. In some embodiments, the one or more shielding moieties are configured to sterically hinder the depletion agent(s) from interacting with a molecule on the surface of a cell, such as a membrane-bound form of the target. A depletion agent may be oriented on a particle relative to one or more shielding moieties such that the shielding moieties sterically inhibit the depletion agent from binding to a molecule on the surface of a cell. A depletion agent may be oriented on a particle such that the shielding moieties sterically inhibit the depletion agent from binding to a molecule on the surface of a cell, such as a membrane-bound form of the target. In some embodiments, the one or more depletion agents are disposed on the depletion particle such that the depletion agents are sterically hindered from binding to a molecule on the surface of a cell. In some embodiments, the molecule on the surface 11 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 of the cell is a membrane form of the depletion target. In some embodiments, the one or more depletion agents are disposed on the depletion particle such that the depletion agents are sterically hindered from binding to a membrane-bound form of the target. In some embodiments, the depletion agents are disposed on the depletion particle such that they are sterically inhibited from binding to a molecule on the surface of a cell, such as a membrane-bound form of the target. In some embodiments, the depletion agents are oriented on the depletion particle such that they are sterically inhibited from binding to a molecule on the surface of a cell, such as a membrane-bound form of the target. The terms “sterically hindered” and “sterically inhibited” are used interchangeably herein. In some embodiments, the particles are as disclosed for example in U.S. Patents 9,623,081 and 9,907,831 and in U.S. Publication No.: 2018 / 0256747 the disclosures of each of which are incorporated by reference in their entirety. In some embodiments, the particle comprises shielding molecules comprising the shielding moieties. In some embodiments, the particle comprises a coating, such as a plurality of coating molecules provided on the surface of the particle. The coating may comprise a plurality of shielding molecules. The terms “shielding molecules” and “coating molecules” are used interchangeably herein. In some embodiments, the shielding moieties or molecules comprise a polymer. In some embodiments, the shielding moieties and / or shielding molecules are hydrophilic. In some embodiments the polymer is selected from polyethylene glycol (PEG), a poly(amino acid), polylactate, polylactic acid, a sugar, a lipid, polyglutamic acid, polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyvinyl acetate (PVA), poly(ethylene glycol- b-lactic acid-co-glycolic acid) (PEG-PLGA), poly(ethylene glycol-b-lactic acid) (PEG-PLA), poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol) (PEG-PLGA-PEG), poly(ethylene glycol-b-(DL-lactic acid)-b-ethylene glycol) (PEG-PLA-PEG), polycaprolactone- PEG (PCL-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), poly(lactic acid-co-PEG) (PLA- PEG), poly(methyl methacrylate)-PEG (PMMA-PEG), a polypeptoid, poly(sarcosine), and a combination thereof. In some embodiments, the particle is disclosed for example in US patents 9,623,081; 9,907,831; 10,420,817; 10,653,790; 10,888,602; 11,771,744 and US patent application US2022 / 0133905, the disclosures of each of which are incorporated by reference in their entirety. The term “NaNot” as in FIG.4 and FIG 5. denotes a depletion particle as described herein. The term “antibody” refers to whole antibodies including antibodies of different isotypes, such as IgM, IgG, IgA, IgD, and IgE antibodies. The term “antibody” includes a polyclonal antibody, a monoclonal antibody, a chimerized or chimeric antibody, a humanized antibody, a 12 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 primatized antibody, a deimmunized antibody, and a fully human antibody. The antibody can be made in or derived from any of a variety of species, e.g., mammals such as humans, non-human primates (e.g., orangutan, baboons, or chimpanzees), horses, cattle, camelids, pigs, sheep, goats, dogs, cats, rabbits, guinea pigs, gerbils, hamsters, rats, and mice. The antibody can be a purified or a recombinant antibody. The term “antibody fragment,” “biomolecule-binding fragment,” “antigen-binding portion of an antibody” and similar terms refer to a fragment of an antibody that retains the ability to bind to a target antigen. Such fragments include, e.g., a single chain antibody, a single chain Fv fragment (scFv), an Fd fragment, an Fab fragment, an Fab’ fragment, or an F(ab’)2 fragment. An scFv fragment is a single polypeptide chain that includes both the heavy and light chain variable regions of the antibody from which the scFv is derived. In addition, nanobodies, intrabodies, minibodies, triabodies, and diabodies are also included in the definition of antibody and are compatible for use in the methods described herein (see, e.g., Todorovska et al., J Immunol Methods 248(1):47-66 (2001); Hudson and Kortt J Immunol Methods 231(1):177-189 (1999); Poljak Structure 2(12):1121-1123 (1994); Rondon and Marasco Annual Review of Microbiology 51:257-283 (1997), the disclosures of each of which are incorporated herein by reference in their entirety). Bispecific antibodies (including DVD-Ig antibodies) are also embraced by the term “antibody.” Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. As used in herein, the term “antibody” also includes, e.g., single domain antibodies such as camelid single domain antibodies. See, e.g., Muyldermans et al., Trends Biochem Sci 26:230- 235(2001); Nuttall et al., Curr Pharm Biotech 1:253-263(2000); Reichmann et al., J Immunol Meth 231:25-38(1999); PCT application publication nos. WO 94 / 04678 and WO 94 / 25591; and U.S. Patent Nos.6,005,079, 6,015,695, and 7,794,981, all of which are incorporated herein by reference in their entireties. In some embodiments, the disclosure provides single domain antibodies comprising two VH domains with modifications such that single domain antibodies are formed. As used herein, an antibody against a soluble target, for example an anti-sTNF, anti- sTNFR1 or anti-sTNFR2 antibody is an antibody that binds selectively to an epitope present on the soluble target. As used herein, the term “cytokine” refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them. For instance, a monokine is generally 13 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 referred to as being produced and secreted by a mononuclear cell, such as a macrophage and / or monocyte. Many other cells however also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor- alpha (TNFα), and Tumor Necrosis Factor beta (TNFβ). The term “nucleic acid” refers to DNA or RNA. A nucleic acid may be single stranded or double stranded. A nucleic acid may comprise single stranded regions and / or double stranded regions. A nucleic acid comprises a nucleotide sequence, which is the order of consecutive nucleotides in the nucleic acid, read from 5’ to 3’. A nucleic acid may comprise multiple nucleotide sequences. For example, a double stranded nucleic acid comprises two nucleotide sequences that each span the length of the nucleic acid, wherein one nucleotide sequence may be the reverse complement of the other nucleotide sequence. A nucleic acid also comprises nucleotide sequences that are shorter than the length of the nucleic acid. For example, a single stranded nucleic acid that is ten nucleotides long has two nucleotide sequences that are nine nucleotides long. Similarly, a single stranded nucleic acid that is ten nucleotides long has three nucleotide sequences that are eight nucleotides long. The nucleotides of a nucleic acid may be, for example, cytosine (C), guanine (G), adenine (A), thymine (T), and / or uracil (U). The nucleotides may be modified or unmodified. For example, one or more nucleotides may be methylated. A nucleic acid may comprise a nucleotide analog and / or an unnatural base pair. The nucleotides of a nucleic acid may comprise 5-methylcytosine, pseudouridine, dihydrouridine, inosine, xanthosine, and / or 7- methylguanosine. As used herein the term “effective amount” or “therapeutically effective amount,” in an in vivo setting, means a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of the disorder being treated or to otherwise provide a desired pharmacologic and / or physiologic effect, e.g., modulate (e.g., enhance) an immune response to an antigen. The precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease, and the treatment being effected. In some aspects, the present disclosure provides a method of treating a disease or condition in a patient by administering a composition comprising particles as described herein to the patient. In some embodiments, the disclosure relates to a method of reducing the concentration of a biomolecule in a patient, such as the concentration of the biomolecule in a bodily fluid of the 14 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 patient (e.g., blood and / or extracellular fluid), by administering a composition comprising particles as described herein to the patient. In some aspects, the method of treating a disease or condition comprises administering a composition comprising particles as described herein, wherein the particles are magnetic; allowing the particles to circulate in the vasculature of a subject; and then removing the particles from the circulation by magnetic force. For example, blood from the circulation may be passed through a region of magnetic field, causing the magnetic particles to become trapped, while the blood is returned to the circulation. The magnetic field may be applied within a particle trap device placed in a flow path for blood from the circulation, through the trap device and back into the circulation, for example as disclosed by Herrmann et al. op cit. In some aspects, the method of treating a disease or condition comprises passing plasma from the subject through a device, such as an extracorporeal device, configured to deplete one or more targets from the plasma, followed by returning the depleted plasma to the circulation of the subject. In some embodiments the device comprises immobilized capture agents, for example provided on a wall such as the wall of a tube, on a stationary phase or on a porous matrix within the device. Such devices include but are not limited to: immune absorption (“immunepheresis”) devices that contact plasma from the circulation with immobilised capture agents for those species; devices using particles to capture the species from the circulation, the particles either remaining located primarily within the device or being permitted to circulate and then being recaptured, for example using magnetic force; or selective dialysis devices in which the species pass selectively from circulation via an element of the device to a second fluid. The device may comprise a device known in the art for use in removal of a target from the circulation (e.g., blood or blood plasma) of a subject such as is described in e.g., Altobelli C. et al, Kidney Blood Press Res.2023;48(1):66-78; and WO2007104298A2; each of which is herein incorporated by reference in their entirety. As used herein, the term “treating” or “treatment” includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject’s condition. The term “treating” includes prophylactic and / or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject), then the treatment is prophylactic (i.e., it protects the subject against developing the unwanted condition); whereas, if it is administered after manifestation of the unwanted condition, 15 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). As used herein, a mammal can be a human, a non-human primate (e.g., monkey, baboon, or chimpanzee), a horse, a cow, a camelid, a pig, a sheep, a goat, a dog, a cat, a rabbit, a guinea pig, a gerbil, a hamster, a rat, or a mouse. In some embodiments, the mammal is an infant (e.g., a human infant). In certain preferred embodiments, the subject is a human. As used herein, a subject mammal “in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non- human mammals), would reasonably benefit from a given treatment. The term “preventing” is art-recognized, and when used in relation to a condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject mammal relative to a subject which does not receive the composition. Suitable human doses of any of the compositions described herein can further be evaluated in, e.g., Phase I dose escalation studies. See, e.g., van Gurp et al., Am J Transplantation 8(8):1711- 1718 (2008); Hanouska et al., Clin Cancer Res 13(2, part 1):523-531 (2007); and Hetherington et al., Antimicrobial Agents and Chemotherapy 50(10):3499-3500 (2006). Examples of Neurodegenerative diseases that may be treated using the methods and particles described herein include Multiple Sclerosis (MS), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS – Motor Neuron Disease), Mild Cognitive Impairment (MCI), Ataxia, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy, motor neuron diseases, dementia, spinocerebellar ataxia, spinal muscular atrophy, plaque related diseases (e.g., diseases associated with an increased plaque load in the brain), peripheral neuropathy and Traumatic Brain Injury (TBI). Examples of demyelinating diseases that may be treated with the methods and particles described herein include: multiple sclerosis (MS), neuromyelitis optica (NMO, Devic’s disease), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), leukodystrophy such as adrenoleukodystrophy or metachromatic leukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson’s disease, spinal cord injury, traumatic brain 16 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen- Kornzweig syndrome, Marchiafava-Bignami syndrome, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, radiation- induced demyelination, idiopathic inflammatory demyelinating disease, chronic inflammatory demyelinating polyneuropathy, autoimmune peripheral neuropathy, acute disseminated encephalomyelitis, adrenomyeloneuropathy, Leber's hereditary optic neuropathy, or human T-cell lymphotropic virus (HTLV)-associated myelopathy. Methods of Treatment In certain aspects, the disclosure provides methods for treatment of neurodegenerative diseases, such as multiple sclerosis (MS) and myelin-related disorders, through selective depletion of soluble targets from a body fluid of a subject, such as the cerebrospinal fluid (CSF) or the circulation. In some embodiments the soluble target is depleted from the CSF of a subject by depletion of the target from the circulation. Example targets are soluble TNF (sTNF), the soluble form of TNFR1, and the soluble form of TNFR2. In certain aspects, the method comprises administrating particles to the subject, the particles being configured to deplete the target from the body fluid of the subject. The particles described herein have unique features enabling pathway interventions that are not possible with existing drugs. This disclosure describes the importance of soluble vs membrane forms of TNF in MS, reasons for failure of previous anti-TNF approaches, potential importance of sTNFR1 and / or sTNFR2 in MS, and preclinical data supporting the proposed mode of action of the particles in both the relapsing and PIRA (progression independent of relapse activity) modes of MS disease. A summary of the proposed mode of action of the methods and particles described herein is as follows. While the present disclosure primarily discusses MS, the signaling pathways and pathogenic species described herein are active also in other neurodegenerative and myelin-related disorders, such as those discussed above, and similar conclusions as to the importance of sTNF, sTNFR1 and / or sTNFR2 can be drawn. The methods and compositions disclosed herein are considered to be applicable and effective for use in those disorders also. TNF-α has been implicated in the etiology of MS for more than 30 years. And yet, the use of conventional TNF-inhibiting drugs has been a dismal failure. Recent studies have clarified that sTNF signaling through the TNF receptor 1 (TNFR1) drives the pathogenic role of TNF in MS (FIG.2), while membrane TNF (mTNF) signaling through TNFR2 plays a profound 17 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 neurorestorative role, counterbalancing the effect of sTNF (FIG.1). TNF-inhibiting drugs cannot distinguish sTNF from mTNF, which explains why they aggravate MS. In addition, sTNFR1 is the product of one of the most significant mutated genetic drivers of MS (Gregory 2012). sTNFR1 and sTNFR2 are consistently and significantly elevated in the sera and CSF of MS patients and patients with other neurodegenerative diseases, corresponding with severity of disease. Previously sTNFR1 and sTNFR2 have not been considered to be drivers of neurodegenerative disease, and in general have been thought of only as potential biomarkers or at most as general inhibitors of TNF signaling through both mTNFR1 and mTNFR2. In early work on mouse models of MS, using autoimmune encephalitis driven by transfer of activated T cells, sTNFR1 was presented as being beneficial through its ability to inhibit TNF (see e.g. Selmaj K. et al., J Neuroimmunol.56(2) 135-141 (1995)). Though adoptive T cell transfer was later found to be an incomplete model of naturally-developing MS as it doesn’t model the development phase of disease, the erroneous impression of sTNFR1 as being broadly beneficial has remained. In contrast, shown herein is that, unexpectedly, soluble TNF receptors, in particular sTNFR1, preferentially antagonize mTNF compared with sTNF, inhibiting neurorestorative TNFR2 signaling, thereby increasing sTNF neurotoxicity in MS, and that the high concentration of sTNFR1 / 2 in MS patients actually drives and worsens disease by the mechanism summarized in FIG.3. Note that while in FIGs.3-5 the role of sTNFR1 is shown and sTNFR2 is not, sTNFR2 can also antagonize mTNF-TNFR2 signaling to a degree that depends on the concentration of sTNFR2 and its affinity for mTMF. Further, other neurodegenerative diseases have an etiology in which TNFR1 signaling drives disease-promoting inflammation and TNFR2 signaling drives homeostatic and disease-countering regeneration, and so can inhibit the establishment and counter the progression of disease. Particles capable of rapid and deep depletion of specific soluble targets, without any impact on biochemically identical membrane forms of the same target, and with an excellent safety profile were developed. Particles against sTNF (see FIG.4), sTNFR1 (see FIG.5), and sTNFR2 were developed (see Examples), suitable for treating MS and other neurodegenerative diseases. In some embodiments, the methods and particles of this disclosure are described with reference to MS. It will be understood that the methods and particles can be used to treat other neurodegenerative and myelin-related diseases based on known features of those diseases and features disclosed herein. In some embodiments, the methods herein provided comprise promoting neuron myelination, inhibiting neuron demyelination, enhancing the generation of oligodendrocytes, 18 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 increasing oligodendrocyte precursor cell proliferation, increasing oligodendrocyte precursor cell differentiation to form oligodendrocytes and / or maintaining or increasing the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting the depletion target(s) promotes neuron myelination in the subject. In some embodiments, depleting the depletion target(s) inhibits neuron demyelination in the subject. In some embodiments, depleting the depletion target(s) enhances the generation of oligodendrocytes in the subject. In some embodiments, depleting the depletion target(s) increases oligodendrocyte precursor cell proliferation in the subject. In some embodiments, depleting the depletion target(s) increases oligodendrocyte precursor cell differentiation to form oligodendrocytes in the subject. In some embodiments, depleting the depletion target(s) maintains or increases the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject in the subject. In certain aspects, the present disclosure provides methods of modulating myelination in a subject suffering from a myelin-related disease or disorder. In some embodiments, the methods disclosed herein comprise promoting myelination of neurons in a subject in need thereof by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some aspects, the present disclosure provides methods of promoting neuron myelination in a subject in need thereof comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise inhibiting demyelination of neurons in a subject in need thereof by administering one or more particles (e.g., anti-sTNF, anti- sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some aspects, the present disclosure provides methods of inhibiting demyelination of neurons in a subject in need thereof comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise maintaining the myelination of neurons in a subject in need thereof at a level substantially similar to the level of myelination of a healthy control subject by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some aspects, the present disclosure provides methods of maintaining the myelination of neurons in a subject in need thereof at a level substantially similar to the level of myelination of a healthy control subject comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. 19 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In certain aspects, the present disclosure provides methods of enhancing the generation of oligodendrocytes (ODGs) in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise enhancing the generation of ODGs in a subject in need thereof by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In certain aspects, the present disclosure provides methods of maintaining or increasing the number of oligodendrocytes (ODGs) or oligodendrocyte precursor cells (OPCs) in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise maintaining or increasing the number of oligodendrocytes (ODGs) or oligodendrocyte precursor cells (OPCs) in a subject in need thereof by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In certain aspects, the present disclosure provides methods of modulating ODG cell density in a subject suffering from a myelin-related disease or disorder (e.g., MS). In some embodiments, the methods of modulating ODG cell density comprise depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise promoting ODG cell density in a subject in need thereof by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti- sTNFR2 particles) disclosed herein to the subject. In some embodiments, the methods disclosed herein comprise promoting ODG cell density by depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise inhibiting the loss of ODG cell density in a subject in need thereof by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, the methods disclosed herein comprise inhibiting the loss of ODG cell density by depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise maintaining the ODG cell density in a subject in need thereof at a cell density substantially similar to the cell density of a healthy control subject by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, the methods disclosed herein comprise maintaining the ODG cell density in a subject in need thereof at a cell density 20 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 substantially similar to the cell density of a healthy control subject by depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In certain aspects, the present disclosure provides methods of modulating oligodendrocyte precursor (OPC) cell density in a subject suffering from a myelin-related disease or disorder (e.g., MS). In some embodiments, the methods of modulating OPC cell density comprise depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise promoting OPC cell density in a subject in need thereof by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, the methods disclosed herein comprise promoting OPC cell density by depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise inhibiting the loss of OPC cell density in a subject in need thereof by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, the methods disclosed herein comprise inhibiting the loss of OPC cell density by depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods disclosed herein comprise maintaining the OPC cell density in a subject in need thereof at a cell density substantially similar to the cell density of a healthy control subject by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, the methods disclosed herein comprise maintaining the OPC cell density by depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the present disclosure provides methods of increasing OPC differentiation to form ODGs comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods of increasing OPC differentiation to form ODGs comprise depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, the methods comprise inducing endogenous OPC differentiation to form ODGs in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, induction of OPC differentiation to form ODGs is characterized by an increase in myelin basic protein expression. 21 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the present disclosure provides methods of increasing OPC proliferation comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods of increasing OPC proliferation comprise depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, the present disclosure provides methods of inducing, promoting, and / or modulating OPC maturation comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. In some embodiments, the methods of inducing, promoting, and / or modulating OPC maturation comprise depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some preferred embodiments, the depletions targets include sTNFR1 (e.g., the depletion target is sTNFR1, or the depletion targets are sTNFR1 and sTNFR2, or the depletion targets are sTNFR1, sTNFR2 and sTNF). In some preferred embodiments, the depletion target is sTNFR1. In some embodiments, the depletion target is sTNFR2. In some embodiments, the depletion target is sTNF. In some preferred embodiments, the depletion targets are sTNFR1 and sTNF. In some embodiments, the depletion targets are sTNFR2 and sTNF. In some embodiments, the depletion targets are sTNFR1 and sTNFR2. In some preferred embodiments, the depletion targets are sTNFR1, sTNFR2 and sTNF. In some embodiments, depleting the one or more depletion targets comprises administering to the subject a composition comprising a depletion particle. In some embodiments, depleting sTNFR1 comprises administering to the subject a composition comprising a depletion particle. In some embodiments, depleting sTNFR2 comprises administering to the subject a composition comprising a depletion particle. In some embodiments, depleting sTNF comprises administering to the subject a composition comprising a depletion particle. In some embodiments, depleting sTNFR1 and sTNF comprises administering to the subject a composition comprising a depletion particle. In some embodiments, depleting sTNFR2 and sTNF comprises administering to the subject a composition comprising a depletion particle. In some embodiments, depleting sTNFR1 and sTNFR2 comprises administering to the subject a composition comprising a depletion particle. In some embodiments, depleting sTNFR1, sTNFR2 and sTNF comprises administering to the subject a composition comprising a depletion particle. 22 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the depletion particle comprises one or more depletion agents, wherein the one or more depletion agents selectively bind to one of the depletion targets. In some embodiments, the one or more depletion agents comprise an antibody or a target biomolecule-binding fragment of an antibody, a non-antibody scaffold protein, a nucleic acid, an aptamer, or a nucleic acid analog, a target-binding portion of a TNF family protein, a TNF mutein, or a target-binding portion of a TNF receptor family protein. In some embodiments, the one or more depletion agents comprise an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the one or more depletion agents comprise a non-antibody scaffold protein. In some embodiments, the one or more depletion agents comprise a nucleic acid, an aptamer, or a nucleic acid analog. In some embodiments, the one or more depletion agents comprise a nucleic acid. In some embodiments, the one or more depletion agents comprise an aptamer. In some embodiments, the one or more depletion agents comprise a nucleic acid analog. In some embodiments, the one or more depletion agents comprise a target-binding portion of a TNF family protein. In some embodiments, the one or more depletion agents comprise a TNF mutein. In some embodiments, the one or more depletion agents comprise a target-binding portion of a TNF receptor family protein. In some embodiments, the depletion particle further comprises one or more shielding moieties, wherein the one or more shielding moieties inhibit interactions between the depletion agent(s) and a molecule on the surface of a cell, such as a membrane form of the depletion target(s). In some embodiments, the depletion particle further comprises one or more shielding moieties, wherein the one or more shielding moieties inhibit interactions between the depletion agent(s) and a membrane form of the depletion target(s). In some embodiments, the depletion particle further comprises a coating, wherein the coating inhibits interactions between the depletion agent(s) and a molecule on the surface of a cell, such as a membrane form of the depletion target(s). In some embodiments, the coating comprises shielding moieties. In some embodiments, the shielding moieties comprise a polymer. In some embodiments, the polymer is hydrophilic. In some embodiments, the polymer is selected from polyethylene glycol (PEG), a poly(amino acid), polylactate, polylactic acid, a sugar, a lipid, polyglutamic acid, polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyvinyl acetate (PVA), poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol) (PEG- PLGA-PEG), polycaprolactone-PEG (PCL-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), 23 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 poly(lactic acid-co-PEG) (PLA-PEG), poly(methyl methacrylate)-PEG (PMMA-PEG), a polypeptoid, poly(sarcosine), and a combination thereof. In some embodiments, the first depletion particle comprises one or more of a first depletion agent that selectively binds to a first depletion target selected from sTNFR1, sTNFR2, and sTNF and the second depletion particle comprises one or more of a second depletion agent that selectively binds to a second depletion target differing from the first depletion target. In some embodiments, the first depletion particle further comprises one or more of a first shielding moiety, wherein the one or more first shielding moieties inhibit interactions between the first depletion agent(s) and a membrane form of the first depletion target and the second depletion particle further comprises one or more of a second shielding moiety, wherein the one or more second shielding moieties inhibit interactions between the second depletion agent(s) and a membrane form of the second depletion target. In some embodiments, the first depletion particle further comprises a first coating, wherein the first coating inhibits interactions between the first depletion agent(s) and a membrane form of the first depletion target and the second depletion particle comprises a second coating, wherein the second coating inhibits interactions between the second depletion agent(s) and a membrane form of the second depletion target. In some embodiments, the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNF, the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNFR2, or the first depletion agent selectively binds to sTNFR2 and the second depletion agent selectively binds to sTNF. In some embodiments, the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNF. In some embodiments, the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNFR2. In some embodiments, the first depletion agent selectively binds to sTNFR2 and the second depletion agent selectively binds to sTNF. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody, a non-antibody scaffold protein, a nucleic acid, an aptamer, or a nucleic acid analog, a target-binding portion of a TNF family protein, a TNF mutein, or a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein. In some embodiments, the first depletion agent 24 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 comprises a nucleic acid. In some embodiments, the first depletion agent comprises an aptamer. In some embodiments, the first depletion agent comprises a nucleic acid analog. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises a TNF mutein. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein. In some embodiments, the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody, a non-antibody scaffold protein, a nucleic acid, an aptamer, or a nucleic acid analog, a target-binding portion of a TNF family protein, a TNF mutein, or a target-binding portion of a TNF receptor family protein. In some embodiments, the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the second depletion agent comprises a non-antibody scaffold protein. In some embodiments, the second depletion agent comprises a nucleic acid. In some embodiments, the second depletion agent comprises an aptamer. In some embodiments, the second depletion agent comprises a nucleic acid analog. In some embodiments, the second depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the second depletion agent comprises a TNF mutein. In some embodiments, the second depletion agent comprises a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody and the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody and the second depletion agent comprises a non- antibody scaffold protein. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody and the second depletion agent comprises a nucleic acid. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody and the second depletion agent comprises an aptamer. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody and the second depletion agent comprises a nucleic acid analog. 25 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody and the second depletion agent comprises a target- binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody and the second depletion agent comprises a target- binding portion of a TNF mutein. In some embodiments, the first depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody and the second depletion agent comprises a target- binding portion of a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein and the second depletion agent comprises a non-antibody scaffold protein. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein and the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein and the second depletion agent comprises an antibody or a nucleic acid. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein and the second depletion agent comprises an antibody or an aptamer. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein and the second depletion agent comprises an antibody or a nucleic acid analog. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein and the second depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein and the second depletion agent comprises a target-binding portion of a TNF mutein. In some embodiments, the first depletion agent comprises a non-antibody scaffold protein and the second depletion agent comprises a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises a nucleic acid and the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the first depletion agent comprises a nucleic acid and the second depletion agent comprises a nucleic acid. In some embodiments, the first depletion agent comprises a nucleic acid and the second depletion agent comprises an aptamer. 26 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the first depletion agent comprises a nucleic acid and the second depletion agent comprises a nucleic acid analog. In some embodiments, the first depletion agent comprises a nucleic acid and the second depletion agent comprises a non-antibody scaffold protein. In some embodiments, the first depletion agent comprises a nucleic acid and the second depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises a nucleic acid and the second depletion agent comprises a target-binding portion of a TNF mutein. In some embodiments, the first depletion agent comprises a nucleic acid and the second depletion agent comprises a target-binding portion of a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises an aptamer and the second depletion agent comprises an aptamer. In some embodiments, the first depletion agent comprises an aptamer and the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the first depletion agent comprises an aptamer and the second depletion agent comprises a nucleic acid. In some embodiments, the first depletion agent comprises an aptamer and the second depletion agent comprises a nucleic acid analog. In some embodiments, the first depletion agent comprises an aptamer and the second depletion agent comprises a non-antibody scaffold protein. In some embodiments, the first depletion agent comprises an aptamer and the second depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises an aptamer and the second depletion agent comprises a target-binding portion of a TNF mutein. In some embodiments, the first depletion agent comprises an aptamer and the second depletion agent comprises a target-binding portion of a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises a nucleic acid analog and the second depletion agent comprises a nucleic acid analog. In some embodiments, the first depletion agent comprises a nucleic acid analog and the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. 27 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the first depletion agent comprises a nucleic acid analog and the second depletion agent comprises a nucleic acid. In some embodiments, the first depletion agent comprises a nucleic acid analog and the second depletion agent comprises an aptamer. In some embodiments, the first depletion agent comprises a nucleic acid analog and the second depletion agent comprises a non-antibody scaffold protein. In some embodiments, the first depletion agent comprises a nucleic acid analog and the second depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises a nucleic acid analog and the second depletion agent comprises a target-binding portion of a TNF mutein. In some embodiments, the first depletion agent comprises a nucleic acid analog and the second depletion agent comprises a target-binding portion of a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises a TNF family protein and the second depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises a TNF family protein and the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the first depletion agent comprises a TNF family protein and the second depletion agent comprises an aptamer. In some embodiments, the first depletion agent comprises a TNF family protein and the second depletion agent comprises a nucleic acid. In some embodiments, the first depletion agent comprises a TNF family protein and the second depletion agent comprises a nucleic acid analog. In some embodiments, the first depletion agent comprises a TNF family protein and the second depletion agent comprises a non-antibody scaffold protein. In some embodiments, the first depletion agent comprises a TNF family protein and the second depletion agent comprises a target-binding portion of a TNF mutein. In some embodiments, the first depletion agent comprises a TNF family protein and the second depletion agent comprises a target-binding portion of a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises a TNF mutein and the second depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises a TNF mutein and the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. 28 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the first depletion agent comprises a TNF mutein and the second depletion agent comprises a nucleic acid. In some embodiments, the first depletion agent comprises a TNF mutein and the second depletion agent comprises an aptamer. In some embodiments, the first depletion agent comprises a TNF mutein and the second depletion agent comprises a nucleic acid analog. In some embodiments, the first depletion agent comprises a TNF mutein and the second depletion agent comprises a non-antibody scaffold protein. In some embodiments, the first depletion agent comprises a TNF mutein and the second depletion agent comprises a target-binding portion of a TNF mutein. In some embodiments, the first depletion agent comprises a TNF mutein and the second depletion agent comprises a target-binding portion of a target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein and the second depletion agent comprises a target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein and the second depletion agent comprises an antibody or a target biomolecule-binding fragment of an antibody. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein and the second depletion agent comprises a nucleic acid. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein and the second depletion agent comprises an aptamer. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein and the second depletion agent comprises a nucleic acid analog. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein and the second depletion agent comprises a non-antibody scaffold protein. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein and the second depletion agent comprises a target-binding portion of a TNF mutein. In some embodiments, the first depletion agent comprises a target-binding portion of a TNF receptor family protein and the second depletion agent comprises a target-binding portion of a target-binding portion of a TNF receptor family protein. 29 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the first shielding moiety or the first coating comprises a polymer. In some embodiments, the first shielding moiety comprises a polymer. In some embodiments, the first coating comprises a polymer. In some embodiments, the second shielding moiety or the second coating comprises a polymer. In some embodiments, the second shielding moiety comprises a polymer. In some embodiments, the second coating comprises a polymer. In some embodiments, the polymer is hydrophilic. In some embodiments, the polymer is selected from polyethylene glycol (PEG), a poly(amino acid), polylactate, polylactic acid, a sugar, a lipid, polyglutamic acid, polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyvinyl acetate (PVA), poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)- b-ethylene glycol) (PEG-PLGA-PEG), polycaprolactone-PEG (PCL-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), poly(lactic acid-co-PEG) (PLA-PEG), poly(methyl methacrylate)- PEG (PMMA-PEG), a polypeptoid, poly(sarcosine), and a combination thereof. In some embodiments, the composition further comprises a third depletion particle. In some embodiments, the third depletion particle comprises one or more of a third depletion agent that selectively binds to a third depletion target differing from the first depletion target and the second depletion target. In some embodiments, the composition comprises a first depletion particle, a second depletion particle, and a third depletion particle. In some embodiments, the first depletion particle comprises a first depletion agent, the second depletion particle comprises a second depletion agent, and the third depletion particle comprises a third depletion agent. In some embodiments, the first depletion agent comprises a first antibody or a first target biomolecule-binding fragment of an antibody, the second depletion agent comprises a second antibody or a second target biomolecule-binding fragment of an antibody, and the third depletion agent comprises a third antibody or a third target biomolecule-binding fragment of an antibody. In some embodiments, the first depletion agent comprises a first non-antibody scaffold protein, the second depletion agent comprises a second non-antibody scaffold protein, and the third depletion agent comprises a third non-antibody scaffold protein. In some embodiments, the first depletion agent comprises a first nucleic acid, the second depletion agent comprises a second nucleic acid, and the third depletion agent comprises a third nucleic acid. In some embodiments, the first depletion agent comprises a first aptamer, the second depletion agent comprises a second aptamer, and the third depletion agent comprises a third aptamer. In some embodiments, the first depletion agent comprises a first nucleic acid analog, the 30 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 second depletion agent comprises a second nucleic acid analog, and the third depletion agent comprises a third nucleic acid analog. In some embodiments, the first depletion agent comprises a first target-binding portion of a TNF family protein, the second depletion agent comprises a second target-binding portion of a TNF family protein, and the third depletion agent comprises a third target-binding portion of a TNF family protein. In some embodiments, the first depletion agent comprises a first TNF mutein, the second depletion agent comprises a second TNF mutein, and the third depletion agent comprises a third TNF mutein. In some embodiments, the first depletion agent comprises a first target-binding portion of a TNF receptor family protein, the second depletion agent comprises a second target-binding portion of a TNF receptor family protein, and the third depletion agent comprises a third target-binding portion of a TNF receptor family protein. In some embodiments, the first depletion agent is a depletion agent herein disclosed, the second depletion agent is a depletion agent herein disclosed, and the third depletion agent is a depletion agent herein disclosed. In some embodiments, the first, second, and third depletion agents are substantially the same type of depletion agents. In some embodiments two of the three depletion agents are substantially the same type of depletion agents and the third is a different type of depletion agent. In some embodiments, the first, second, and third depletion agents are different types of depletion agents. In some embodiments, the third depletion particle further comprises one or more of a third shielding moiety, wherein the one or more third shielding moieties inhibit interactions between the third depletion agent(s) and a membrane form of the third depletion target. In some embodiments, the third depletion particle comprises a third coating, wherein the third coating inhibits interactions between the third depletion agent(s) and a membrane form of the third depletion target. In some embodiments, the first depletion agent selectively binds to sTNFR1, the second depletion agent selectively binds to sTNF, and the third depletion agent selectively binds to sTNFR2. In some embodiments, the depletion particle comprises one or more of a first depletion agent and one or more of a second depletion agent. In some embodiments, the depletion particle further comprises one or more shielding moieties, wherein the shielding moieties inhibit interactions between the first depletion agent(s), the second depletion agent(s), and membrane forms of the depletion targets. 31 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the depletion particle further comprises a coating, wherein the coating inhibits interactions between the first depletion agent(s), the second depletion agent(s), and membrane forms of the depletion targets. In some embodiments, the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNF, the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNFR2, or the first depletion agent selectively binds to sTNFR2 and the second depletion agent selectively binds to sTNF. In some embodiments, the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNF. In some embodiments, the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNFR2. In some embodiments, the first depletion agent selectively binds to sTNFR2 and the second depletion agent selectively binds to sTNF. In some embodiments, the depletion particle further comprises a third depletion agent. In some embodiments, the first depletion agent selectively binds to sTNFR1, the second depletion agent selectively binds to sTNF, and the third depletion agent selectively binds to sTNFR2. In some embodiments, the methods herein disclosed comprise administering a selective sTNF antagonist, wherein the sTNF antagonist comprises an antibody or a TNF mutein. In some embodiments, the methods herein disclosed comprise administering a selective sTNF antagonist, wherein the sTNF antagonist comprises an antibody. In some embodiments, the methods herein disclosed comprise administering a selective sTNF antagonist, wherein the sTNF antagonist comprises a TNF mutein. In some embodiments, the methods herein disclosed comprise administering a selective sTNF antagonist, wherein the sTNF antagonist comprises an antibody or a TNF mutein and one or more particles herein disclosed. In some embodiments, the methods herein disclosed comprise administering a selective sTNF antagonist, wherein the sTNF antagonist comprises an antibody and one or more particles herein disclosed. In some embodiments, the methods herein disclosed comprise administering a selective sTNF antagonist, wherein the sTNF antagonist comprises a TNF mutein and one or more particles herein disclosed. In some embodiments, the particles herein disclosed are magnetic and the method further comprises removing the particles from a body fluid of a subject by magnetic force. In some embodiments, the present disclosure provides methods for promoting myelination, inhibiting demyelination, and / or maintaining a healthy level of myelination of central nervous 32 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 system neurons in a subject suffering from a myelin-related disorder, the method comprising administering to the subject a therapeutically effective amount of the particles disclosed herein, or a pharmaceutical composition comprising the particles disclosed herein. In some embodiments, the subject has a myelin-related disorder. In some embodiments, the myelin-related disorder is: multiple sclerosis (MS), neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophies, neonatal white matter injury, age-related dementia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), adrenoleukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, spinal cord injury, traumatic brain injury, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, metachromatic leukodystrophy, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barre syndrome, Charcot-Marie- Tooth disease, Bell's palsy, radiation-induced demyelination, idiopathic inflammatory demyelinating disease, chronic inflammatory demyelinating polyneuropathy, autoimmune peripheral neuropathy, acute disseminated encephalomyelitis, adrenomyeloneuropathy, Leber's hereditary optic neuropathy, or human T-cell lymphotropic virus (HTLV)-associated myelopathy. In some embodiments, the neurodegenerative disease or disorder or the myelin-related disorder is MS. the neurodegenerative disease or disorder or the myelin-related disorder is progression independent of relapse activity (PIRA) MS. In some embodiments, MS is primary progressive MS (PPMS). In some embodiments, MS is relapsing and remitting MS (RRMS). In some embodiments, MS is secondary progressive MS (SPMS). In some embodiments, the methods herein disclosed comprise administering a therapeutically effective amount of a second therapeutic agent. In some embodiments, the second therapeutic agent is a selective inhibitor of sTNF, optionally wherein the selective inhibitor of sTNF is a TNF mutein or a small molecule allosteric TNF inhibitor. In some embodiments, the second therapeutic agent is a selective inhibitor of sTNF, wherein the selective inhibitor of sTNF is a TNF mutein. In some embodiments, the second therapeutic agent is a selective inhibitor of sTNF, wherein the selective inhibitor of sTNF is a small molecule allosteric TNF inhibitor. 33 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the methods herein disclosed comprise administering a therapeutically effective amount of a second therapeutic agent and one or more of the depletion particle(s) herein disclosed. In some embodiments, the second therapeutic agent is selected from glatiramer acetate, ocrelizumab, alemtuzumab, fingolimod, dalfampridine, natalizumab, teriflunomide, interferon beta-1a, interferon beta-1b, peginterferon beta-1a, dimethyl fumarate, rituximab, daclizumab, ofatumymab, laquinimod, masitinib, siponimod, ozanimod, ponesimod, ibudilast, vatelizumab, minocycline, ibrutinib, tolebrutinib, cladripine, temelimab, daclizumab, and MD1003 (biotin), or a combination of any of them. In some embodiments, the second therapeutic agent and the depletion particle are administered simultaneously. In some embodiments, the second therapeutic agent and the depletion particle are administered sequentially. In some embodiments, the depletion particle is administered to the circulation of the subject. In some embodiments, administration of the depletion particle to the circulation of the subject depletes the target from the CSF of the subject. In certain aspects the present disclosure provides methods of treating inflammation, such as CNS inflammation, in a subject in need thereof comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, the body fluid is the cerebrospinal fluid (CSF) or the circulation of the subject. In some embodiments, the body fluid is the CSF of the subject. In some embodiments, the body fluid is the circulation of the subject. In certain preferred embodiments, depletion of depletion target(s) (e.g., sTNFR1, sTNFR2, and / or sTNF) from the circulation causes depletion of those depletion target(s) from the CSF. The term “the circulation,” as used herein is a broad term and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and is not to be limited to a special or customized meaning), and therefore refers without limitation to the contents (e.g., the blood) of the circulatory system of the subject including, but not limited to the contents of arteries, veins, capillaries, etc. In some embodiments, depletion of the one or more depletion targets reduces inflammation in the subject compared to an untreated control subject. An “untreated control” subject refers to a subject that is afflicted with any of the diseases or disorders herein disclosed with a severity level substantially similar to that of a subject that is treated according to any of the methods of treatment herein disclosed. 34 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In some embodiments, the severity of inflammation in the subject is determined by assessing one or more inflammatory markers. In some embodiments, the inflammatory markers are the number of inflammatory infiltrate cells (e.g., number of foci of inflammatory infiltrates), the number of activated microglia, and / or the number of activated astrocytes, observed in an tissue (e.g., a central nervous system tissue) of the subject. In some embodiments, the subject has a neurodegenerative disease or disorder or is a model organism for a neurodegenerative disease or disorder. In certain aspects, the present disclosure provides methods of restoring neuronal myelination comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject by administering one or more particles (e.g., anti-sTNF, anti-sTNFR1, and / or anti-sTNFR2 particles) disclosed herein to the subject. In some embodiments, neuronal myelination is restored compared to an untreated control subject. In some embodiments, restoration of myelination is assessed by immunostaining for demyelination and / or immunostaining for axonal degeneration. A myelin-related disorder can include any disease, condition (e.g., those occurring from traumatic spinal cord injury and cerebral infarction), or disorder resulting in abnormalities of the myelin sheath. Abnormalities can be caused by loss of myelin referred to as demyelination, dysfunctional myelin referred to as dysmyelination or failure to form enough myelin referred to as hypomyelination. A myelin related disorder as used herein can arise from a genetic disorder or from a variety of neurotoxic insults. The particles disclosed herein can be administered alone or in combination with another agent to a subject suffering from a myelin-related disease or disorder. An “on cycle” is the period of time (e.g., number of days or weeks) deemed appropriate by a skilled medical professional that the particles, or pharmaceutical composition comprising the particles disclosed herein, are being administered to the subject, and will vary depending on the nature of the disease, the dose of the particles, or pharmaceutical composition, being administered, the health of the patient, the intended result, and the like. An “off cycle” is the period of time between “on cycles”. By way of example, a cycle of treatment regimen for treating multiple sclerosis can be an on cycle for at least six months, followed by an off cycle for at least three months, wherein the on- and off- cycles are optionally repeated. As will be appreciated by those of skill in the art, a cycle having any combination of the number of “on” and “off” cycle days can be designed as deemed appropriate by a skilled medical professional. 35 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Administration methods include administering an effective amount (i.e., an effective amount) of a particle or pharmaceutical composition of disclosed herein at different times during the course of therapy or concurrently in a combination form. The methods of the present disclosure include all known therapeutic treatment regimens. In certain embodiments, the particle or pharmaceutical composition is administered intravenously, intrathecally, subcutaneously, intramuscularly, intranasally, or orally. As used herein, the term “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment. “Effective amount” means that amount of active compound such as a particle or composition disclosed herein that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated. The effective amount of a particle or composition of the present disclosure in such a therapeutic method is from about 0.01 mg / kg / day to about 1000 mg / kg / day, from about 0.1 mg / kg / day to about 100 mg / kg / day, from about 0.5 mg / kg / day to about 50 mg / kg / day, or from about 1 mg / kg / day to 10 mg / kg / day. In some embodiments, the effective amount of a depletion agent provided in a composition described herein is from about 0.001 mg / kg / day to about 100 mg / kg / day, from about 0.01 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg / kg / day, or from about 0.1 mg / kg / day to 1 mg / kg / day. Particles or compositions described herein may be administered multiple times per day, daily, or at intervals of 2 to 7 days, 1 to 12 weeks, 3 to 12 months. In certain aspects, the present disclosure provides a method of inducing oligodendrocyte precursor cell (OPC) differentiation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the particles disclosed herein or a pharmaceutical composition comprising the same. In certain embodiments, the subject is suffering from a myelin-related disorder, such as multiple sclerosis. In certain embodiments, the subject is human. “Demyelination” as used herein, refers to the act of demyelinating, or the loss of the myelin sheath insulating the nerves, and is the hallmark of myelin-related disorders. In certain embodiments, the myelin-related disorder is selected from neuromyelitis optica (NMO), optic neuritis, pediatric leukodystrophies, neonatal white matter injury and age-related dementia. 36 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In certain embodiments, the myelin-related disorder is multiple sclerosis. In certain embodiments, the MS is classified as primary progressive MS (PPMS). In certain embodiments, the MS is classified as relapsing and remitting MS (RRMS). In certain embodiments, the MS is classified as secondary progressive MS (SPMS). In one embodiment, the subject suffering from multiple sclerosis has an EDSS score from about 1 to about 9.5. In a particular aspect, the subject suffering from multiple sclerosis has an EDSS score from about 2 to about 8.5. In another aspect, the subject suffering from multiple sclerosis has an EDSS score from about 2.5 to about 8.0. In a further aspect, the subject suffering from multiple sclerosis has an EDSS score from about 3.0 to about 7.5, such as from about 3.0 to about 7, from about 3.0 to about 6.5, from about3.5 to about 6.5 or from about 4.0 to about 6.5. In another embodiment, the subject suffering from multiple sclerosis has an EDSS score of at least 1.5. In one aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 2.0. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 2.5. In yet another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 3.0. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 3.5. In a further aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 4.0. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 4.5. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 5.0. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 5.5. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 6.0. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 6.5. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 7.0. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 7.5. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 8.0. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 8.5. In another aspect, the subject suffering from multiple sclerosis has an EDSS score of at least 9.0. In another embodiment the subject suffering from multiples sclerosis has an EDSS score of 1.0, 1.5, 2.0, 2.5, 3.0.3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0 or 9.5. As used herein, the Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. It is widely used in clinical trials and in the assessment of people with MS. (See: Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). 37 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Neurology.1983 Nov; 33(11): 1444-52 and Haber A, LaRocca NG. eds. Minimal Record of Disability for multiple sclerosis. New York: National Multiple Sclerosis Society; 1985.) The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a medical professional, usually a neurologist. EDSS steps 1.0 to 4.5 refer to people with MS who are able to walk without any aid and is based on measures of impairment in eight functional systems (FS): pyramidal – weakness or difficulty moving limbs; cerebellar – ataxia, loss of coordination or tremor; brainstem – problems with speech, swallowing and nystagmus; sensory –numbness or loss of sensation; bowel and bladder function; visual function; cerebral (or mental) functions and other. Each functional system is scored on a scale of 0 (no disability) to 5 or 6 (more severe disability). EDSS steps 5.0 to 9.5 are defined by the impairment to walking. Although the scale takes account of the disability associated with advanced MS, most people will never reach these scores. Expanded Disability Status Scale (EDSS) 38 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 *Excludes cerebral function grade 1 Demyelination of axons in chronic MS can result in axon degeneration and neuronal cell death, but more specifically, MS destroys oligodendrocytes, the highly specialized CNS cells that generate and maintain myelin. Myelin-related disorders which can be treated or ameliorated by the methods of the present disclosure include a disorder characterized by a myelin deficiency. Insufficient myelination in the central nervous system has been implicated in a wide array of neurological disorders. Among these are forms of cerebral palsy wherein a congenital deficit in forebrain myelination in children with periventricular leukomalacia, contributes to neurological morbidity ( Goldman, S. A., et al. (2008), Stem cell-based strategies for treating pediatric disorders of myelin. Hum Mol Genet.17, R76-83). At the other end of the age spectrum, myelin loss and ineffective repair may contribute to the decline in cognitive function associated with senescence (Kohama et al., (2011), Age-related changes in human and non-human primate white matter: from myelination disturbances to cognitive decline, Age (Dordr) 34(5):1093–1110). Therefore, it is contemplated that effective compounds and methods of enhancing myelination and / or remyelination may have substantial therapeutic benefits in halting disease progression and restoring function in MS and in a wide array of neurological disorders. Myelination of neurons requires oligodendrocytes. The term “myelination”, as used herein, refers to the generation of the nerve’s myelin sheath by replacing myelin producing cells, 39 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 maintaining their numbers, or restoring their function. The neurons that undergo remyelination may be in the brain, spinal cord, or both the brain and spinal cord. “Promoting Myelination” as used herein refers to increasing the rate of myelin production as compared to a baseline level of myelin production rate in a subject. An increase in the rate of myelin production can be determined using imaging techniques or functional measurements. A “baseline level of myelin production rate” as used herein, refers to the rate of myelin production in subject being treated before the onset of treatment. In certain embodiments, the particles or the pharmaceutical compositions disclosed herein are administered in combination with a therapeutically effective amount of an MS therapeutic agent. “MS therapeutic agents” as used herein, refers to therapeutic agents known to be used in treating MS. Such therapeutic agents include, but are not limited to, Copaxone (glatiramer acetate), Ocrevus (ocrelizumab), Campath (Lemtrada or alemtuzumab), Gilenya, Ampyra (dalfampridine), Tysabri (natalizumab), Aubagio (teriflunomide), Rebif , Avonex, Betaseron, Plegridy, Interferon Beta-1a, dimethyl fumarate, fingolimod, rituximab, Zinbryta, Ofatumymab, Nerventra (laquinimod), Masitinib, Siponimod, Ozanimod, Ponesimod, ibudilast, vatelizumab, minocycline, ibrutinib, PRN2246, Cladripine, GNBAC1, daclizumab, and MD1003 (biotin). In certain embodiments, the particles or the pharmaceutical compositions disclosed herein can be administered in combination with cognitive enhancing (nootropic) agents. Exemplary agents include any drugs, supplements, or other substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals. Non- limiting examples include racetams (e.g., piracetam, oxiracetam, and aniracetam), nutraceuticals (e.g., bacopa monnieri, panax ginseng, ginko biloba, and GABA), stimulants (e.g., amphetamine pharmaceuticals, methylphenidate, eugeroics, xanthines, and nicotine), L-Theanine, Tolcapone, Levodopa, Atomoxetine, and Desipramine. A further embodiment for treating a subject suffering from a myelin-related disorder is to administer a therapeutically effective amount of the particles or pharmaceutical compositions disclosed herein along with a therapeutically effective amount of additional oligodendrocyte differentiation and / or proliferation inducing agent(s) and / or anti-neurodegenerative disease agent. Examples of anti-neurodegenerative disease agents include L-dopa, cholinesterase inhibitors, anticholinergics, dopamine agonists, steroids, immunomodulators including interferons, monoclonal antibodies, and glatiramer acetate and modulators (e.g., inhibitors) of SARM1, a new class of NADase enzyme (see Essuman, Neuron, Vol.93, Issue 6, pa 1334, March 22, 2017). 40 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents. The phrase “combination therapy” embraces the conjoint administration of particles or pharmaceutical compositions disclosed herein. In some embodiments, combination therapy includes the conjoint administration of one or more particles disclosed herein and an additional therapeutic agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of each. When administered as a combination, the particles or pharmaceutical compositions disclosed herein and an additional therapeutic agent can be formulated as separate compositions. Administration of these therapeutic agents in combination with particles or pharmaceutical compositions disclosed herein typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). MS is a progressive and debilitating autoimmune disease where immune attack on nerves results in demyelination and loss of nerve function leading to motor dysfunction, paralysis, cognitive dysfunction, poor quality of life and reduced lifespan. Dysregulation of TNF signaling has been shown to drive MS pathogenesis. Existing TNF inhibitor (TNFi) drugs do not address the TNF dysregulation but rather exacerbate disease. MS is now understood to be driven by inflammatory attack on myelin producing cells (oligodendrocytes, or ODGs) and their precursors (oligodendrocyte precursor cells or OPCs) leading to death of these cells and consequent loss of neuronal signal transmission along with concurrent direct neurotoxicity (note herein the terms ‘oligodendrocyte’ and ‘oligodendroglial cell’ are synonymous, as are ‘oligodendrocyte precursor’ and ‘oligodendroglial precursor’). Cell death stems from TNFR1 signaling, driven by sTNF (Fresegna 2020). Signaling by mTNF through TNFR2 normally counteracts this pathobiology and in homeostasis maintains a healthy population of oligodendrocytes and OPCs (Madsen 2016, Desu 2022). sTNF can cross the normal blood-brain barrier (BBB) (Fresegna 2020), and in MS drives BBB disruption which in turn causes increased permeability to soluble factors such as sTNF as well as infiltrating immune cells (Balasa 2021). This sequence establishes a vicious cycle of destruction of the protective barrier and consequent leakage of pathogenic factors into the CNS compartment. 41 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 sTNF levels in cerebrospinal fluid (CSF) and in circulation are similar in MS (Martynova 2020), implying that sTNF equilibrates readily across the BBB. Together these facts point to the likelihood that clearance of sTNF (and similarly sTNFR1 / 2) from circulation will lead to enhanced clearance of these targets from the CSF. Data from Example 2 herein shows that clearance of sTNF, sTNFR1 and sTNFR2 from circulation has efficacy in a mouse model of MS. While a significant genetic mutational locus for MS susceptibility is the TNFR1 gene and the most common single nucleotide polymorphism in TNFR1 leads to an alternatively spliced, secreted form of TNFR1 (de Jager 2009) which is significantly elevated in MS patients (Gregory 2012), hitherto no known causal role for sTNFR1 in driving MS was known. There is no cure for MS to date, and existing treatments carry a high side effect burden; at best they reduce frequency and severity of relapse but do little to slow disease progression and accumulated disability, or to promote remyelination or recovery of neural function (Amin 2023). Most patients experience a first phase of MS comprising recurring inflammatory episodes, with a pattern of relapse / remission and cumulative neurodegenerative damage persisting for years, before transitioning to a progressive form of disease, while a subset of patients exhibits progressive disease from the beginning. Existing drugs for treatment of MS provide some efficacy for the relapse / remitting mode of the disease. The greatest unmet need with the most accumulated disability occurs due to progression independent of relapse activity (PIRA). PIRA starts early during course of MS despite control of episodic relapse activity and continues through the remainder of the patients’ lifetimes. There is no treatment for PIRA and the associated accumulated disability. Details of the present study that depletion of targets selected from sTNF, sTNFR1 and sTNFR2, and administration of particles against sTNF and sTNFR1, and / or sTNFR2 are effective for treatment of MS-PIRA are set out below. For a graphical depiction of MS etiology and proposed particle intervention, see FIGs.1-5. In some embodiments, the subject has MS and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, and administering the particle or composition to the subject depletes sTNF from a body fluid of the subject. In some embodiments, the subject has MS and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1, and administering the particle or composition to the subject depletes sTNFR1 from a body fluid of the subject. In some embodiments, the subject has MS and the methods herein disclosed comprise administering a particle or a composition 42 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 herein disclosed to the subject, wherein the particle or composition targets sTNFR2, and administering the particle or composition to the subject depletes sTNFR2 from a body fluid of the subject. In some embodiments, the subject has MS and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR1, and administering the particle or composition to the subject depletes sTNF and sTNFR1 from a body fluid of the subject. In some embodiments, the subject has MS and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR2, and administering the particle or composition to the subject depletes sTNF and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has MS and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1 and sTNFR2, and administering the particle or composition to the subject depletes sTNFR1 and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has MS and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, sTNFR1, and sTNFR2, and administering the particle or composition to the subject depletes sTNF, sTNFR1, and sTNFR2 from a body fluid of the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS in the subject. In some embodiments, the subject has MS-PIRA and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, and administering the particle or composition to the subject depletes sTNF from a body fluid of the subject. In some embodiments, the subject has MS-PIRA and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1, and administering the 43 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 particle or composition to the subject depletes sTNFR1 from a body fluid of the subject. In some embodiments, the subject has MS-PIRA and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR2, and administering the particle or composition to the subject depletes sTNFR2 from a body fluid of the subject. In some embodiments, the subject has MS-PIRA and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR1, and administering the particle or composition to the subject depletes sTNF and sTNFR1 from a body fluid of the subject. In some embodiments, the subject has MS-PIRA and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR2, and administering the particle or composition to the subject depletes sTNF and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has MS-PIRA and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1 and sTNFR2, and administering the particle or composition to the subject depletes sTNFR1 and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has MS-PIRA and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, sTNFR1, and sTNFR2, and administering the particle or composition to the subject depletes sTNF, sTNFR1, and sTNFR2 from a body fluid of the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS-PIRA in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS-PIRA in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS-PIRA in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS-PIRA in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats MS-PIRA in the subject. 44 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Differential Effects of sTNF and mTNF in MS TNF is a proinflammatory cytokine which serves as a master driver of innate and adaptive immune activation; it can also mediate direct cell killing of infected or transformed cells via apoptosis. TNF exists in two forms: 1) membrane TNF (mTNF) is expressed on the membrane surface of activated immune cells, primarily myeloid cells (monocytes, macrophages, microglial cells in CNS) as well as certain T cells & natural killer (NK) cells; and 2) soluble TNF (sTNF), released from precursor mTNF on activated immune cells into surrounding fluid (blood or interstitial fluid in inflamed tissue). sTNF can be delivered in paracrine fashion without the cell- cell contact required for mTNF. sTNF also activates and recruits surrounding immune cells. The difference in function of sTNF and mTNF explains both the drawbacks of existing TNF inhibitor (TNFi) drugs and the potential of the particles herein provided for treating MS. TNF is expressed by activated immune cells as mTNF and sTNF, the latter forming from mTNF via cleavage of the extracellular domain of mTNF by the protease ADAM17 (Kalliolias 2016). Both forms are pleiotropic, depending on the type and context of cells receiving the TNF signal. sTNF is delivered focally in close proximity to a target cell; it delivers an inflammatory – sometimes cytotoxic – signal, and also drives production of chemokines, recruiting additional immune cells to the site of inflammation. mTNF requires direct contact with the signal-receiving cell and thus mediates even more focal effects than sTNF. Both sTNF and mTNF exist as a bioactive homotrimeric complex, for which sTNF gradually dissociates into inactive monomers while mTNF trimers are stabilized by the cell membrane. However, as the monomerization half- life is longer than the half-life in circulation, in vivo sTNF is considered as predominantly trimeric. TNF signals through two receptors, TNFR1 and TNFR2 (Kalliolias 2016, Chen 2011, Fischer 2017). TNFR1 is expressed on virtually all cell types (except erythrocytes). TNFR2 is expressed mainly on immune cells, such as regulatory T (Treg) cells and some effector T (Teff) cells, monocytes, macrophages, and other tissue-specific cells such as microglial cells and oligodendrocytes and their precursors in the CNS, involved in neuronal diseases including MS. Both mTNF and sTNF signal through TNFR1; being a soluble mediator, sTNF signals at greater range and more widely than mTNF, which is why TNFR1 signaling is primarily driven by sTNF. Although mTNF can signal through both TNF receptors, only mTNF can signal through TNFR2 (Grell 1995, Fischer 2017) owing to the requirement of coordinated TNFR2 clusters, which mTNF creates during cell-cell contact and which sTNF cannot induce (Faustman 2010). 45 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Signaling through TNFR1 – driven mainly by sTNF – primarily mediates an inflammatory signal which in excess becomes toxic to cells, tissues, and organ systems, especially in the CNS, and in certain contexts can induce cell death directly. Signaling through TNFR2 – driven exclusively by mTNF – primarily activates immunosuppressive / wound healing / restorative cellular programs, hence counteracting TNF driven inflammatory activation including autoimmune pathology. TNFR2 signaling is specifically neuro- regenerative (including remyelinating) in the CNS (reviewed by Fresegna 2020, Maguire 2021). Signaling through both TNFR1 and TNFR2 relies on formation of trimeric receptor complexes comprised of three TNFR monomers and either an sTNF or mTNF trimer (Kucka 2021). In the case of TNFR2 signaling, multiple trimeric receptor complexes need to be clustered together to achieve signaling. sTNF does not elicit this clustering needed for TNFR2 signaling, while mTNF does: this is the origin of the selectivity of mTNF signaling through TNFR2. Soluble forms exist of TNFR1 and TNFR2 – ‘sTNFR1’ and ‘sTNFR2’, collectively ‘sTNFRs’ – which bind to both sTNF and mTNF and can inhibit signaling through their membrane forms. sTNFR1 and sTNFR2 are formed either by cleavage from the cell membrane by the protease ADAM17, or by alternative splicing that truncates the full-length receptor protein outside or within the transmembrane region, leading to secretion of the truncated sTNFR. sTNFR1 and sTNFR2 are present in circulation at much greater concentrations than sTNF and act (i) to maintain sTNF bioactivity by stabilizing the bioactive trimeric form of sTNF against spontaneous breakdown into inactive monomers; (ii) to extend the circulating half-life of sTNF by forming a complex (MW of trimeric sTNF = 51.5 kDa; MW of sTNFR1 = 26 kDa) having a MW above the renal filtration cutoff, and (iii) to antagonize both sTNF and mTNF signaling through the membrane forms of TNFR1 and TNFR2, by blocking membrane TNFR proteins from joining the TNF-receptor complexes, thereby preventing formation of threshold cluster sizes required for signaling. TNF has been well studied as a major driver in MS pathobiology. In MS, TNF inflammation in the CNS, as driven by TNFR1 signaling, results in death of oligodendrocytes and their precursors – essential for myelination of neurons – as well as death of neurons through excitotoxicity. mTNF signaling through TNFR2 drives expansion and maturation of oligodendrocytes from precursors to mature myelinating cells (Madsen 2016, Desu 2021) and protects neurons from excitotoxic death. In contrast, sTNFR1 and sTNFR2 have hitherto been seen only as potential biomarkers of MS and other neurodegenerative diseases. This disclosure shows that in addition to their known role as biomarkers, unexpectedly that they have an active role in disease through their differential effects on signaling by TNF through its two receptors, TNFR1 46 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 and TNFR2, and that depletion of one or both of sTNFR1 and sTNFR2 is expected to have therapeutic effect. Further, in some embodiments, based on its higher affinity for TNF than that of sTNFR2, sTNFR1 is a primary target for depletion in neurodegenerative disease, with depletion of sTNFR2 also conferring benefit when sTNFR1 has been depleted. It has previously been speculated (Ribeiro 2019) that sTNFR1 and sTNFR2 are potentially bioactive in MS, though there has been no evidential support for this prior to this disclosure and no methods of selectively antagonising sTNFR1 or sTNFR2 were proposed. It has not previously been proposed that sTNFR1 and sTNFR2 have differential activity in the mTNFR2 signaling pathway relative to the mTNFR1 pathway. In particular, it has not been shown that sTNFR1 and / or sTNFR2 can antagonise mTNFR2 signaling to a greater degree than mTNFR1 signaling at concentrations found in the CSF or circulation. Role of OPCs, ODGs and Myelination in Pathophysiology of Other NDDs in Addition to MS OPCs and their progeny ODGs are responsible for the following functions in the CNS in health which in turn become dysfunctional in disease: • Differentiation of OPCs to form ODGs and subsequent myelination by ODGs • Neuron support and communication (including conversion of short-term memories to long- term), phagocytic synaptic pruning • Neuronal axon metabolic support • OPCs form part of the BBB and have a support role for other cell types in the BBB – OPC dysfunction leads to loss of BBB integrity • Immunomodulatory / inflammatory mediation and regulation of other inflammatory cells (astrocytes, microglia, other immune cells). The inherent (healthy) potential for differentiation of OPCs to ODGs degrades naturally with age which is thought to be the prevailing reason for age as the strongest prognostic indicator for Alzheimer's disease (Chen 2023). In addition to MS the other main neurodegenerative diseases (NDDs) are Alzheimer's (AD), Parkinson’s (PD) and Amyotrophic Lateral Sclerosis (ALS), along with related diseases incorporating the same causative mechanisms (Panichi 2025). Each of these diseases was originally thought to involve central cellular etiology focused on neurons but now each is recognized to include a major contributing (or causative) role for dysregulated myelination resulting from dysfunction of the OPC and ODG populations, and also the loss of additional neuronal support 47 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 functions performed by these cells. The table below (Panichi 2025) illustrates for each of the main NDDs the main symptoms, ODG dysfunction and potential points of therapeutic intervention, in particular identifying support of the OPC population as being a key intervention. In some embodiments, the subject has a neurodegenerative disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, and administering the particle or composition to the subject depletes sTNF from a body fluid of the subject. In some embodiments, the subject has a neurodegenerative disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1, and administering the particle or composition to the subject depletes sTNFR1 from a body fluid of the subject. In some embodiments, the subject has a neurodegenerative disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR2, and administering the particle or composition to the subject depletes sTNFR2 from a body fluid of the subject. In some embodiments, the subject has a neurodegenerative disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR1, and administering the particle or composition to the subject depletes sTNF and sTNFR1 from a body fluid of the subject. In some embodiments, the subject has a neurodegenerative disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR2, and administering the particle or composition to the subject depletes sTNF and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has a neurodegenerative disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1 and sTNFR2, and administering the particle or composition to the subject depletes 48 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 sTNFR1 and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has a neurodegenerative disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, sTNFR1, and sTNFR2, and administering the particle or composition to the subject depletes sTNF, sTNFR1, and sTNFR2 from a body fluid of the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed treats a neurodegenerative disease in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats a neurodegenerative disease in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats a neurodegenerative disease in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats a neurodegenerative disease in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats a neurodegenerative disease in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats a neurodegenerative disease in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats a neurodegenerative disease in the subject. In some embodiments, the subject has Alzheimer’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, and administering the particle or composition to the subject depletes sTNF from a body fluid of the subject. In some embodiments, the subject has Alzheimer’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1, and administering the particle or composition to the subject depletes sTNFR1 from a body fluid of the subject. In some embodiments, the subject has Alzheimer’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR2, and administering the particle or composition to the subject depletes sTNFR2 from a body fluid of the subject. In some embodiments, the subject has Alzheimer’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR1, and administering the particle or 49 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 composition to the subject depletes sTNF and sTNFR1 from a body fluid of the subject. In some embodiments, the subject has Alzheimer’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR2, and administering the particle or composition to the subject depletes sTNF and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has Alzheimer’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1 and sTNFR2, and administering the particle or composition to the subject depletes sTNFR1 and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has Alzheimer’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, sTNFR1, and sTNFR2, and administering the particle or composition to the subject depletes sTNF, sTNFR1, and sTNFR2 from a body fluid of the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed treats Alzheimer’s Disease in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Alzheimer’s Disease in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Alzheimer’s Disease in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Alzheimer’s Disease in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Alzheimer’s Disease in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Alzheimer’s Disease in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Alzheimer’s Disease in the subject. In some embodiments, the subject has Parkinson’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, and administering the particle or composition to the subject depletes sTNF from a body fluid of the subject. In some embodiments, the subject has Parkinson’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1, 50 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 and administering the particle or composition to the subject depletes sTNFR1 from a body fluid of the subject. In some embodiments, the subject has Parkinson’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR2, and administering the particle or composition to the subject depletes sTNFR2 from a body fluid of the subject. In some embodiments, the subject has Parkinson’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR1, and administering the particle or composition to the subject depletes sTNF and sTNFR1 from a body fluid of the subject. In some embodiments, the subject has Parkinson’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR2, and administering the particle or composition to the subject depletes sTNF and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has Parkinson’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1 and sTNFR2, and administering the particle or composition to the subject depletes sTNFR1 and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has Parkinson’s Disease and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, sTNFR1, and sTNFR2, and administering the particle or composition to the subject depletes sTNF, sTNFR1, and sTNFR2 from a body fluid of the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed treats Parkinson’s Disease in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Parkinson’s Disease in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Parkinson’s Disease in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Parkinson’s Disease in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Parkinson’s Disease in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Parkinson’s Disease in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 51 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 from a body fluid of the subject using a method, particle, or composition herein disclosed treats Parkinson’s Disease in the subject. In some embodiments, the subject has ALS / MND and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, and administering the particle or composition to the subject depletes sTNF from a body fluid of the subject. In some embodiments, the subject has ALS / MND and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1, and administering the particle or composition to the subject depletes sTNFR1 from a body fluid of the subject. In some embodiments, the subject has ALS / MND and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR2, and administering the particle or composition to the subject depletes sTNFR2 from a body fluid of the subject. In some embodiments, the subject has ALS / MND and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR1, and administering the particle or composition to the subject depletes sTNF and sTNFR1 from a body fluid of the subject. In some embodiments, the subject has ALS / MND and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF and sTNFR2, and administering the particle or composition to the subject depletes sTNF and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has ALS / MND and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNFR1 and sTNFR2, and administering the particle or composition to the subject depletes sTNFR1 and sTNFR2 from a body fluid of the subject. In some embodiments, the subject has ALS / MND and the methods herein disclosed comprise administering a particle or a composition herein disclosed to the subject, wherein the particle or composition targets sTNF, sTNFR1, and sTNFR2, and administering the particle or composition to the subject depletes sTNF, sTNFR1, and sTNFR2 from a body fluid of the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed treats ALS / MND in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats ALS / MND in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats ALS / MND in 52 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed treats ALS / MND in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats ALS / MND in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats ALS / MND in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed treats ALS / MND in the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed promotes neuron myelination in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed promotes neuron myelination in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed promotes neuron myelination in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed promotes neuron myelination in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed promotes neuron myelination in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed promotes neuron myelination in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed promotes neuron myelination in the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed inhibits neuron demyelination in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed inhibits neuron demyelination in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed inhibits neuron demyelination in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed inhibits neuron demyelination in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed inhibits neuron demyelination in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed inhibits neuron 53 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 demyelination in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed inhibits neuron demyelination in the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed enhances the generation of oligodendrocytes in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed enhances the generation of oligodendrocytes in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed enhances the generation of oligodendrocytes in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed enhances the generation of oligodendrocytes in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed enhances the generation of oligodendrocytes in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed enhances the generation of oligodendrocytes in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed enhances the generation of oligodendrocytes in the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell proliferation in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell proliferation in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell proliferation in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell proliferation in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell proliferation in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell proliferation in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of 54 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell proliferation in the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell differentiation to form oligodendrocytes in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell differentiation to form oligodendrocytes in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell differentiation to form oligodendrocytes in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell differentiation to form oligodendrocytes in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell differentiation to form oligodendrocytes in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell differentiation to form oligodendrocytes in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases oligodendrocyte precursor cell differentiation to form oligodendrocytes in the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed maintains the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed maintains the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed maintains the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed maintains the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed maintains the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body 55 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 fluid of the subject using a method, particle, or composition herein disclosed maintains the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed maintains the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNF from a body fluid of the subject using a method, particle, or composition herein disclosed increases the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed increases the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNF and STNFR1 from a body fluid of the subject using a method, particle, or composition herein disclosed increases the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNF and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNFR1 and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. In some embodiments, depleting sTNF, sTNFR1, and STNFR2 from a body fluid of the subject using a method, particle, or composition herein disclosed increases the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject. Alzheimer's Disease (AD) The OPC / ODG / myelination axis is now recognized as a primary target and leading driver of AD pathogenesis (Chen 2023; Zou 2023). Despite the classical understanding of AD pathogenesis being driven by Aβ amyloid plaques and, more recently Tau neurofibrillary tangles, there are many pathologic changes that precede these hallmarks and so are points of intervention. The protein signature of AD is the processed Aβ fragment of the Amyloid Precursor Protein (APP), which is incorporated into plaques, but it is now established that preceding the appearance of Aβ amyloid plaques and cognitive symptoms an “AD hostile environment” is established in part due to pathologic activity of pre-plaque small oligomers of Aβ fragments, consisting of mitochondrial 56 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 dysfunction and oxidative stress, ensuing release of danger-associated molecular patterns (DAMPs), which in turn cue infiltration and activation of inflammatory cells (neuroinflammation) (Zou 2023). Of all cell systems in the CNS, the OPC / ODG / myelin axis is one of the most sensitive to all of these early insults. The inflammatory stimuli prevent normal differentiation of OPCs to ODGs and drive an alternative non-myelinating inflammatory OPC phenotype (described further in the next section Oligodendroglial Progenitor Cells (OPC) in Health and Disease). The mitochondrial dysfunction and oxidative stress are most detrimental to existing ODGs as these cells have greatly reduced anti-oxidant support, are extremely metabolically active due to the dual demands of myelin biosynthesis and axonal bioenergetics support for neurons, and so suffer greatly from mitochondrial dysfunction and elaboration of reactive oxygen species and the ensuing oxidative stress (Zou 2023). This early / key role of the OPC / ODG / myelination axis is represented in animal models of AD. Reduced / dysfunctional myelination is noted in AD-key anatomical areas of the brain (e.g. hippocampus) in the 5XFAD transgenic mouse model as early as 1-month age, which precedes appearance of Aβ amyloid plaques and behavioral / cognitive deficits (Gu 2018; Wu 2018). Demyelination occurs in this model prior to depletions in OPCs, which in turn were triggered to differentiate in order to resupply ODGs. While this occurred, myelin was not restored, indicating that dysfunctional ODGs are a result of AD pathology (Zota 2024). Early inflammatory response also was concurrent with demyelination and likewise preceded appearance of Aβ amyloid plaques. An additional recent study in the 5XFAD mouse model further extends the role of demyelination to cause Aβ amyloid plaque accumulation, due to distraction of microglia towards phagocytic cleanup of myelin debris instead of clearing plaques (Depp 2023). This observation is in line with the normal age-related loss of myelination that occurs in humans, and in that study is suggested to be the preceding causative event that predisposes the AD-affected brain to accumulate plaques. In addition, new research has identified ODGs as a key cell type (in addition to the classic understanding of neurons) being involved in the production of Aβ leading to accumulation of plaques, and that the ODG source of Aβ contributes largely to neuronal dysfunction (Rajani 2024). Thus, a way to restore the OPC / ODG / myelin axis could have profound therapeutic potential for Alzheimer’s patients and use of the 5XFAD mouse model is useful in testing the methods and compositions disclosed herein for their therapeutic activity in AD. Parkinson’s Disease (PD) and related (MSA, LBD) The traditional hallmark of PD pathogenesis is specific neurotoxicity in the substantia nigra (SN) of specialized neurons responsible for producing dopamine. The causative protein is α- 57 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 synuclein (α-Syn ) which often presents in mutated forms in PD patients; these forms are prone to intracellular aggregation leading to cytotoxicity, along with acting as the main component of Lewy bodies, one of the pathologic hallmarks of PD and the related condition Lewy Body Disease (LBD). Single cell RNA sequencing (scRNA-Seq) has identified cell types in the ODG lineage to be dramatically affected in PD (Campos 2025), in addition to neurons. α-Syn aggregates are present in, and induce readily detectable pathogenic signatures in, ODGs in both PD and MSA patients. Although traditionally thought to be non-myelinated, SN neurons are now known to be myelinated and enmeshed with ODGs and thus impacted by ODG dysfunction (Campos 2025). In addition, despite lower myelination of dopaminergic neurons in the SN, they exist in a 1:1 ratio with OPCs, which provide important non-canonical (i.e. other than myelinating) support to the neurons in terms of synapse pruning, neurotransmitter communication with neurons and axonal bioenergetic support (Fitzgerald 2025). Iron imbalance is a key hallmark of PD and ODGs have the highest iron content, and consequent impact on iron balance, of any cell type in the CNS. ODGs also have notably reduced intracellular anti-oxidant levels compared with other cell types and this, together with iron accumulation, means that ODGs are exquisitely sensitive to oxidative stress including the iron-associated production of reactive oxygen species. It is now clear that the non- myelinating functions of OPCs and ODGs are key to SN neuronal health and function and direct pathologic impact to these cells results in the hallmark neurotoxicity of PD. Similar to AD and Aβ, neuroinflammation, mitochondrial dysfunction, oxidative stress and release of DAMPs are all hallmarks of PD, due to the toxic effects of α-Syn oligomers on mitochondria in ODGs and neurons. ODGs in PD display an alternate pathogenic phenotype including increased protein aggregate stress, increased inflammatory capacity and reduced capacity for terminal differentiation into myelin-producing mature ODGs (Bae 2023). Consistent with this growing awareness of ODG / myelination being a key target of PD pathology, there are now non-invasive sophisticated MRI techniques available for PD patients which identify major deficits in the white matter areas including myelination of the brain in PD, thus reinforcing that ODG / myelin dysfunction is key in PD progression (Yang 2023). Multiple Systems Atrophy (MSA) MSA is a less common but more acutely deadly synucleinopathy than PD, affecting broader areas of the CNS (Hsiao 2023) and also featuring demyelination in the brain. The definitive diagnosis for MSA (post-mortem) is presence of α-Syn aggregates in ODGs, underscoring the central role of ODGs in the pathogenesis of MSA. α-Syn aggregates are initially phagocytosed by the OPCs and remain present through differentiation into ODGs, but with their presence the 58 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 OPC / ODG axis becomes dysfunctional. Once ODGs contain α-Syn aggregates they lose their ability to produce myelin, to provide axonal bioenergetics support to, and communication with, neurons and to regulate iron levels; also, the existing OPCs divert to an inflammatory phenotype promoting worsening neuroinflammation. Animal models in PD and MSA There are many α-Syn transgenic (Tg) mouse models where the α-Syn transgene (wild type or mutant) expression is put under control of either a general neuronal promoter (Dovonou 2023) or more specifically an ODG-specific promoter such as those for myelin basic protein (MBP) (Shults 2005) or CNP (2',3'-cyclic nucleotide 3'-phosphodiesterase – a myelin-related protein abundant in differentiating ODGs) (Yazawa 2005), but these Tg mouse lines recapitulate more of an MSA phenotype rather than that of PD. The traditional α-Syn Tg mouse models that were developed for PD produce initial neurodegeneration including axonal degeneration but with an intact myelin sheath, implying that the early pathology in these models is neural in origin rather than oligodendroglial (Giasson 2002, Lee 2002). In these Tg models overexpression strength and use of more broadly active promoters commonly leads to an exaggeratedly rapid clinical course that diverges from human PD (Zhou 2025). ODG can take up α-Syn protein locally released from neighboring cells such as neurons (Chavarria 2022) thus enabling pathogenic cell spreading of α- Syn aggregates, accelerating the disease course. Weaker Tg expression systems have become available more recently and better represent the pathology of human PD. For instance, a model (Grigoletto 2017) consisting of a hemizygous version of one of the original α-SynA53T models (Giasson 2002) showed neuronal degeneration but also ODG pathology and demyelination more representative of human PD. Such models will be useful to test the therapeutic effects of the methods and compositions disclosed herein in PD and related synucleinopathies. Amyotropic Lateral Sclerosis (ALS) and FTLD ALS is a lethal motor neuron disease with a rapid course (typically 2-5 years from diagnosis to death) with no effective treatments (Suk 2020). This progressive degenerative disease centers on motor neurons in the spinal cord as well as motor cortex regions of the brain. A small fraction (<10%) of patients display familial forms of disease wherein two key proteins are identified as pathogenically mutated: SOD1 (superoxide dismutase-1) and TDP43 (an RNA binding protein). The vast majority of patients display sporadic forms of the disease but with a common signature of mutated or overexpressed TDP43 or in some cases other RNA binding proteins (e.g. FUS). Besides ALS, frontotemporal lobar dementia (FTLD) is another TDP43- associated neurodegenerative disease with similarly dire clinical course (Suk 2020). 59 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Recent studies have shown the ODG lineage to be a key site of the pathogenic process of ALS (Raffaele 2021). ODGs are the most frequent cell type to house aggregated TDP43 and are dysfunctional even to the extent of undergoing necroptosis in ALS. Likewise, differentiation of OPCs to ODGs is blocked, instead being diverted to an inflammatory phenotype at the expense of their additional non-canonical functions such as support for neuronal communication and axon bioenergetics. Healthy myelination is severely impacted as a result of increased degeneration of mature ODGs, in addition to reduced replenishment by OPCs, with malformation of myelin and consequent impact on motor neurons and motor cortex (Jamet 2024). Development of Tg models of ALS using TDP43 was more challenging than those for PD due to excessive toxicity of early overexpression models for native or mutated TDP43 (Wegorzewska 2010). A recent model has been described that more closely resembles clinical ALS, with slower course and primary involvement of ODGs and demyelination, resulting in paralysis over the course of 12mo (Yang 2022). Such a mouse model will be useful in evaluating the methods and compositions described herein for therapeutic intervention in a preclinical ALS- type pathology. Oligodendroglial Progenitor Cells (OPC) in Health and Disease; impact of TNFR2 signaling OPCs are approximately 5-8% of total cells in the CNS) (Buchanan 2025) and differentiate into ODGs to support (re)myelination. OPCs have many immune functions and are plastic in response to varying stimuli; they are the only glial cell type to receive both excitatory and inhibitory synaptic input from neurons. They express a large array of neurotransmitter receptors for direct input from neurons and play large roles in higher cognitive functions of the CNS including memory and learning. OPCs signal to neurons, and also influence / control synapse status (axonal arborization and synapse phagocytosis). They are also important in the neurovascular unit - they have an important role in maintaining BBB integrity, they interact with pericytes, and they disrupt BBB integrity in direct response to inflammatory cytokines. OPCs play an important role in CNS health and disease and loss of OPC number and potential to differentiate into ODGs is involved in MS and other neurodegenerative and myelin-related, such as demyelinating conditions; an agent that can both reduce neuroinflammation and drive OPC to ODG differentiation and subsequent remyelination would have utility in broad range of diseases (Zveik 2024, Marangon 2024). 60 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 OPC are heavily influenced by TNFR2 signaling (Desu 2021). Differentiation of OPCs to form ODGs is driven by signaling via TNFR2 on OPCs by mTNF on neighboring cells, including astrocytes (Madsen 2016). Inflammatory stimuli and signals derived from demyelination providing additional stimulation for proliferation and differentiation, but only in the context of simultaneous TNFR2 signaling. OPC proliferation prior to differentiation to ODGs is driven by PDGF-AA (platelet-derived growth factor AA) binding to PDGFRα on OPCs; PDGFRα expression on OPCs is in turn driven by FGF2 (fibroblast growth factor 2) stimulation of OPCs. OPC proliferation is asymmetric, with one daughter cell retaining a self-renewing OPC phenotype and one daughter cell taking on immature ODG phenotype for further differentiation into mature ODGs. OPCs are also heavily influenced by inflammatory cytokines, in particular the “Th1 cocktail” representative of typical inflammatory cytokine signatures present in vivo, of TNFα, IL- 1β, IFNγ, which lead to the following effects; all of these are exacerbated when TNFR2 signaling on OPCs is blocked: (i) Induction of inflammatory immune functions including antigen presentation and release of inflammatory chemokines, which recruit further inflammatory cell types into inflamed tissue. (ii) Reduced differentiation of OPCs into ODGs, especially differentiation into mature MBP+ ODG. (iii) Reduced PDGFRα expression on OPCs and thus reduced proliferative potential. (iv) Reduced dendrite network of mature ODGs (less myelin and less axonal support), meaning the ODGs are less effective functionally. In summary, TNFR2 signaling drives differentiation of OPCs to ODGs; further, when TNFR2 signaling is intact, inflammatory stimuli are effective at stimulating OPC proliferation and enhanced differentiation of OPCs into ODGs, i.e. TNFR2 signaling induces immunomodulatory activity of OPC in response to inflammatory stimuli rather than propagating the inflammatory activity. When TNFR2 signaling is blocked, all of these factors contribute towards worsening pathology. On this basis, enhancing TNFR2 signaling, or reducing inhibition of TNFR2 signaling arising as part of a disease / disorder, may be therapeutic in neurodegenerative and / or myelin-related disorders. Methods and compositions of the disclosure relevant to OPCs and ODGs The present disclosure describes methods and compositions that promote in subjects in need thereof one or more of: proliferation of OPCs, differentiation of OPCs to ODGs, maintenance 61 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 of OPC and / or ODG populations at a healthy level, increase of OPC and / or ODG populations, and restoration of OPC and / or ODG populations from a lower level characteristic of disease towards a healthy level. Such maintenance and / or restoration of OPC and ODG populations is demonstrated in Example 2 in a preclinical model of MS. The present disclosure describes methods of treatment and compositions for treatment of conditions that involve loss of OPCs and / or ODGs, comprising preventing or restoring loss of OPCs and / or ODGs that either results from a disease or disorder or that is causal in its development or progression. Such methods of treatment and compositions are demonstrated in a mouse model of MS in Example 2, in which restoration of OPCs and OPGs to a healthy level is shown in association with efficacy in reducing clinical indications of disease: reduced paralysis and reduced loss of body weight. The present disclosure also describes methods and compositions for prevention of demyelination and / or of re-myelination following demyelination, in myelin-related disorders. Such restoration of myelination is associated with maintenance or restoration of the ODG population in the CNS. Reduced demyelination associated with restored ODG density in a mouse model of MS is also demonstrated in Example 2. While Example 2 describes a model for MS, the involvement of loss of OPCs and / or ODGs in a range of disorders as described in Desu and Marangon (op cit) means that the methods and compositions described herein will be applicable to other neurodegenerative disorders, for example to myelin-related disorders. Examples of such disorders are listed above. Preclinical Evidence of Differential Roles of TNFR1 and TNFR2 in MS Early preclinical studies provide detailed characterization of the role of TNF in MS. The predominant experimental MS model in mice, experimental autoimmune encephalitis (EAE), along with laboratory manipulations like transgenic mouse strains, show many similarities to clinical MS (reviewed in Steeland 2018, Fresegna 2020). Simple TNF knock-out (KO, both sTNF and mTNF) leads to mice with delayed onset of EAE but, once established, higher mortality than in EAE in wild-type (WT) mice, suggesting that TNF plays a dual role which is not limited to inflammatory pathology but also involves restorative activity (Liu 1998). In contrast, mice transgenic to express mTNF only (no sTNF) were protected from EAE, supporting both the pathogenic nature of sTNF as well as both the non-pathogenic and the restorative roles of mTNF (Alexopoulou 2006). 62 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 TNFR1 KO as well as double KO of TNFR1+TNFR2 protected mice from EAE whereas TNFR2 KO led to more severe EAE with high mortality relative to WT (Eugster 1999). These data build a strong case for the pathologic effects of sTNF signaling through TNFR1 and are consistent with additional data showing that sTNF is directly neurotoxic and drives apoptosis of critical oligodendrocytes (Madsen 2016), responsible for maintaining the myelin sheath on neuronal axons, facilitating proper nerve cell function. The preclinical data are also consistent with the detailed characterization of TNFR2 signaling which drives oligodendrocyte precursors to proliferate and differentiate to restore nerve function through remyelination (the most important feature of successful cessation / recovery from progressive MS and accumulated disability) (Madsen 2016). The following table summarizes these preclinical results: KO: knock-out mouse WT: wild-type mouse With regard to MS-PIRA, newly developed preclinical models (James 2020, Bates 2022) recapitulate the overarching pathological features of MS-PIRA and document dysregulation of TNF signaling. These models will be useful in the preclinical testing of candidate particle interventions and their impact on the MS-PIRA pathology and clinical sequelae common to both these models and patients. Clinical Evidence of sTNF Signaling Dysregulation in MS The role of sTNF in clinical MS is also well documented. sTNF levels in blood and CSF are elevated in MS patients compared to healthy controls, increase further with severity of disease and are significantly reduced in MS patients after receiving beneficial drug treatment compared to untreated patients (Bai 2019, Martynova 2020, Martins 2011). Shocking results were obtained in early clinical studies in MS patients using two different TNFi drugs (infliximab and etanercept) which non-selectively inhibit both sTNF and mTNF, thereby inhibiting signaling through both 63 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 TNFR1 and TNFR2. Instead of ameliorating symptoms, the TNFi drugs exacerbated the clinical state of MS patients, leading to rapid termination of the studies. There have been no further attempts to treat MS patients with TNFis (Wagner 2019). Chronic neuropathic pain is one of the most impactful clinical symptoms to MS patients’ quality of life (Maguire 2021). sTNF enhances nociceptor (pain receptor) hyperexcitability as well as spinal neuron hyperexcitability leading to central sensitization, both key hallmarks of neuropathic pain – one of the most insidious forms, resistant to most pain medications. Pain prevalence in MS patients ranges from 23-90% depending on the study and worsens with disease progression, leading to significant reduction in quality of life (Young 2017). One such study (Brochet 2009) examined a cohort of MS patients over a two-year period and reported 73.5% of patients with significant pain; 44% of patients reported significant reduction in quality of life. Again, TNFR2 was shown to be a key target for pain resolution: TNFR2 KO mice exhibited non- resolving chronic pain using a chronic constriction injury model whereas in WT mice a TNFR2 agonist evoked enhanced and expedited recovery from pain (Fischer 2019b). PIRA Mode of MS The greatest unmet need with the most accumulated disability in MS is PIRA. PIRA is primarily a disease of grey matter (Relapse-remitting disease is located in white matter) and the key pathological signature of PIRA is the formation of meningeal lymphoid aggregates (MLAs) (Magliozzi 2023). MLAs appear as tertiary lymphoid structures (TLS) outside grey matter; they comprise a variety of immune cells including B & T lymphocytes, myeloid cells and others. The brains of patients in the PIRA phase of MS exhibit “outside-in” gradients of pathology, which are proximal to the MLAs and are directed inward into the cerebral cortex as well as the cerebellum and thalamus (Magliozzi 2022). The structure of the PIRA pathology and associated molecular data implies an active diffusion gradient of soluble inflammatory factors streaming into CNS tissues from the MLAs in the arachnoid spaces, driving associated PIRA pathologies. TLS+ patients have elevated sTNF and sTNFR1 in CSF compared to TLS- patients (Magliozzi 2022) and degree of grey matter damage also correlates with elevations in sTNF and sTNFR1 (Magliozzi 2018), as does the degree of neuronal loss and inflammatory cell infiltration. Consistent with these elevations in sTNF and sTNFR1, MLA+ / TLS+ patients exhibit characteristic TNF dysregulation (Magliozzi 2019, referred to as ‘follicle positive’ or ‘F+’ patients in that paper) with elevated TNFR1 signaling primarily in neurons and ODG, where it is cytotoxic for both as represented by elevated levels of necroptosis – a form of sTNF-driven cell death. This 64 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 TNF dysregulation is further pronounced in MLA+ / TLS+ patients, in terms of reduced levels of TNFR2 signaling, primarily in astrocytes and microglia. mTNF signaling through the TNFR2 receptor is primarily restorative; reduced TNFR2 signaling in PIRA patients results in loss of neurorestorative activity. Clinical study design and trial conduct of anti-sTNF and anti-sTNFR1 / 2 particles in PIRA+ MS patients is facilitated by non-invasive methods to identify these patients and expedite clinical readouts. A key MRI hallmark of MLA+ MS-PIRA is the appearance of paramagnetic rim lesions (PRL), which correlate closely with MLAs and can be used to identify PIRA patients for study inclusion (Ransohoff 2023, Giovanoni 2022). A key clinical endpoint to assess in therapeutic interventions for PIRA is Confirmed Disease Worsening (CDW) as indicated by an increase of ≥1.0 pt in EDSS score (Expanded Disability Status Scale). A key caveat is that the rate of EDSS worsening is not consistent across course of disease, with the most rapid change occurring during EDSS 2-5 (Lublin 2022). Thus patients entering clinical study at EDSS 2-4 should have the best prospects for exhibiting timely delay in EDSS increase compared to controls. Preclinical Data on Novel Therapeutics Targeting TNF Signaling in MS Preclinical research has progressed on prototype second generation TNFi interventions in MS which are more selective in their targeting. One agent, XPro1595, employs TNF muteins capable of specifically inactivating sTNF without affecting mTNF (Steed 2003; Zalevsky 2007). Using the EAE mouse model, selective inhibition of sTNF with XPro1595 led to reduced EAE clinical severity, increased remyelination and levels of oligodendrocyte precursor cells (OPC) as well as concordant enhanced axon preservation, and reduction of inflammatory cytokines (IL-1β, IL-6, IFN-γ, CCL2, CCL5 and CXCL10) (Brambilla 2011). Also, in the EAE model, comparison of XPro1595 (sTNF inhibition) versus etanercept (sTNF + mTNF inhibition) showed that inhibition of sTNF / TNFR1 signaling reduces EAE disease whereas inhibition of both sTNF / TNFR1 and mTNF / TNFR2 signaling worsens EAE disease, underscoring the indispensable role of beneficial TNFR2 signaling for MS therapy (Taoufik 2011). This dominant beneficial role of TNFR2 signaling in MS was further highlighted in a follow up study (Madsen 2016) where mice, with conditional TNFR2 KO only in oligodendroglial (ODG) cells, were induced to undergo EAE. The resulting EAE disease in ODG TNFR2 KO mice was worse than in WT mice, including increased nerve axon loss and myelin pathology, reduced remyelination, and, of special significance, resulted in total loss of all therapeutic benefit of sTNF 65 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 inhibition by XPro1595. These data make clear that maintaining intact mTNF / TNFR2 signaling when intervening in MS is of at least equal importance versus inhibiting sTNF / TNFR1 signaling specifically. This line of reasoning has been strengthened by preclinical studies of a new class of TNFR2 agonists, constructed with high order multimerization of TNF to simulate the polyvalent cell surface expression of mTNF. Use of these TNFR2 agonists in the EAE model also led to reduced clinical severity and neuropathic pain, OPC differentiation, reduced neurodegeneration and improved remyelination. However, maximal effect was only achieved when treatment was initiated early, at onset of pain and before clinical symptoms of EAE (Fischer 2019a). A more clinically realistic intervention of the TNFR2 agonists at onset of EAE symptoms had limited effect on EAE disease and no effect on pain when used as monotherapy. Very recent preclinical work has been published (Pegoretti 2023) combining these revelatory data and testing a combination regimen of a TNFR1 antagonist and a TNFR2 agonist in a humanized mouse model of EAE, with comparison to single treatments with each of the agents on their own vs untreated control. The single agent TNFR1 antagonist and TNFR2 agonist each showed a trend towards disease reduction compared to control, whereas only the combo treatment led to dramatic and statistically significant (p < 0.01) reduction in disease. The combo treatment helped to prevent body weight loss whereas neither of the single treatments showed any benefit compared to control. The combo treatment led to statistically significant (p < 0.05) reduction in demyelination whereas neither single treatment showed any effect compared to control. Limitations of Experimental Therapeutic Agents as clinical treatments Selective sTNF / TNFR1 antagonists and TNFR2 agonists developed to date are likely to have serious drawbacks in clinical use. TNF muteins including Xpro1595 are variants of natural TNF that replace one TNF monomer in trimeric TNF, binding with higher affinity than a natural TNF monomer, locking into a distorted non-signaling trimeric formation. There is a class-wide liability to such drugs: modification and distortion of an important “self” protein like TNF into non-natural conformations will not only promote formation of anti-drug antibodies (ADAs) leading to loss of response, but will also induce a subset of antibodies that recognize both the distorted TNF as well as native TNF, potentially leading to a catastrophic loss of TNF function systemically. The leading candidate of this type, Xpro1595 (Steed 2003), is in development primarily in Alzheimer’s disease, and does not appear to be progressing in MS. Xpro1595 is a peptide drug, a 66 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 class known to elicit ADAs, resulting in loss of response (LOR), and will have a short half-life in circulation. It will also be more difficult to manufacture than competing IgG antibody drugs. Further, the mode of action includes the step of dissociation of one TNF monomer from the trimer before the mutein can re-form the trimer. Such dissociation is very slow in the presence of sTNFR1, which is present at higher concentration than TNF in vivo, and re-association with TNF relies on a high local concentration of mutein. For these two reasons, Xpro1595 will need to be dosed at high concentration to achieve efficacy, increasing the risk of ADA formation. Small molecule allosteric TNFi drugs distort the TNF trimer to inhibit high affinity binding to TNF-Rs. They are under development by UCB, BMS and Abbvie (see review by Chedotal 2023). However, the mode of action – to intercalate between monomers of the TNF trimer, distorting its conformation – means that they are unlikely to be selective for sTNF over mTNF (for example, a leading candidate from UCB binds membrane TNF as it forms intracellularly (Vugler 2022)), and so will have the same challenges as current TNFi drugs and thus be contraindicated for use in MS patient populations. Furthermore, distortion of the TNF conformation may also cause immunogenicity of the distorted TNF, inducing formation of anti-drug antibodies that cross-react with native TNF, as described above. Selective antibody TNFR1 antagonists were used in some of the preclinical studies summarized above, such as ATROSIMAB (Pegoretti 2023), that block both sTNF and mTNF binding and signaling through TNFR1. This regimen is not used clinically and would be expected to result in intolerable systemic immunosuppression. Active TNFR2 agonists of the type used in preclinical studies (discussed above) employ non-natural and high valency amino acid sequences. Such drugs would be challenging to manufacture at pharmaceutical scale and would be highly immunogenic in repeat long-term (real- world) clinical use, leading to LOR from ADAs. In contrast, depletion of targets such as sTNF and sTNFR1 / 2 by particles offers much more rapid binding kinetics than mutein candidates, with the additional advantage of no loss-of-response (LOR) from ADAs. LOR is primarily driven by direct interaction between B-cells and a drug, leading to production of antibodies intended to neutralize the drug as a potential antigen. The use of shielded particles as disclosed in US patent 10,888,602 (incorporated herein by reference) will also prevent interaction between B-cells and biological capture agents forming part of the particles, thereby preventing formation of ADAs. 67 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 TNFR signaling in other neurodegenerative diseases Other neurodegenerative diseases are characterised by deleterious pro-inflammatory TNFR1 signaling by sTNF being counteracted by beneficial homeostatic or restorative TNFR2 signaling by mTNF. This may be accompanied by raised sTNFR1 / 2 in circulation and / or in the CSF, which hitherto have been seen as biomarkers of disease (see e.g. Dong 2015). The present disclosure shows that sTNFR1 and sTNFR2 are drivers of neurodegenerative diseases and their depletion from CSF and / or circulation is predicted to have therapeutic effect. Depletion from the circulation will lead to depletion from the CSF, assisted by the damaged, leaky nature of the BBB in these diseases. Application of the present disclosure is not limited to diseases or individual patients in which sTNFR1 / 2 are above the normal range. Depletion of sTNFR1 / 2 in subjects with clinical signs of disease but without sTNFR1 / 2 raised above a level typical of healthy controls will increase restorative TNFR2 signaling relative to TNFR1 signaling, which is the aim of therapeutic treatment. By way of example TNFR1 and TNFR2 signaling and depletion of sTNFR1 or sTNFR1 and sTNFR2 are discussed below in the neurodegenerative diseases Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Mild Cognitive Impairment, often a precursor condition to AD. Depletion of sTNFR1 and sTNFR2 in other neurodegenerative diseases in which TNFR2 signaling is beneficial is within the scope of the present disclosure. Raised levels of sTNF, sTNFR1 and sTNFR2 have been found in serum / plasma and CSF of patients in a range of neurodegenerative diseases (see table 1). sTNFR1 / 2 levels in MS The levels of circulating plasma sTNFR1 and sTNFR2 (collectively, sTNFR1 / 2), and the level of sTNFR1 / 2 in CSF, of MS patients have been found in many studies to be significantly higher (2x) in MS patients compared with healthy controls (HC) (see table 1). sTNFR2 levels are also elevated in MS patient plasma compared with healthy controls and further elevation of sTNFR1, as well as the sTNFR1 / sTNFR2 ratio, is predictive of increased disability as well as disease progression (Ribeiro 2019). Significantly, sTNFR levels in CSF are even more elevated than in serum, with sTNFR1 skewed much higher than sTNFR2 and rising higher still with disease progression thus implicating the local CNS tissue specific elevations in sTNFR1 as being highly relevant to MS pathology (Magliozzi 2021). 68 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 sTNFR1 / 2 in Parkinson’s Disease Inflammation in the CNS driven by sTNF is a driver of PD (Probert 2015, McCoy 2008), indicating that mTNFR1 signalling is damaging. Selective sTNF inhibition by Xpro1595 is beneficial in mouse models of PD. mTNFR2 agonists promote neuronal survival in a mouse PD model (Fischer 2011) and mTNFR2 signalling is protective in glutamate-driven neuronal excitotoxicity (Papazian 2021). Serum and CSF sTNF and serum sTNFR1 are significantly raised in PD patients compared with HC (Scalzo 2009, Rocha 2014). TNFR1 polymorphisms SNP- 609G / T and SNP+36A / G are associated with greatly reduced risk of PD (Kruger 2000): SNP- 609G / T is shown to result in reduced circulating sTNFR1 (Kruger 2000) and SNP+36A / G is one of the polymorphisms associated with the sTNFR1-deficiency condition TRAPS. sTNFR2 has not been studied in relation to PD and sTNFR2 was not found to be elevated in PD compared with HC by Scalzo et al. (Scalzo 2009). However, based on the finding herein that sTNFR2 can become an inhibitor of mTNFR2 signaling when sTNFR1 is depleted, it is predicted that sTNFR2 is also a target for depletion in PD. This efficacy is predicted to be additive to that from depletion of sTNFR1 and may only be apparent when sTNFR1 is depleted. sTNFR1 / 2 in Alzheimer’s Disease and MCI sTNFR1 and sTNFR2 are significantly raised in AD compared with in healthy controls (Jiang 2011) and patients with Mild Cognitive Impairment (MCI) who have higher plasma or CSF sTNFR1 and sTNFR2 levels move significantly more frequently to full AD (Buchhave 2010). Deletion of TNFR2 enhanced AD-like symptoms of plaque formation and microglial activation in a mouse model, while later re-expression of TNFR2 partially reversed these effects (Jiang 2014). sTNF signalling through mTNFR1 is damaging and mTNF signaling through mTNFR2 is neuroprotective in AD (Orti-Casan 2019). Selective inhibition of sTNF by Xpro1595 is effective in mouse models to reduce amyloid beta plaque formation and neuronal damage, while selective inhibition of neuronal TNFR2 expression diminished activation of microglia, which are responsible for amyloid beta clearance, leading to increased amyloid beta and tau accumulation (Steeland 2018). TNFR2 agonists are effective in combination with sTNF inhibition in a mouse model (Orti- Casan 2022) to increase microglial clearance of plaques (Orti-Casan 2023). Jiang et al. (Jiang 2011) found CSF sTNFR1 raised by around 1.4x in AD and sTNFR2 raised by around 2x compared with healthy controls (Table 1). The concentrations found by Jiang et al. are low compared with those found in CSF in MS by Pezzini et al. (Pezzini 2023) – which might arise from a different assay method - but the fold increase in disease vs HC is similar. 69 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 sTNFR1 / 2 in ALS / Motor Neuron Disease Signaling through TNFR1 drives disease in ALS and signaling through TNFR2 is considered to be anti-inflammatory, leading to underwhelming results from TNFi drugs in clinical trials (Jensen 2022). Levels of sTNF and sTNFR1 / 2 are higher in plasma and CSF of ALS patients compared with HC, with higher levels of sTNF being associated with rapid disease progression in some studies, and higher levels of TNF and TNFR1 are present in post mortem spinal cords (Guidotti 2021). Oligodendrocyte degeneration is a feature of ALS (Zhou 2017), driven by necroptosis (Yuan 2019), with the implication that loss of TNFR2 signaling is involved in loss of oligodendrocytes in ALS as for MS. Aberrant TNF signaling also drives death of motor neurons in ALS. In the SOD1G93A mouse model of ALS TNF and TNFR1 are elevated in spinal cords and additional TNFR1 knock-out abolished elevated TNF levels, indicating an inflammatory auto- amplification loop driven by TNF, and TNFR1 and TNFR2 are specifically upregulated in both damaged (vacuolised) and healthy neurons (Guidotti 2021), showing TNF signaling to be a driver of neuronal death in this model. TNFR1 signaling is damaging and sTNFR1 is greatly increased in the spinal cords of mice in the ‘wobbler’ preclinical model of ALS (Bartsch 2010). Guidotti et al. found sTNF secreted by astrocytes drives neuronal damage in the SODG93A model of ALS; TNFR2 signaling in in vitro astrocyte / neuron co-cultures contributes to neuronal cell death, though this is not confirmed in vivo and, as sTNF blockade was not added to TNFR2 blockade in these experiments, TNFR2 signaling may be acting co-operatively with TNFR1 signaling to promote necroptotic neuronal death. sTNFR1 / 2 in Huntington’s Disease (HD) sTNF is raised in the plasma and CNS of patients with HD and also in mouse models of the disease, and peripheral antagonism of sTNF reduces symptoms in preclinical models (Probert 2015, Bjorkqvist 2008). sTNF signaling drives neuronal excitotoxicity in the YAC128 mouse model of HD; this can be inhibited by the sTNF-selective anti-sTNF mutein XPRO1595 (Chambon 2023). In vivo use of XPRO1595 improved symptoms in the R6 / 2 HD mouse model (Hsaio 2014). In contrast, standard TNFi treatment with Etanercept did not improve symptoms in the R6 / 2 model (Pido-Lopez 2019), in support of selective inhibition of sTNF-TNFR1 signaling and maintenance of mTNF-TNFR2 signaling. 70 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 sTNFR1 / 2 in other neurodegenerative conditions sTNFR1 and sTNFR2 are raised in a wide range of neurodegenerative conditions, and the counteracting effects of increased pro-inflammatory signalling through mTNFR1 with decreased neuroprotective signaling through mTNFR2 is associated with disease (Dong 2015), suggesting that the methods and compositions of the present disclosure apply generally in treatment of neurodegenerative conditions. A further specific examples, sTNFR1 / 2 are raised in diabetic peripheral neuropathy (DPN), with high concentrations of either being associated with risk of DPN (Purohit 2021); sTNFR1 / 2 are raised in traumatic brain injury (TBI) and TNFR1 signaling may exacerbate neuronal damage following injury while TNFR2 signaling may reduce it. The same potential exists in neuronal damage after epileptic seizure (Dong 2015). It can be seen from the literature cited that imbalance of TNFR1 and TNFR2 signaling occurs across a wide range of neurodegenerative conditions. The finding herein that sTNFRs can inhibit TNFR2 signaling shows that the methods and compositions disclosed herein can be applied to counteract that imbalance in those conditions. Table 1. Concentrations of sTNF, sTNFR1 and sTNFR2 (pg / ml) in MS, AD, PD, MCI and other neurodegenerative conditions (OND) compared with Healthy Controls (HC) 71 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Assays: [1], [2]: BioRad 40-Plex and 37-Plex, Bio-Plex 200 system; [3], [4], [5], [6], [8]: R&D Systems ELISA; [7]: Biosource Europe ELISA. sTNFR Inhibition of TNFR Signaling Example 1 below explores the inhibitory effect of soluble TNF receptors – sTNFRs – on signaling though membrane TNFRs. TNF signals through two distinct TNFRs, TNFR1 and TNFR2, that have quite different downstream signaling pathways and cellular effects. Conventionally, sTNFRs are considered to be decoys for TNF, capable of inhibiting TNF signaling through TNFR1 and TNFR2 equally. The example discloses that this view is simplistic, and in fact sTNFRs will inhibit TNFR2 signaling to a much greater extent than TNFR1 signaling, and that this will occur at concentrations in the physiological range of sTNFRs, both in circulation and at localized sites of disease. As the concentration of sTNFRs rises the differential inhibition of TNFR2 vs TNFR1 signaling rises dramatically, and beneficial functions of TNFR2 signaling are inhibited. This effect appears to be central in multiple sclerosis (MS) and is consequently by extension involved in other neurodegenerative conditions. The example derives quantitative values for the degree of signaling inhibition and shows that depletion of sTNFRs can reverse the imbalance seen in disease, offering treatment potential. The example shows that, based on available data for the affinity of sTNFR1 and sTNFR2 for mTNF and sTNF, the effect of sTNFR1 is much greater than that of sTNFR2, making sTNFR1 a primary target in treatment. Finally, the combined effects of depletion of sTNF plus sTNFR1, and of sTNF, sTNFR1 and sTNFR2, are estimated, showing that for concentrations of sTNF and sTNFR1 found in the cerebrospinal fluid (CSF) of MS patients, depletion of sTNF plus sTNFR1 is predicted to be a therapeutic combination, with additional depletion of sTNFR2 having potential to add to the effect, for example in patients with high CSF sTNFR2 levels. When TNF (sTNF or mTNF) approaches a cell surface comprising mTNFRs, the TNF trimer will be captured first by a single mTNFR, then a second and third mTNFR will diffuse laterally across the membrane to bind to the captured TNF trimer to form a trimeric complex of mTNFRs. Each complex comprises only one type of mTNFR: heterocomplexes comprising TNF 72 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 and both of mTNFR1 and mTNFR2 do not form, most likely owing to the different length of the stalk region between the membrane surface and the TNF binding region of mTNFR1 (short) and mTNFR2 (long), leading to mismatch in the location above the cell membrane of the TNF binding regions (Richter 2012). However, as the sTNFRs are not tethered they are both free to form heterocomplexes: sTNFR1 and sTNFR2 can each form complexes with both mTNFR1 and mTNFR2. These complexes will be non-signaling so, in principle, both sTNFR1 and sTNFR2 can inhibit both mTNFR1 and mTNFR2 signaling. The impact of sTNFR binding on mTNFR1 and mTNFR2 signaling is shown in FIGs.6A-6B. It can be seen that signaling is inhibited at a ratio of soluble to membrane receptors of 1:5 for mTNFR2 and 1:2 for mTNFR1 (shown for sTNFR1; similarly for sTNFR2), implying that signaling through mTNFR2 is inherently more sensitive to inhibition by sTNFR1 / 2 than signaling through mTNFR2. Consequently, if sTNFR1 concentration rises in disease, mTNFR2 signaling will be inhibited or even abrogated, while mTNFR1 signaling is relatively unaffected. mTNFR2 forms higher order clusters in which multiple signaling complexes are bound together in a trigonal assembly, eventually forming large, stable hexagonal clusters which signal strongly (Su 2023). When present, sTNFR1 / 2 bound to TNF will form part of the cluster. The strength of signaling in these large clusters depends on the way the sTNFRs are arranged within the cluster: each pair of adjacent trimers in the cluster that comprises only mTNFR2s will signal intracellularly, and the total signal strength of the cluster therefore depends on the number of adjacent mTNFR2-only pairs, and consequently on the exact arrangement of sTNFRs in the cluster. mTNFR1 instead forms a population of small clusters of 2 or 3 trimers, with much of the mTNFR1 remaining in isolated trimeric complexes. One report claims that signaling through mTNFR1 is strengthened in such clusters over the sum of signaling through each of the trimers (Karathanasis 2020) but support for this is not yet confirmed in other publications. Therefore, the signaling strength is through mTNFR1 is proportional to the number of trimeric complexes of TNF with 3 mTNFR1 molecules on the cell surface. The signaling strengths through mTNFR1 and mTNFR2 are derived in Example 1, allowing the effect of the concentration of sTNFRs on mTNFR1 and mTNFR2 signaling to be demonstrated. Signaling strength is described in the example in terms of the concentration of signalling complexes formed by TNF-mTNFR1 / 2 binding. Bioactivity effects downstream of the receptors may be related non-linearly to the concentration of the signaling complexes so the proportional change in bioactivity driven by signaling complex formation may differ from the proportional 73 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 change in the concentrations of the complexes themselves. In particular, bioactivity may saturate at high complex concentration or may be absent below a lower threshold concentration. However, the changes in complex concentration and in particular in the ratio of signaling through mTNFR2 to that through mTNFR1 calculated here are large enough that the predicted changes in signaling at receptor level are highly likely to be reflected in changes in bioactivity. Compositions In some aspects, the present disclosure provides compositions comprising one or more of a depletion particle, described herein. In some embodiments, the composition comprises a depletion particle comprising one or more depletion agent that selectively binds to sTNFR1, sTNFR2, and / or sTNF. In some embodiments, the composition comprises a first depletion particle and a second depletion particle. In some embodiments, the first depletion particle comprises one or more of a first depletion agent that selectively binds to a first depletion target selected from sTNFR1, sTNFR2, and sTNF, and the second depletion particle comprises one or more of a second depletion agent that selectively binds to a second depletion target differing from the first depletion target. In some embodiments, the composition comprises a first depletion particle, a second depletion particle, and a third depletion particle. In some embodiments, the first depletion particle comprises the first depletion particle comprises one or more of a first depletion agent that selectively binds to a first depletion target selected from sTNFR1, sTNFR2, and sTNF, the second depletion particle comprises one or more of a second depletion agent that selectively binds to a second depletion target differing from the first depletion target, and one or more of a third depletion agent that selectively binds to a third depletion target differing from the first depletion target and the second depletion target. In some embodiments, the compositions may be formulated together as a pharmaceutical composition with one or more pharmaceutically acceptable carriers and / or buffer solution (e.g., pharmaceutically acceptable carriers or buffers known to those of skill in the art). In some embodiments, compositions may be specially formulated for administration in liquid form, including those adapted for parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation. In some embodiments, a composition of the present disclosure crosses a blood-brain- barrier, a placental membrane, or a blood-testis barrier. In some embodiments, a pharmaceutical 74 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 composition as provided herein is administered systemically. In some embodiments, administration of the particles or compositions disclosed herein is through a non-parenteral route and a therapeutic is administered parenterally. In some embodiments, pharmaceutical compositions may be formulated for delivery to a cell and / or to a subject via injection, infusion, or inter-cannular delivery. Injection includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intraventricular, intracapsular, intra-orbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intra-cerebrospinal, and intra- stemal injection and infusion. In some embodiments, administration is systemic (e.g., oral, rectal, nasal, sublingual, buccal, or parenteral) or local (e.g., local application on the skin, or intravitreal injection). In some embodiments, one or more compositions is administered systemically. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, six, eight, ten, 12, 15 or 20 or more administrations may be given to the subject during one treatment or over a period of time as a treatment regimen. In some embodiments, administrations may be given as needed, e.g., for as long as symptoms associated with the disease, disorder or condition persist. In some embodiments, repeated administrations may be indicated for the remainder of the subject’s life. Treatment periods may vary and could be, e.g., one day, two days, three days, one week, two weeks, one month, two months, three months, six months, a year, or longer. The dosage of the administered composition can vary based on, e.g., the condition being treated, the severity of the disease, the subject’s individual parameters, including age, physiological condition, size and weight, duration of treatment, the type of treatment to be performed (if any), the particular route of administration and similar factors. The dosage of an administered composition may also vary depending upon other factors as the subject’s sex, general medical condition, and severity of the disorder to be treated. Pharmaceutical compositions according to the present disclosure may be delivered in a therapeutically effective amount. A precise therapeutically effective amount is an amount of a composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to 75 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 characteristics of a therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), physiological condition of a subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), nature of a pharmaceutically acceptable carrier or carriers in a formulation, and / or route of administration. EXAMPLES Example 1. sTNFR1 / 2 Inhibition of TNFR Signaling in MS In this example, the relative strength of mTNFR1 and mTNFR2 signaling is explored, in terms of the concentration of signaling, compared with non-signaling, cell surface TNF-mTNFR complexes as a function of the concentration of sTNFR1 / 2. This example shows that at the levels of sTNFR1 / 2 found in MS patients mTNF-mTNFR2 signaling is inhibited by the presence of sTNFR1 / 2 in non-signaling mTNF-mTNFR2 clusters to a much greater extent than sTNF- mTNFR1 signaling is inhibited. This disclosure proposes that sTNFR1 / 2 are pathogenic factors in MS, causing powerfully selective inhibition of mTNFR2 signaling which results in demyelination. Depletion of sTNFR1 / 2 will therefore increase mTNFR2 signaling to a greater degree than mTNFR1 signaling, supporting proliferation and maturation of oligodendrocyte precursors, hence supporting myelination. Further, in this disclosure it is found that the much higher affinity of sTNFR1 than sTNFR2 for both sTNF and mTNF means that sTNFR1 is likely to be the major player, with sTNFR2 playing a minor role – however, when sTNFR1 is depleted, sTNFR2 may then become an efficient inhibitor and so combined depletion of both sTNFR1 and sTNFR2 may be advantageous. Both sTNF and mTNF will exist in complexes with sTNFRs with the concentration of complexes and free TNF depending on the concentration of sTNFRs. In both circulation and in cerebrospinal fluid (CSF) surrounding the brain and spinal cord, reported concentrations of sTNFR1 / 2 are always at least 10x higher than the concentration of sTNF, meaning that there is always excess sTNFR binding capacity. In the cellular microenvironment of inflammatory disease the local concentrations of mTNF – on immune cells especially – and mTNFRs – on a range of cells – are likely to be higher than in circulation or CSF, but so also will be the local concentration of sTNFR1 / 2 resulting from protease activity on the higher mTNFR level. The concentrations of sTNF, sTNFR1, and sTNFR2 are higher in the CSF in MS patients than in healthy controls (HCs), and are higher than the concentrations in serum by a factor of around 2 (Pezzini 2023) (see table 1). The concentration of all three increases with severity of lesions in MS (Magliozzi 2021). These 76 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 findings imply that the increased circulating concentrations derive from the increased concentration in the CSF and notably, this is in patients with intact, low permeability blood-brain barrier (BBB) (Pezzini 2023), showing the BBB to be at most only a moderate barrier to partitioning of these species from the CSF to the circulation. Within MS lesions the concentrations are likely to be higher, with the species being produced at local sites of inflammation being diluted into the CSF; no measurements of concentration within lesions are available. In this document the relative effect of sTNFR1 and sTNFR2 on TNF signaling through mTNFR1 / 2 will be considered on the basis of the values in the CSF. In the later, progressive stage of MS, progression independent of relapse activity – PIRA, MS lesions in the form of lymphoid follicle-like structures (tertiary lymphoid structures – TLSs) form on the meninges (adjacent to the external surface of the brain), and a region of tissue damage (neuronal death and demyelination) spreads inwards into the grey matter from the lesion, with greatest damage adjacent to the TLS - there is no significant immune cell infiltration into the region from the TLS (Magliozzi 2023). This is indicative of damage resulting from soluble factors diffusing inwards into the grey matter with the TLS as the source. The TLS is in good fluid communication with the CSF (Magliozzi 2023 fig.3) and so the concentrations of sTNF and sTNFR1 / 2 in the CSF are indicative of the concentrations immediately adjacent to the grey matter – which will be the highest concentration in the region in which sTNF and sTNFR1 / 2 are determining mTNFR1 / 2 signaling. In the grey matter below the TLS, the cellular components of the CNS express varying combinations of mTNFR1 and mTNFR2 receptors. Neurons express mTNFR1 (Magliozzi 2021) and mTNFR2 (Steeland 2018); oligodendrocytes (ODGs) express mTNFR1 (Steeland 2018) and mTNFR2 (Probert 2015, fig.1); oligodendrocyte precursors (OPCs) express mTNFR2; microglia express mTNFR2 and mTNF; astrocytes express mTNFR1, mTNFR2 and mTNF (Probert 2015). This study models the interactions (i) of sTNF entering the grey matter from the TLS, or released by activated microglia and astrocytes in the CNS, with mTNFR1 on neurons and oligodendrocytes; and (ii) of sTNFR1 / 2 entering from the TLS, or released in situ in the CNS from mTNFR1 / 2 on each cell type, with both mTNFR1 and mTNFR2. In particular, the study focuses on the reduction of signaling by mTNF (on microglia and astrocytes) through mTNFR2 on ODGs and OPCs, which drives preservation of myelination, and through mTNFR2 on neurons, which protects against sTNF-driven excitotoxicity. The well-defined source, and evidence supporting diffusion of soluble mediators in PIRA, give confidence that the bulk CSF concentrations of sTNF, sTNFR1 and sTNFR2 are an effective lower limit of the concentrations in the TLS and hence deeper in the grey matter lesion, and so if an effect is found in the model for the 77 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 concentrations found in the CSF the effect in vivo in the grey matter, where concentrations may be higher, will be at least as significant. In particular, the ratios between sTNF and sTNFR1 / 2 concentrations will be similar both in the CSF and in the lesion. As the concentrations of sTNFR1 and sTNFR2 are both much greater than the concentration of sTNF, simplified equations can be used to describe the equilibria between them, allowing clear definition of the model. While the local concentrations of mTNF and mTNFR1 / 2 are not known, as sTNF and sTNFR1 / 2 are cleaved by the same protease ADAM17 the ratios of mTNF to mTNFR1 and to mTNFR2 can be taken to be similar to the ratios of sTNF to sTNFR1 and to sTNFR2. In estimating the change in a signaling ratio between mTNFR1 and mTNFR2, only ratios of the concentrations are needed – the absolute values do not need to be known, allowing the effect of changing concentrations of sTNFR1 / 2 to be derived. Given the close fluidic communication between the meningeal TLSs and the circulation, and the ready partitioning of species across the BBB even when intact – which is further increased with the damaged, permeable BBB seen in PIRA – depletion of sTNF and sTNFR1 / 2 from circulation will deplete these species from the CSF adjacent to the TLS, reducing the local concentration driving diffusion into the grey matter. At least for the CNS region immediately adjacent to the TLS, it is expected that the concentrations will be similar to those in the CSF. In the study, the effect of treatment to deplete sTNF and sTNFR1 / 2 on signaling in the grey matter is modelled based on a range of final local concentrations of sTNF and sTNFR1 / 2 that might be achieved within the CNS for achievable degrees of depletion from circulation (80% depletion is readily achieved for sTNFR1 / 2 in vivo using depletion particles as described herein). Comparative kinetics & affinity of TNFR1 & TNFR2 binding to TNF Complexes of trimeric TNF and sTNFRs are categorized as TR0, TR1, TR2, TR3 with the numbers 0 to 3 representing the number of sTNFRs bound to the TNF trimer. The proportion of each complex is determined by the concentration of sTNFRs and the affinity of each sTNFR type for TNF. sTNF, and mTNF on immune cells, approaching cell surface mTNFRs will be in a mixture of complexes with sTNFRs in configurations TR0–TR3. The concentrations of TR0-TR3 can be found from the equilibria for each successive binding of one sTNFR in the complex, in the reactions below: TR0 + sTNFR ^ TR1 TR1 + sTNFR ^ TR2 TR2 + sTNFR ^ TR3 78 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Such complexes will form with both sTNF and mTNF; herein when these are distinguished the terminology sTR0-3 refers to complexes with sTNF and mTR0-3 to complexes with mTNF. sTNFR1 binds TNF with high affinity and a slow off-rate: the dissociation constant Kd = 10, 20, and 200 pM for the 1st, 2ndand 3rdsTNFR1 binding to TNF (McMillan 2021); Grell et al. found a similar affinity for sTNF binding to cell surface mTNFR1 of Kd = 19pM (Grell 1998). The off rate t(1 / 2)off was found to be 33 min for sTNF coupled to cell surface mTNFR1 (Grell 1998) and 11 mins for sTNF coupled to sTNFR1 immobilized on the surface of a Biacore chip (Moosmayer 1996). The off-rate found by Grell et al is an average of the off-rates for the mixture of TR1, TR2 and TR3 configurations found on the cell surface. As the TNF in this experiment is in an equilibrium configuration with mTNFR1, and the local concentration of mTNFR1 is greater than the concentration of sTNF, the sTNF will be mainly in TR2 and TR3 configurations, so the this off-rate may be lower than the off-rate for dissociation of a single sTNFR monomer from TNF, i.e. for configuration TR1 => TR0. On this basis the value of t(1 / 2)off from Grell is taken as an upper limit on t(1 / 2)off for TR1 dissociating to TR0. In Moosmayer et al the sTNF is likely to be bound to a single immobilized mTNFR1 so t(1 / 2) = 11 min is an appropriate estimate for the t(1 / 2) of TR1 => TR0. A t(1 / 2)(off) = 33 min is equivalent to a mean lifetime of any given TR2 or TR3 complex of 46 min and T(1 / 2) = 11 min is equivalent to a mean lifetime of 16 min. The concentration of TR0, TR1, TR2 and TR3 for sTNFR1 in the circulation can be found from the relevant Kd values (McMillan 2021). In contrast, sTNFR2 binds TNF with moderate affinity and fast off-rate. Kd = 0.4 nM for binding of sTNF to mTNFR2, from the average of multiple measurements of TNF-TNFR2 affinity, many of which include avidity effects (see Table 4 for values and sources), representing an upper limit for affinity (i.e. a lower limit for Kd) for binding of TNF to monomeric sTNFR2. Grell (1998) found a Kd value for sTNF binding to mTNFR2 of 0.42 nM, and t(1 / 2)off = 1.1 min. These values are for sTNF bound to 3 mTNFR2s, representing the average values for a mixture of TR3 and TR2 dissociating to form TR0, and so are a lower limit for Kd and an upper limit for t(1 / 2) for monomeric dissociation TR1 => TR0. T(1 / 2)off for sTNF from sTNFR2 immobilized on a surface, i.e. for TR1 => TR0, was found to be 2 min (Moosmayer 1996), in broad agreement with the data from Grell. The similarity in values of dissociation rate between TR1 => TR0 and TR3 => TR0 probably results from high mobility of mTNFR2 in the cell membrane, contributing to the dissociation rate by allowing rapid diffusion away from the complex after dissociation from TR3 to TR2 and from TR2 to TR1. Such an effect would counteract the expected avidity effect of trimeric vs monomeric binding. 79 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Prada et al. (Prada 2021) found a low affinity for sTNFR2 binding to mTNF, Kd = 10 nM. This value is an outlier in the measurements of Kd – it is found from equilibrium binding of bioluminescently-labelled sTNFR2 with mTNF and contrasts with a Kd value of sTNFR1 in the same experiment of 20 pM, in agreement with MacMillan 2021. This is compelling data that sTNFR2 has much lower affinity for TNF than sTNFR1, but differs from values derived from Biacore measurements, which are typically in the range 0.2 – 0.94 nM. There are potential confounding effects in the method of Prada et al. (see Table 4) but, given the affinity of sTNFR1 and sTNFR2 for mTNF were measured in the same experimental conditions, in essence this paper confirms that sTNFR2 has a much lower affinity in monomeric form for TNF than does sTNFR1. On this basis, sTNFR1 and mTNFR1 monomers will form high affinity, long-lived complexes with incoming sTNF or mTNF, while sTNFR2 and mTNFR2 monomers form lower affinity and much shorter-lived complexes. In partial compensation for the low affinity of monomer binding, TNF-mTNFR2 complexation is supported in vivo by formation of higher-order clusters, which lead to high avidity due to polyvalent interactions between cell surface mTNF and mTNFR2. Both membrane and soluble forms of each of TNFR1 and TNFR2 comprise a medium affinity dimerization region, the pre-ligand binding assembly domain or ‘PLAD’. For mTNFR1 the PLAD drives dimerization of pairs of mTNFR1s prior to binding to TNF (Karathanasis 2020). This is thought to enable rapid formation of TR2 complexes once TNF has bound a single mTNFR, which promotes capture of TNF and formation of signaling TR3 complexes. In contrast to mTNFR1, dimerization of mTNFR2s is opposed by a repulsive force mediated by the membrane-anchored stalk region of mTNFR2 which is longer and stiffer than the corresponding stalk region of mTNFR1 (Richter 2012), so mTNFR2 dimers are not found prior to TNF binding. Once bound, mTNF-mTNFR2 trimers associate via the weak (Kd ~ 1 µM) PLAD- PLAD interactions of mTNFR2 on adjacent trimers, leading to high avidity clusters coupled together on the membrane due to these PLAD-PLAD interactions, with trigonal symmetry of each trimer relative to the adjacent trimers (Vanamee 2018), as will be described below. sTNFR1 complexed with TNF can also bind to an adjacent mTNFR1 via its PLAD, allowing the sTNFR1 to enter sTNF or mTNF complexes with mTNFR1. Also, as sTNFR1 is detached from the membrane, when in a complex with mTNF it can align with an adjacent mTNFR2 at a higher level above the cell membrane than mTNFR1 is located, allowing the sTNFR1 PLAD to bind to the mTNFR2 PLAD. As sTNFR1 doesn’t experience the stalk-driven inhibition of PLAD-PLAD binding experienced by mTNFR2, PLAD-PLAD interaction between sTNFR1 and mTNFR2 will happen 80 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 more readily than PLAD-PLAD interaction between pairs of mTNFR2, allowing sTNFR1 to become incorporated in extended mTNF-mTNFR2 signaling clusters. Similarly, as sTNFR2 does not comprise an anchored, stiff stalk region to oppose PLAD-PLAD binding, TNF-sTNFR2 complexes will also enter complexes with both mTNFR1 and mTNFR2 though, as the affinity of sTNFR2 for TNF is much lower than that of mTNFR1, mTNFR1 will readily displace sTNFR2 from TNF-sTNFR2-mTNFR1 complexes so, unless sTNFR2 is present at high concentration, these complexes won’t form. TNFR1 signaling occurs when incoming TNF (sTNF or mTNF) is bound by three mTNFR1 receptors. For mTNFR1 the PLAD-PLAD association is strong and, while small multi- trimer clusters do form (Su 2023), clustering is not needed for signaling and signal strength depends only on the number of trimers comprising mTNFR1s. In contrast, as the PLAD-driven association of mTNFR2 is weak compared with that of mTNFR1 (Richter 2012, Kucka 2021) small clusters of two or three trimers are uncommon in mTNF-mTNFR2 signaling. Instead, mTNF- mTNFR2 clusters are most stable in larger, hexagonally symmetric higher order complexes (Vanamee 2018, Su 2023), which often comprise closed hexagonal rings. In such rings, signaling strength is proportional to the number of adjacent trimer pairs in the cluster where both trimers comprise three mTNFR2s. Lang et al. (Lang 2016) found Kd = 0.04 nM for sTNF-mTNFR1, which binds into single trimeric complexes (Karathanasis 2020) and Kd = 0.08 nM for sTNF- mTNFR2, which binds into clusters comprising multiple trimeric complexes (Vanamee 2018), showing the power of clustering to overcome the low affinity of monomeric mTNFR2 for TNF. Based on the finding by Prada et al (Prada 2021) here it is assumed that, as the affinity of monomeric sTNFR2 for TNF is at least 20x and maybe 1000x lower than that of monomeric sTNFR1, to a first approximation the complexation of both sTNF and mTNF by sTNFR2 is negligible compared with that by sTNFR1, at comparable levels of sTNFR1 and sTNFR2. Therefore, in this example sTNFR1 is considered to be the primary species that controls the formation of signaling TNF-mTNFR1 / 2 clusters and the effect of sTNFR1 binding to TNF is calculated. The effect of sTNFR2 is considered separately. sTNF, and mTNF on cells, present in the MS lesion will be complexed with sTNFR1. Clearly, fully sTNFR-bound complex TR3 will not bind to membrane TNFRs but the high affinity of monomeric TNFR1 / TNF binding means that TR0, TR1 and TR2 complexes of sTNFR1 will all be efficiently bound by mTNFR1. For mTNFR2, the lower affinity of monomeric mTNFR2 for TNF means that while each of TR0, TR1 and TR2 might bind transiently, for stable binding a 81 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 dimer complex is needed, limiting binding to TR0 and TR1. Further, it is argued below that TR1 is unlikely to be captured efficiently and so only TR0 configurations will signal through mTNFR2. sTNF-mTNFR complexes are internalized following signaling (with a half-life of around 15 mins) (Grell 1998), but non-signaling complexes remain on the cell surface, enabling them to participate in extended receptor monomer dissociation and replacement processes. In mTNFR1 signaling, sTNFR1 TR0, TR1 and TR2 complexes are bound stably by mTNFR1. TR0 complexes can immediately bind to neighbouring mTNFR1 receptors to form a trimeric signaling complex. Once TR1 and TR2 are bound to the cell membrane, owing to the high local concentration of mTNFR1 on the cell surface, sTNFR1 will gradually exchange for mTNFR1 to form signaling complexes. TR1 is bound in a complex TR1-(mTNFR1)2and will lose sTNFR1 and gain mTNFR1 to form signaling TNF-(mTNFR1)3complexes on a timescale of 16 mins (from t(1 / 2) = 11 min., Mossmayer 1996). TR2 is bound in a complex TR2-(mTNFR1) and will exchange two sTNFR1 to form signaling TNF-(mTNFR1)3 complexes over a timescale of 45 mins (from t(1 / 2) = 33 min, Grell 1998). On this basis, following exchange of sTNFR1 for mTNFR1, both TR1 and TR2 will form signaling complexes, though as the rate of dissociation of TR2 to TR0 is so much slower than the rate for TR1 to TR0 and is greater than the half-life for receptor internalisation, in practice TR2 will signal much less effectively than TR1. The binding affinity of the third mTNFR1 to TNF is 10x lower than that of the second mTNFR2 (McMillan 2021), so to a first approximation TR2 complexes will last on the surface of order 10x shorter time than TR1 complexes. On this basis, TR2 is assumed to contribute around 10% the contribution of TR1 to mTNFR1 signaling. Therefore, to estimate the signaling probability through mTNFR1, in the following TR1 is assumed to have 100% and TR2 is assumed to have 10% of the binding and signaling probability of TR0. The robustness of this assumption is tested in the Results section. In contrast, in mTNFR2 signaling binding of each individual mTNFR2 monomer to TNF has a much lower affinity than binding of sTNFR1 to TNF, so sTNFR1 will be a powerful and long-lived inhibitor of mTNFR2 binding. Any sTNFR1 bound to mTNF will remain bound as the mTNF forms complexes with mTNFR2. The rapid dynamics of mTNFR2 association and dissociation, including dissociation from clusters as found by Grell (1998), means that there is no time for sTNFR1 to dissociate during the lifetime of the TNF-sTNFR1-mTNFR2 cluster. This, together with the steric limitation on diffusion away of sTNFR1 following dissociation, through the narrow, sterically congested intercellular space, implies permanent abrogation of mTNFR2 signaling involving any TNF-sTNFR1 complex: i.e., only TR0 will signal through mTNFR2. 82 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 A further assumption in this example is that sTNFR1 effects on mTNF signaling are taken to be the same as those on sTNF signaling. The above dissociation timescales have been assumed for binding of sTNF-sTNFR1 complexes to mTNFRs when sTNFR1 can diffuse freely away from the surface following dissociation, allowing replacement by the (abundant) mTNFR1 on the membrane next to the complex. For mTNF-sTNFR1 complexes binding to mTNFR1 in the close confines of cell-cell interaction, diffusion of sTNFR1 away from the complex following dissociation will be severely sterically limited, with the result that effective off-rates are likely to be significantly lower, and replacement of sTNFR1 by mTNFR1 in mTNF-sTNFR1-mTNFR1 binding may even be negligible. However, there is no available data on the kinetics of mTNF- mTNFR1 interaction that would allow the effects of sTNFR1 on mTNF signaling to be distinguished from the effects on sTNF signaling, so here the effects are taken to be the same. To summarize the assumptions outlined above, the effects of the complexes sTR0-sTR3 (sTNFR1 complexed with sTNF) and mTR0-mTR3 (sTNFR1 complexed with mTNF) on mTNFR1 and mTNFR2 signaling are as in Table 2: Table 2. mTNFR1 and mTNFR2 signaling by TNF-sTNFR complexes Calculation of relative signaling strength through mTNFR1 & mTNFR2 The calculation considers the interactions between sTNF, mTNF, sTNFR1 / 2 and mTNFR1 / 2 in the intercellular space within the CNS, comprising cell surfaces of CNS cells with their associated species, and sTNF and sTNFR1 / 2 within the CSF in the intercellular space. For example, in MS-PIRA, the relevant region is surrounding and below the meningeal TLS lesion, where the CSF bathing the TLS is in contact with the grey matter and contains sTNF and 83 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 sTNFR1 / 2. The calculation will also apply to mTNFR1 / 2 signaling in the circulation and in tissues adjacent to the circulation, if concentrations of sTNF, sTNFR1 / 2 found in the circulation are used instead of those in the CSF. The relative signaling strength through mTNFR1 and mTNFR2 is estimated by these steps: 1) Describing the strength of TNFR1 signaling in terms of the concentrations of sTNF, mTNF and sTNFR1, by deriving the proportions of TNF in states TR0-3. 2) Describing the strength of TNFR2 signaling in terms of the effect of non- signaling TNF / sTNFR1 complexes in reducing signaling in mTNFR2 clusters, with the assumption that only TR0 complexes can form a signaling cluster. 3) Estimating the change in the signaling strength in each of the TNFR1 and TNFR2 pathways between the disease and healthy states, and between the treated and untreated disease states. 4) Describing the change in the ratio of TNFR2 to TNFR1 signaling as the ratio of the change in signaling in the TNFR2 pathway to the change in the TNFR1 pathway as a function of the concentration of sTNF, sTNFR1 and sTNFR2. While sTNF does bind mTNFR2 in non-signaling complexes, this effect is not included here because in the presence of both mTNFR1 and mTNFR2, the rapid off-rate of sTNF from mTNFR2, plus freedom of sTNF to migrate by diffusion and the higher affinity of mTNFR1, will lead to capture by mTNFR1 of sTNF that has dissociated from mTNFR2. As mTNFR1 and mTNFR2 do not form heterodimers, such replacement involves complete dissociation of the TNF from mTNFR2 molecules on the cell surface, followed by re-capture by mTNFR1. Once sTNF has bound to the first mTNFR1, mTNFR2 can no longer bind and further mTNFR1 monomers rapidly associate to form TR2 and TR3 complexes. Therefore, the population of sTNF-mTNFR2 complexes on a cell surface comprising both mTNFR1 and mTNFR2 will be very low. In contrast, when mTNF binds mTNFR2, both mTNF and mTNFR2 are anchored in two locations, in the cell membrane and at the binding interface and so are effectively immobile, greatly reducing the dissociation rate – mTNFR1 is unable to replace mTNFR2 in these circumstances. Therefore, while mTNFR2 can decoy sTNF from mTNFR1 to a small degree, it cannot decoy mTNF. Based on the ratio of the affinities of sTNF for mTNFR1 and mTNFR2, calculations suggest the effect for likely ratios of mTNFR1 to mTNFR2 in the modelled environment is around a 5% reduction in sTNF-mTNFR1 signaling – this is negligible relative to the effects of sTNFR1. 84 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Signaling strength through mTNFR1 The signal strength S(R1) through mTNFR1 is defined here as the concentration of TNF- mTNFR1 complexes on the cell surface multiplied by a factor S(sig, 1) that is the probability that each bound TNF-mTNFR1 complex will signal. S(R1) describes the extracellular signaling process: bioactivity resulting from signaling is related to S(R1) by intracellular processes that will amplify, in general non-linearly, the signal transduced by TNFR1. However here it is assumed that to first approximation the intracellular processes are the same in disease, healthy controls and in treated disease, so ratios of signal strength between these conditions are reasonably described by ratios of S(R1). sTNF and mTNF both signal through mTNFR1, so S(R1) is given by:^^(^^1) = ([^^^^^^^^ − ^^^^^^^^^^1] + ^^[^^^^^^^^ − ^^^^^^^^^^1])^^(^^^^^^, 1)where [sTNF-mTNFR1] is the concentration of sTNF-mTNFR13 signaling complexes on the cell surfaces within the intercellular volume being considered in the model, and [mTNF- mTNFR1] is the concentration of mTNF- mTNFR13complexes. The parameter X allows for any difference in signaling driven by mTNF relative to that driven by sTNF at the same concentration of each, as averaged within the intercellular space considered in the model. Likely values of X are discussed below. From the discussion above about relative concentrations of sTNF, mTNF and sTNFR1, [mTNFR1] is greater than [sTNF] and [mTNF], so the concentration of these complexes can bedescribed by simplified equilibrium equations: The ratio of signaling strength through TNFR1 in MS to that in HC is: 85 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 concentrations being averaged over the volume of intercellular space being considered. Su et al. (Su 2022) use a molecular dynamics simulation to find that in the geometry of mTNF and mTNFR1 binding, mTNF is constrained to be in closer alignment with mTNFR1 prior to association, leading to a higher on-rate for mTNF association compared with sTNF (which is free to diffuse and rotate); they find mTNF to have a 2.5x higher affinity for mTNFR1 than doessTNF, i.e.^ௗ౩^ొూ / ^^ొూ^భis approximatel[^்ேி]ಾೄ [^்ேிோ^]ಾೄ^ௗ^^ొూ / ^^ొూ^భ y 2.5. The ratios and [^்ேிோ^]ಹ^ are unknown, butboth [sTNF] and [sTNFR1] are increased in MS relative to HC (and are expected to be reduced on treatment). A starting estimate is to assume to first approximation that [sTNF] in the CSF is proportional to [mTNF] and [sTNFR1] is proportional to [mTNFR1]. Magliozzi et al. (Magliozzi 2021) find [sTNF] raised in MS CSF by 7.7x and [sTNFR1] by 1.7x relative to HC (in terms of pg / ml / pg total protein) (see Table 1 for values of [TNF], [sTNFR1] and [sTNFR2] in MS), so thefollowing is taken gene expressionanalysis for TNFR1 / 2 in grey matter in post-mortem MS patient brains versus control brains (Magliozzi 2019, fig.3). The expression of TNFR1 was increased around 3x in lesions in the precentral gyrus in tertiary lymphoid structure positive (’F+’) MS vs. in HC, and around 2x outside lesions and in tertiary lymphoid structure-negative (F-) brains. Expression of TNFR2 was increased by 4x-5x in F- MS brains vs controls, and negligibly raised in F+ cases. Taken together, these results are consistent with mTNFR protein expression being raised to the same extent as measured CSF sTNFR concentration. From eqn.1: 86 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Similarly, in treatment for MS, the ratio of signal strength through TNFR1 in the treated condition (MSTx) to the untreated (MS) is: The ratios[^்ேி]ಾೄ^^ [^்ேி]ಾೄand[^்ேிோ^]ಾೄare also unknown. Here it can be considered that [mTNF] and [mTNFR1] are unchanged at the initiation of treatment and may change during successful treatment towards the levels typical in HC. In contrast, depletion of sTNF and sTNFR1 from circulation will rapidly deplete these from the CSF and hence from the site of MSinflammation, leading to a rapid decrease in α. So to a first approximation at the start of treatment,[^்ேி]ಾೄ^^[^்ேி]ಾೄ and [^்ேிோ^]ಾೄ^^[^்ேிோ^]ಾೄ are both set equal to 1, and the immediate effect of treatment asbeing: can be assessed. After treatment progresses, [^^^^^^^^]ெௌ்௫may change to approach the healthy value i.e.[^்ேி]ಾೄ^^approaches[^்ேி]ಹ^= 1 / 7.7 and similarl[^்ேிோ^]ಾೄ^^ [^்ேிோ^]ಹ^[^்ேி]ಾೄ [^்ேி]ಾೄy[^்ேிோ^]ಾೄapproaches[^்ேிோ^]ಾೄ= 1 / 1.7. So, after a period of treatment the change in signaling is likely to be smaller than at the start, even though the depth of depletion of sTNF and sTNFR1 may be the same. During treatment ^^ெௌ்௫is reduced below ^^ெௌby depletion of sTNF – a value of ^^ெௌ்௫= 0.2^^ெௌis later used to represent a degree of depletion of sTNF of 80%. The parameters α and X set the sensitivity of the model to [sTNF]. The value of α represents the ratio of the concentration of sTNF within the intercellular space adjacent to cells bearing mTNFR1 receptors to the concentration of mTNF, averaged over the intercellular volume available to those same receptors. sTNF is shed continuously by cells through cleavage of mTNF and will diffuse within the intercellular volume until bound by mTNFR1 or cleared into the circulation. In general, sTNF is expected to signal over the entire volume of modelled intercellular space remote from the source, which is localised on immune cells in sub-regions of that volume, 87 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 while mTNF is only available within those sub-regions. Therefore, the concentration of sTNF available for signaling within the whole volume will likely exceed that of mTNF in, i.e. α > 1. In the model α in the range 1 to 10 was taken. The parameter X sets the relative signaling efficiency of mTNF vs sTNF through mTNFR1 for a given concentration and affinity. Considering that (i) close cellular alignment is required for mTNF-mTNFR1 signaling, while sTNF can signal throughout the volume and (ii), clusters larger than a single trimeric complex are not necessary in mTNFR1 signaling, X is expected to be less than 1 – i.e. sTNF signaling is favored over mTNF signaling through mTNFR1 for the same concentration of each. Therefore, X in the range 0 (only sTNF signals through mTNFR1) to 1 (both sTNF and mTNF signal equally) was taken. The effects of the choice of α and X are discussed below. Signaling strength through mTNFR2 Only mTNF signals through mTNFR2, so S(R2) is given by:^^(^^2) = [^^^^^^^^ − ^^^^^^^^^^2] ^^(^^^^^^, 2)for [mTNFR2] > [mTNF] 88 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Following a period of treatment,[^்ேி]ಾೄ^^[^்ேி]ಾೄapproaches 1 / 7.7 and [^்ேிோଶ]ಾೄapproaches 1 / 2.2 so, as for mTNFR1 signaling, the change in signaling is likely to be smaller than at the start of treatment, even though the depth of depletion of sTNFR1 may be the same. However, cell surface concentrations will change slowly relative to the depletion of sTNFR1 / 2, so herein only the effect at the start of treatment is considered. Impact on signaling of occupancy of surface receptors in TNFR1 and TNFR2 signaling Next the values of S(sig, 1) and S(sig, 2) for the above equations are found. Signaling through mTNFR1 Signaling through mTNFR1 requires only the formation of a trimeric cluster of TNF plus three mTNFR1 receptors. It was discussed above that both TR0 and TR1 complexes with sTNFR1 will bind and signal, and TR2 will bind and signal with a probability reduced owing to the extended time needed for replacement of two sTNFR1s by two mTNFR1s. Therefore, the probability of signaling is proportional to the probability PTRn of sTNF or mTNF being in complexes TR0, TR1 or TR2: S(sig, R1) = PTR0 + PTR1 + 0.1 PTR2 [9] Signaling through mTNFR2 Next an expression for S(sig, 2) in the TNFR2 pathway is found. TNF-mTNFR2 complexes form clusters comprising a chain of TNF trimers each bound to either two or three TNFRs, which can be either of mTNFR2 or sTNFR1 (complexes of TNF comprising only one mTNFR2 and no sTNFR1 terminate a chain and so do not form large clusters). Signaling happens when a pair of adjacent trimers in a cluster each comprise three mTNFR2s. From the discussion above, only TR0 89 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 complexes can form part of a signaling pair as mTNFR2 can’t replace sTNFR1 in the lifetime of the complex. The presence of a sTNFR1 in a complex in the cluster means that any complex adjacent to that one can’t form a signaling pair with it. To find the signal strength for a given cluster of TNF-mTNFR2 complexes, each distinct configuration of a number of TR0 trimers distributed over the positions in the cluster is considered, the probability of that configuration being formed, and the signaling strength of that configuration, i.e. the number of adjacent pairs there are in the configuration. As the configurations are all mutually exclusive, the total signal strength is then the sum of the signal strengths of all of the configurations. For simplicity, mTNF-mTNFR2 signaling is assumed to result from formation of closed hexagonal clusters of mTNF trimers, as envisaged by Vanamee and Faustmann (Vanamee 2018). Su et al. (Su 2023) used a computer model to confirm that mTNF-mTNFR2 trimers exist in clusters of a mean size consistent with formation of hexagonal clusters (Su 2023, fig.4e; size: 18-24 proteins in the nomenclature in that paper, in which TNF trimers count as 1 protein) and, at least in the example shown by Su et al., the majority of clustered trimers are in this configuration (see Su 2023, fig.5c). A single hexagonal cluster is shown in FIG.7A with each TNF trimer at a vertex. For each configuration of a given number of TR0 complexes in the ring, the probability of signaling for each configuration of TR0 trimers is the probability that at least 2 TR0s are bound at adjacent positions in the hexagon, and the signal strength of that configuration is the number of adjacent pairs of TR0s in the configuration multiplied by the probability of the configuration. The contribution to the total signaling strength for that number of Tr0 complexes is then the sum of all of the individual configurations each multiplied by the number of adjacent pairs in that configuration. For n TR0s, the signal strength s(n) is given by: S(n) = PTR0n× (1 – PTR0)6-n× ( 1 x N(n, 1 pair) + 2 x N(n, 2 pairs) + 3 x N(n, 3 pairs) + 4 x N(n, 4 pairs) + 5 x N(n, 5 pairs) 6 x N(n, 6 pairs) ) Where: PTR0is the probability that a TNF trimer is in state TR0; N(n, 1 pair) is the number of configurations of n TR0s with 1 pair of adjacent TR0s N(n, 2 pairs) is the number of configurations of n TR0s with 2 pairs of adjacent TR0s N(n, 3 pairs) is the number of configurations of n TR0s with 3 pairs of adjacent TR0s 90 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 The total signal mTNFR2 signal strength, S(sig, 2) is the sum of the signaling strength from all the configurations of each of n = 2 to 6 signaling trimers: S(sig, 2) = s(2) + s(3) + s(4) + s(5) + s(6) The configurations are inspected individually, with the positions of the TR0 trimers labelled as in FIG.7A: For 2 bound TR0s There are 6 configurations of adjacent positions (12, 23, 34, 45, 56, 61) each with signal strength 1 s(2) = PTR02x (1 – PTR0)4x 6 For 3 bound TR0s Zero adjacent TR0 pairs: configurations 135 and 246: N(3, 0 pairs) = 2 1 adjacent TR0 pair: configurations 124, 125, 235, 236, 346, 341, 451, 452, 562, 563, 613, 614: N(3, 1 pair) = 12 2 adjacent TR0 pairs: configurations 123, 234, 345, 456, 561, 612: N(3, 2 pairs) = 6 ^ s(3) = PTR03x (1 – PTR0)3x (1 x 12 + 2 x 6) = PTR03x (1 – PTR0)3x 24 For 4 bound TR0s Zero or 1 adjacent pairs: no configurations are possible 2 adjacent TR0 pairs: configurations 1245, 2356, 3461, 1235, 2346, 3451, 4562, 5613, 6124 N(4, 2 pairs) = 9 3 adjacent TR0 pairs: configurations 1234, 2345, 3456, 4561, 5612, 6123 N(4, 3 pairs) = 6 ^ s(4) = PTR04x (1 – PTR0)2x (2 x 9 + 3 x 6) = PTR04x (1 – PTR0)2x 36 For 5 bound TR0s There will always be 4 adjacent pairs: 6 configurations. N(5, 4 pairs) = 6 ^ s(5) = PTR05x (1 – PTR0) x 6 x 4 = PTR05x (1 – PTR0) x 24 For 6 bound TR0s 91 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 s(6) = PTR06x 6 Summing the individual signal strengths for each number of ligands that are bound, S(sig, R2) = 6PTR02{ (1 – PTR0)4+ 4PTR0(1 – PTR0)3+ 6PTR02(1 – PTR0)2+ [ TR03PTR0) + PTR0410] 4P (1 – } The terms in curly brackets reduce to equal 1, and hence eqn.

[0010] reduces to the simple form S(sig, R2) = 6PTR02

[0011] The simple form of eqn.

[0011] is suggestive that other clusters than the hexagonal ring might follow the same rule. The process above was repeated for three different clusters: a linear array of 6 complexes (FIG.7B), a linear array of 4 complexes with two branched complexes (again a total of 6 complexes) (FIG.7C), and a ring of 6 with a single branch complex (total 7 complexes) (FIG. 7D). In each case, S(sig, 2) = NPTR02, where N is the number of adjacent pairs in the cluster (5 for the linear 6 array and for the branched 4 array; 7 for the 6-ring with one branch). This implies that the same rule is likely to apply to larger clusters, beyond the reach of visual inspection. This finding gives confidence that the equation for S(sig, 2) derived above is robust to variation in both the pattern and the size of the clusters of complexes. The above values of S(sig, 1) and S(sig, 2) can now be used in equations for the relative signaling strength through each of TNFR1 and TNFR2. Ratios of signaling through TNFR2 to through TNFR1 Differences in the ratio of signaling strength through TNFR1 and TNFR2 in moving from HC to MS and from MS to MSTx are found from the ratios: ratios of the values of equations [7] / [2] and[8] / [4] For MS compared with HC: 92 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 ^^(^^^^^^, 2)ெௌ^^^^(^^2)ெௌ / ு^ 2.2 ^^(^^^^^^, 1)^^^^(^^1) = ൬ெௌ / ு^ 1.7^ ெௌ^൬^^ெௌ + 2.5 ^^(^^^^^^, 2)

[0012] ு^^^ு^ + 2.5 ^ ^^(^^^^^^, 1) ൠு^For MSTx compared with MS, at the start of treatment: ^^(^^^^^^, 2) ெௌProbabilities of TR0-TR3 as a function of sTNFR1 concentration Next the values of PTR0 PTR1 and PTR2 to be used in the above equations are calculated. Complexation of TNF with sTNFR1 sTNFR1 impacts TNF signaling through the proportion of TNF in the different complexes TR0-TR3. This is found from the equilibria for each successive association of monomeric sTNFR1 to the TNF trimer. Assuming [sTNFR1] >> [TNF], simplified equations can be used; [R1] is used for [sTNFR1] for brevity. ^^^^0 + ^^1 → ^^^^1 ^^^^^ = [^^^^0][^^1] / [^^^^1] [^^^^1] / [^^^^0] = [^^1] / ^^^^^

[0014] ^^^^1 + ^^1 → ^^^^2 ^^^^ଶ = [^^^^1][^^1] / [^^^^2] [^^^^2] / [^^^^1] = [^^1] / ^^^^ଶ

[0015] ^^^^2 + ^^1 → ^^^^3 ^^^^ଷ = [^^^^2][^^1] / [^^^^3] [^^^^3] / [^^^^2] = [^^1] / ^^^^ଷ

[0016] [^^^^^^] = [^^^^0] + [^^^^1] + [^^^^2] + [^^^^3] 93 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 PTR1, PTR2and PTR3are found from equations

[0017] and

[0014] -

[0016] . Based on the high affinity of TNF for sTNFR1 found by McMillan et al. (McMillan 2021), the proportion of TNF that is in state TR0 is very low for physiological concentrations of sTNFR1: at [sTNFR1] = 40 pM ^^்ோ^= 6.9% and at [sTNFR1] = 200 pM, ^^்ோ^= 0.2%, showing the profound effect of sTNFR1 concentration on TNFR2 signaling. Proportions of TNF that are in complexes TR0-TR3 at a range of sTNFR1 concentrations are shown in Table 3, with the resulting probability of signalling through mTNFR1 S(sig, 1), and through mTNFR2, S(sig, 2). It can be seen that the probability S(sig, 2) falls to a very low level at higher sTNFR1 concentration – this is driven by the [R1]2and [R1]3terms in the denominator of equation 17. Table 3. Percentage of TNF in each of TR0-TR3 as a function of [sTNFR1] and resulting probabilities of signaling through mTNFR1 and mTNFR2 Results: Effect of increased sTNF and sTNFR1 in MS compared with HC The ratio of the change in TNFR2 signaling to the change in TNFR1 signaling is found for the transition from HC to MS using the values of ^^^^(^^2) / ^^^^(^^1) from equation 12 with the ratio 94 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 S(sig, 2) / S(sig, 1) from equations 17 plus

[0014] -

[0016] .. The values of α(MS) and α(HC) are taken to be the same. The ratio of signaling through TNFR1 relative to signaling through TNFR2 is a measure of potential damage in MS. The change in this ratio in MS patients relative to healthy controls for given concentrations of TNF and sTNFR1 shows the degree to which TNF signaling is disordered in MS. FIG.8 shows the fold change in the ratio of mTNFR1 to mTNFR2 signaling on moving from HC, with CSF sTNFR1 concentration = 40 pM (the lower end of the range for HC – (Hu 2021)) to MS with elevated CSF sTNFR1 (on the x axis), for a corresponding elevation of sTNF of 7.7x over HC as found in MS patients. The deleterious mTNFR1 / mTNFR2 signaling ratio rises dramatically, mainly driven by a decrease in mTNFR2 signaling. With a CSF [sTNFR1] value of order 200 pM in MS (mean value 4453 ± 3213 pg / ml = 171 ± 124 pM for MW of sTNFR1 = 26 kDa, Pezzini 2023), the mTNFR1 / mTNFR2 signaling ratio increases by over 100x (FIG.8, upper trace) – i.e. mTNFR2 signaling is significantly downregulated. This shows the power of sTNFR1 to tip the balance from beneficial mTNFR2 signaling towards deleterious mTNFR1 signaling in MS. As a test of a key assumption, the lower trace in FIG.8 shows the change in signaling ratio if mTNFR1 signaling is assumed to be by TR0 only – i.e. the same as for mTNFR2 – rather than from TR0, TR1 and 10% of TR2 (this is an extreme assumption). The increase in deleterious mTNFR1 / mTNFR2 signaling ratio is apparent at a lower but still significant level, showing the robustness of the predictions for sTNFR1 effects in MS. Results: Effect of depletion of sTNFR and sTNFR1 in MS In treatment, it is proposed to deplete sTNF and sTNFR1 in the circulation, resulting in depletion from the CSF. Depletion of sTNF will reduce pro-inflammatory signaling through mTNFR1. Depletion of sTNFR1 will restore mTNF signaling through mTNFR2, with at least the aim to achieve a level typical of health. Depletion of sTNFR1 will also increase mTNFR1 signaling to a degree but, owing to the extreme sensitivity of mTNFR2 signaling to sTNFR1, the mTNFR2 / mTNFR1 signaling ratio is dramatically increased. In the following figures the initial effect of sTNF and sTNFR1 depletion treatment is shown, based on equations 13 - 17. In treatment, depletion of sTNF is represented by decreasing α by a depletion factor δ, while [mTNF] is taken to stay the same: ^^(^^^^^^^^) = (1 − ^^)^^(^^^^). As an example, δ may be 0.8, for 80% depletion of sTNF.The parameters α(MS) and X are set equal to 1 in the results in FIG.9 and FIG.10. 95 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 FIG.9 shows the fold change increase in the beneficial mTNFR2 / mTNFR1 signaling ratio (note this is the inverse of the deleterious mTNFR1 / mTNFR2 signaling ratio shown in FIG.8) as sTNFR1 is depleted from the CSF from an initial concentration of 200 pM, representing the upper end of the concentration found by Pezzini et al. The upper trace shows the fold change in mTNFR2 / mTNFR1 signaling ratio with depletion of sTNFR1 when sTNF is depleted simultaneously by 80%. The middle trace shows the fold change in signaling ratio when sTNF is not depleted, showing the majority of the beneficial effect on signaling ratio to be based on reduced sTNFR1 inhibition of mTNF-mTNFR2 signaling. Again, the lowest trace shows the fold change in signaling ratio with the assumption that mTNFR1 signaling is driven only by TR0 – the increase in signaling ratio is smaller but still significant. Effect of sTNFR2 on mTNFR2 / mTNFR1 signaling ratio sTNFR2 has a similar affinity for mTNF as has mTNFR2, and has higher PLAD-PLAD affinity for mTNFR2 than the PLAD-PLAD affinity of mTNFR2 dimers, as the inflexible stalk region that reduces PLAD-PLAD affinity for mTNFR2 is severed in sTNFR2. Therefore, sTNFR2 can be incorporated into mTNF-mTNFR2 complexes, where it will inhibit signaling. As sTNFR2 has a lower affinity for sTNF and mTNF than does sTNFR1, when sTNFR1 is raised in disease the effect of simultaneously raised sTNFR2 on mTNFR2 signaling is expected to be smaller. The extent to which this is true depends on the real in vivo affinities of sTNFR2 versus sTNFR1 – the available data showing very high affinity of sTNFR1 for TNF (Kd1= 10 pM, Kd2= 20 pM, McMillan 2021; Kd1= Kd2= 20 pM, Prada 2021), is from measurements made in buffer and the affinity in the high protein environment of the intercellular space may be lower. Importantly, when sTNFR1 is depleted in treatment the effect of sTNFR2 on mTNF-mTNFR2 signaling is likely to become more significant: when sTNFR1 is depleted, the sTNFR2 remains behind to block signaling. This results in a reduced effect of sTNFR1 depletion on mTNFR2 / mTNFR1 signaling ratio, which can be rescued by also depleting sTNFR2. The effects of sTNFR2 are (i) to compete with sTNFR1 for binding TNF, reducing the apparent affinity of binding, and (ii) to associate with TNF and with TNF-sTNFR1 complexes to increase their degree of complexation. In this section for clarity the terminology is changed to write TR12 for a complex TNF-(sTNFR1)2, previously denoted by TR2; TR2 for TNF-sTNFR2, and TR1R2 for TNF-(sTNFR1)1(sTNFR2)1, etc. sTNFR2 associates with TR0 to form TR2, with TR1 to form TR1R2 and with TR12to form TR12R2, etc. In line with the assumptions earlier in Example 1, given the much higher affinity of sTNFR1 than of sTNFR2 for TNF (of order 20x) and longer t(off) (t1 / 2(off) for sTNFR2 is 1-2 96 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 min. versus 33 min. for sTNFR1, discussed above), a mTNFR1 receptor diffusing in the membrane is assumed to be able to replace sTNFR2 during the lifetime of complexes bound to the membrane surface at a first mTNFR1, so complexes containing sTNFR2 are taken to signal through mTNFR1, while as before only the TR0 unbound TNF trimers signal through mTNFR2. Trimeric complexes containing sTNFR2 will not be captured by mTNFR1 and so will not signal. The effect of sTNFR2 is found by solving equations similar to Eqns.14-17, extended to include both sTNFR1 and sTNFR2 in equilibria with TNF and its complexes. Writing T for TR0, R1 for sTNFR1, R2 for sTNFR2, TR1 for TNF-sTNFR1, TR2 for TNF-sTNFR2 etc. and [T]0for the total concentration of TNF, the complete set of equilibria and associated simplified equilibrium equations are below: ^^ + ^^1 → ^^^^1 ^^^^^ = [^^][^^1] / [^^^^1] [E1]^^ + ^^2 → ^^^^2 ^^^^^′ = [^^][^^2] / [^^^^2] [E2]^^^^1 + ^^1 → ^^^^1ଶ ^^^^ଶ = [^^^^1][^^1] / [^^^^1ଶ] [E2]^^^^1 + ^^2 → ^^^^1^^2 ^^^^ଶ′ = [^^^^1][^^2] / [^^^^1^^2] [E4]^^^^2 + ^^1 → ^^^^1^^2 ^^^^ଶ = [^^^^2][^^1] / [^^^^1^^2] [E5]^^^^2 + ^^2 → ^^^^2ଶ ^^^^ଶ′ = [^^^^2][^^2] / [^^^^2ଶ] [E6]^^^^1ଶ + ^^1 → ^^^^1ଷ ^^^^ଷ = [^^^^1ଶ][^^1] / [^^^^1ଷ] [E7]^^^^1ଶ + ^^2 → ^^^^1ଶ^^2 ^^^^ଷ′ = [^^^^1ଶ][^^2] / [^^^^1ଶ^^2] [E8]^^^^1^^2 + ^^1 → ^^^^1ଶ^^2 ^^^^ଷ = [^^^^1^^2][^^1] / [^^^^1ଶ^^2] [E9]^^^^1^^2 + ^^2 → ^^^^1^^2ଶ ^^^^ଷ′ = [^^^^1^^2][^^2] / [^^^^1^^2ଶ] [E10]^^^^2ଶ + ^^1 → ^^^^1^^2ଶ ^^^^ଷ = [^^^^2ଶ][^^1] / [^^^^1^^2ଶ] [E11]^^^^2ଶ + ^^2 → ^^^^2ଷ ^^^^ଷ′ = [^^^^2ଶ][^^2] / [^^^^2ଷ] [E12][^^]^ = [^^] + [^^^^1] + [^^^^2] + [^^^^1ଶ] + [^^^^1^^2] + [^^^^2ଶ] + [^^^^1ଷ]

[0018] + [^^^^1ଶ^^2] + [^^^^1^^2ଶ] + [^^^^2ଷ]The concentrations [T] and of the various complexes are found by inserting the equilibrium equations E1 - E12 into Eqn.18. In complexes comprising sTNFR2, the sTNFR2 is assumed to bereplaced by mTNFR1 and so complexes ^^^^2, ^^^^1^^2 and ^^^^2ଶ are taken to signal throughmTNFR1. McMillan et al. found that binding of a first and second sTNFR1 to TNF reduced the affinity of the third binding site on TNF for sTNFR1 by 10x relative to the second – hence complex ^^^^1ଶis assumed to have 10% of the signaling strength of T and TR1 through mTNFR1 97 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 (as before). The same is assumed for binding of sTNFR2, so on this basis, ^^^^2, ^^^^1^^2, and ^^^^2ଶare taken to have 10% of the signal strength of ^^^^2. FIG.10 shows the effect of the presence of sTNFR2 on the mTNFR2 / mTNFR1 signaling ratio as a function of sTNFR1 concentration, for a high concentration of sTNFR2 (200 pM), above that seen in CSF in MS or HC by Pezzini et al. but in line with measurements in plasma by others (note the concentration in the intercellular space may be much higher than in CSF or plasma), and for depletion of sTNFR2 to a low concentration of 40 pM, more typically found in CSF for MS (Pezzini 2023). FIG.10 shows the fold change in mTNFR2 / mTNFR1 signaling ratio as a function of [sTNFR1] relative to the ratio at [sTNFR1] = 200 pM, in a MSTx treatment scenario with sTNF also depleted by 80%. These are the same parameters as for FIG.9, though in FIG.10 the scale is limited to [sTNFR1] = 40 – 120 pM for clarity. Two cases for [sTNFR2] are shown: (i) with [sTNFR2] = 200 pM, i.e. no depletion and (ii), for [sTNFR2] = [sTNFR1], i.e. sTNFR2 is depleted alongside sTNFR1 from 200 pM to 40 pM. Two cases for Kd(TNF-sTNFR2) are shown: (i) Kd(TNF-sTNFR2) = 0.4 nM, as found by Grell (Grell 1998) and Rahman (Rahman 2006), see Table 4; (ii) Kd = 1 nM, as found by Xu (Xu 2023). For Kd = 10 nM, as suggested by Prada et al. (Prada 2021), the change in sTNFR2 contributes negligibly to the effects of sTNFR1 depletion. The result from FIG.9 for [sTNFR2] = 0 is shown for comparison. As seen in FIG.10, as sTNFR1 is depleted from 200 pM in the presence of 200 pM sTNFR2, the signaling ratio increases to a lesser extent than if sTNFR2 is not present – sTNFR2 remains to inhibit mTNFR2 signaling as sTNFR1 is removed. If sTNFR2 is depleted alongside sTNFR1, the increase in signaling ratio is greater than if sTNFR2 is not present, as the fold change is plotted against a decreased signaling ratio at [sTNFR2] = 200 pM compared with that for [sTNFR2] = 0. However, for each set of Kd assumptions in FIG.10, the increase in signaling ratio with sTNFR1 depletion is very large, even for a high concentration (200 pM) of sTNFR2. The increase in signaling ratio is approximately doubled if sTNFR2 is depleted alongside sTNFR1. The increase is sensitive to the affinity of sTNFR1 binding to TNF. FIG.10 shows the effect of choosing Kd1to be 20 pM rather than 10 pM, in line with (Prada 2021), while keeping Kd2= 20 pM and Kd3= 200 pM: the fold change increase in signaling ratio with sTNFR1 depletion is decreased, and the effect of sTNFR2 is increased, as would be expected for a lower affinity binding of sTNFR1. However, the overall conclusion is unchanged by the higher Kd1value: the fold change of mTNFR2 / mTNFR1 signaling ratio with sTNFR1 depletion is still large, and depletion of sTNFR2 enhances the effect. The conclusion is that depletion of sTNFR1 alone will be therapeutic in MS; depletion of sTNFR2 will also be therapeutic but likely to have lesser effect, and with an effect that rises once 98 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 sTNFR1 is depleted. Therefore, combined depletion of sTNFR1 and sTNFR2 may be beneficial to increase the effectiveness of treatment over depletion of sTNFR1. This may depend on the concentration of sTNFR2 present in serum and / or CSF in MS patients. In animal models, there is little detailed published information available about the affinity and kinetics of sTNFR1 / 2 binding to TNF, and these might differ from the values in human used in this Example, so in experiments depletion of sTNFR2 will be validated alongside depletion of sTNFR1 and / or sTNF. In Example 2, depletion of sTNFR2 along with depletion of sTNFR1 and sTNF is found to have significant effect over and above depletion of sTNFR1 and sTNF alone, supporting the findings in Example 1. Effect of choice of parameters in the model At the outset in Example 1, the two parameters α – the ratio[^்ேி][^்ேி]of the concentrations of sTNF and mTNF averaged over the intercellular space within the MS lesion, and X, the ratio of signalling by mTNF to sTNF through mTNFR1, were included with both values set to 1. The conclusions from this example are robust to different values of the parameters α and X, which are unknown as no data is available, but are selected to have values likely to be encountered in vivo. FIG.11 shows the effect of setting α = 1 and 10 and X = 1 and 0 (i.e. mTNF does not signal through mTNFR1), for depletion factors δ = 0.8 (i.e. sTNFR1 is 80% depleted) and δ = 0.6. For α = 10, depletion of sTNF has a greater impact on the mTNFR2 / mTNFR1 signaling ratio; for X = 0, the effect of depletion of sTNFR1 is even greater than for X = 1. The conclusion of Example 1, that mTNFR2 / mTNFR1 signaling ratio is increased significantly on depletion of sTNF, depletion of sTNFR1, or depletion of both simultaneously, is maintained for different choices of these parameters in the model. Conclusions from Example 1 1) sTNFR1 is a powerful inhibitor of mTNFR2 signaling and an increase in concentration of sTNFR1 differentially inhibits mTNFR2 over mTNFR1 signaling. 2) In MS, typical concentrations of sTNFR1 found in the CSF are sufficient to greatly increase the deleterious mTNFR1 / mTNFR2 signaling ratio. 3) The increased concentrations of sTNFR1 in circulation are also sufficient to increase this ratio. 4) Depletion of sTNFR1, or depletion of sTNF and sTNFR1 together, creates a profound decrease in mTNFR1 / mTNFR2 signaling ratio, i.e. an increase in the beneficial 99 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 mTNFR2 / mTNFR1 signaling ratio, predicting a powerful therapeutic effect in restoring mTNFR2 signaling. 5) Depletion of sTNF plus sTNFR1 is predicted to have a greater affect than depletion of sTNF alone. 6) Depletion of sTNFR1 by 80%, from 200 to 40 pM, is modelled to give an increase in mTNFR2 / mTNFR1 signaling ratio sufficient to reverse the decrease in this ratio modelled in moving from a healthy condition to MS. 7) sTNFR2 is a minor contributor to inhibition of mTNFR2 signaling when sTNFR1 is present, but when sTNFR1 is depleted sTNFR2 may become a significant inhibitor. 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The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells. Mol. Neurodegen.19:53 (2024). Example 2: Efficacy in Acute EAE mouse model of MS The EAE MOG35-55 model is the most commonly used preclinical model for MS and results in rapid and robust induction of EAE disease with emphasis on motor neuron disease in the spinal cord (Glatigny 2018, Lassman 2017). Depletion from circulation by particles of (i) sTNF, (ii) sTNF plus sTNFR1, and (iii) sTNF plus sTNFR1 and sTNFR2 was tested in an EAE model in comparison with vehicle and with Etanercept, with the readouts being (1) combined clinical disease score (EAE score), which measures paralysis; (2) change in body weight (BW), which measures general morbidity and specific motor deficits related to feeding; (3) histological analysis of spinal cords to measure inflammation and neurodegeneration including demyelination and (4) immunohistochemical analysis of spinal cords to measure the presence or loss of cells supporting myelination: oligodendrocytes (ODG) and oligodendrocyte precursor cells (OPC), all in comparison with naïve mice. The experimental procedure in the EAE model was as follows. Mice were immunized on day 1 with MOG35-55 / CFA (complete Freund’s adjuvant) (Hooke cat no. EK-2110, Hooke Laboratories, Lawrence MA, USA). The pertussis toxin component of the kit was injected i.p. at 2hr and 24hr after injection of MOG35-55 / CFA. Mice were scored daily for EAE based on the following: 0: no changes in motor function; 1: limp tail, wobbly walk; 2: limp tail and weakness of hind legs; 3: limp tail and complete paralysis of hind legs or limp tail and paralysis of one front leg and one hind leg; 4: limp tail, complete hind leg and partial front leg paralysis; 5: complete hind and front leg paralysis or death. Disease onset was at days 10-14 after injection, which was then re- named day 1 of disease for each individual mouse. In the main study, 5 groups of 18 mice were assigned: vehicle EAE control; anti-sTNF particles; anti-sTNF and anti-sTNFR1 particles; anti-sTNF, anti-sTNFR1 and anti-sTNFR2 particles (referred to herein as the ‘triple combination’ group); etanercept. Mice were grouped at day of disease for the same mean EAE score and followed for a further 17 days. Anti-sTNFR1 and anti-sTNFR2 particles were injected i.v. by tail vein at a dose of 200 µg in 100 µl vehicle, daily 111 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 starting at day 1 of disease for 12 doses. Anti-sTNF particles were injected as above for a total of 8 doses rather than 12, owing to experimental difficulties. Etanercept was dosed at 10 mg / kg subcutaneously. Q3D. At the end of the study, at days 15 to 19 of disease for each mouse depending on the timing of the start of disease, the 10 mice from each group were selected for histological and immunohistochemical (IHC) analysis: these were selected to be the mice with the 5 highest and the 5 lowest EAE scores at that point. A group of 3 naïve mice was also used for comparison in the histology and IHC study. Histological and immunohistochemical analyses are described below. Fabrication and testing of depletion particles A 100 nm diameter core silica nanoparticle (NP) was formed using the Stober silica process to coat silica over a 40 nm diameter gold seed core. PEG coating molecules and capture agent were coupled to the silica surface. PEG molecules were selected to achieve stability of the particles in solution and to shield the capture agent from interactions with target on cell surfaces as described in Example 13. Stability of the resulting shielded particle was tested by incubation of the particles in media with analysis of the DLS (dynamic light scattering) diameter at intervals. The DLS diameter was stable at 179 nm, PDI = 0.13 over 4 hr in 0.15M Na / PBS, and at 179 nm decreasing only to 174 nm, PDI constant at 0.15, in over 7 days in culture media RPMI 1640, showing the particles to be stable and usable in vivo. Capture agents were as follows: anti-mouse sTNFR1 particles used an anti-mouse TNFR1 antibody, clone 47803, R&D Systems cat. no. MAB425, that binds the extracellular region of TNFR1; anti-mouse sTNFR2 particles were made using anti-mouse TNFR2 antibody, clone TR75-32.4, Biolegend cat. no.113202, that binds the extracellular region of TNFR2; anti-sTNF particles were made using anti-mouse TNF antibody, clone TN3.19-12, Biolegend cat. no.506111, that binds to both monomeric and trimeric TNF. All antibodies were immobilized at a ratio of 0.1 mg antibody to 1.0 mg of NP. Anti-sTNFR1 / 2 particles were tested for capture performance as in Example 13. Anti-sTNF particles were tested as follows. BD mouse sTNF ELISA ‘OptEIA™ Mouse TNF ELISA Set II’ (Cat. No.558534) was used to measure recombinant TNF protein spiked at 0.5 ng / ml into PBS pH 7.4 plus 1% BSA; proteins were the standard from the ELISA kit and R&D Systems Cat. No.410-MT (carrier-free). Particles were added to the test solution to a final concentration of 6 or 24 ug / ml and incubated for times of 5, 15 and 60 min at 37C to mimic in vivo depletion in mice at an equivalent dose of 0.25 mg / kg or 1.0 mg / kg of particles. Particles were spun out of the test solution at each time point 112 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 (14,000 x g, 1 minute) and residual sTNF was measured by ELISA. Particles at 6 ug / ml deplete recombinant sTNF spiked-in at 0.5 ng / ml by 59%, 74% and 78% at 5, 15 and 60 minutes, and particles at 24 ug / ml by 71%, 84% and 92% respectively; capture was not affected by sTNFR1 or sTNFR2 additionally spiked in at 4 ng / ml. These concentrations are typical of the high end of the range in EAE model mice. This shows that particles used in this example are able to deplete sTNF in the presence of sTNFR1 / 2, as will be found in vivo, and at the dose used in the study (200 ug / mouse, i.e. approximately 240 ug / ml in plasma) will have significant additional capacity to capture sTNF over and above the amount that is present during the study (plasma sTNF was measured at around 25 pg / ml in vehicle-treated EAE mice in the study). Circulation time of particles was tested in vivo. A dose of 3.5 mg of particles in 500 ul saline was injected i.v. via tail vein in rats and blood was sampled at 2, 4, 8 and 24 hr after injection. Whole blood was analysed for gold using ICP / MS to detect the gold particle core. The percentage of the injected particles remaining in circulation was measured by the remaining percentage of the injected dose of gold. Particles cleared with an approximately monophasic profile; anti-sTNFR1 and anti-sTNFR2 particles had a half-life in circulation of 7.5 hr and anti- sTNF particles had a half-life of 3.5 hr. This shows the particles to have a long enough circulation time for use in the EAE model. Scaling for circulation time in human patients, the anti-sTNFR1 / 2 particles are expected to have a half-life of around 30 hr, long enough for therapeutic use. Both these and the anti-sTNF particles will be improved in clinical development to increase circulation time. Definition of study period as the period of peak disease The EAE model is known to induce disease that develops rapidly and reaches a sustained peak, before entering a remission phase in which symptoms gradually decrease and finally resolve. In this it represents the relapsing / remitting form of early-stage MS, though with much more rapid development of disease following onset than in human MS. After reaching peak disease rapidly, the model typically shows more heterogeneity in terms of mice showing some signs of lessening of disease in terms of clinical score and body weight (BW) loss. During this lessening of disease phase, it is more difficult to delineate therapeutic benefit from underlying disease lessening in the model, and thus the best window to compare therapeutic effect of interventions is during the Peak Disease phase, which shows the least amount of variability across individual animals in terms of disease scores and BW loss. 113 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 In this study, therapeutic benefit in the model was assessed during the peak disease period to avoid confounding effects of spontaneous remission. The peak disease period was defined with respect to the control (vehicle) group and the effects of treatment in the therapeutic groups was assessed relative to the EAE score and BW during that period. EAE score data during peak disease is shown in Table 5 for the vehicle group with respect to the elapsed days of disease since onset; treatment started at the day of onset. Based on n = 18 mice in the Vehicle Group, each animal’s individual peak score of disease (standard EAE disease scale of 0-5 with 5 representing death) was either 3.0 or 3.5, thus the threshold of 3.0 was adopted to represent Peak Disease for this study. The number of mice per day at ≥ 3.0 EAE Score was tabulated to determine the Peak Disease Period. Table 5. Peak disease profile of EAE *Day 1 = Day of onset of EAE disease for each individual animal The peak disease period was defined by the period wherein the mean EAE score is greater than 90% of the individual highest daily reading. By this criterion, the peak disease period was days 4 - 8: by including further days, the mean EAE score fell below 90% of the peak. Further, the selected peak disease period had lower variability (lower S.D. of the EAE score, S.D. = 0.23 - 0.32) bounded by greater S.D. outside this period (S.D. = 0.35 - 0.39), again showing days 4 - 8 to be the limits of the peak disease period. Effect of treatment in the EAE model Effect of treatment on paralysis Mean EAE scores from mice in each group from onset of disease (treatment started on the day of onset) through the peak disease period are shown in FIG.18. All particle treatment groups showed significant therapeutic benefit (p < 0.05) compared to vehicle on an individual daily basis during the peak disease period, while etanercept did not. 114 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 The effect of treatment versus vehicle is shown in Table 6. Taking the treatment period (the peak disease period) as a whole, treatment with anti-sTNF particles, anti-sTNF particles plus anti- sTNFR1 particles, and treatment with anti-sTNF particles, anti-sTNFR1 particles and anti-sTNFR2 particles gave average EAE scores decreasing in that order, showing therapeutic benefit from anti- sTNF particles alone, increased benefit from adding anti-sTNFR1 particles, and further increased benefit from adding anti-sTNFR2 particles. All particle treatment groups gave significant benefit relative to vehicle (p < 0.01), while treatment with etanercept did not (p = 0.285). For treatment with the triple combination of anti-sTNF, anti-sTNFR1 and anti-sTNFR2 particles the benefit was highly significant (p = 0.0002). Table 6. Comparison of treatment effects on EAE Score during Peak Disease Period Further, treatment with the triple combination of particles showed significant benefit compared with anti-sTNF particles alone, supporting a causal effect of circulating sTNFR1 and sTNFR2 on progression of disease in this MS model. Effect of treatment on body weight (BW) as a measure of disease As an additional endpoint to evaluate therapeutic efficacy, the EAE model also showed significant effect in terms of loss of BW of animals during the course of disease (motor disease / paralysis resulting in reduced feeding). Therapeutic intervention can elicit a benefit in terms of BW changes (i.e., lessen BW loss) if effects on motor function are substantial enough to translate to improved mobility and feeding. The percent change in BW across the disease peak is shown in Table 7. 115 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Table 7. Comparison of treatment effects for Body Weight loss at Peak Disease Period Treatment with anti-sTNF plus anti-sTNFR1 particles showed a trend towards increased therapeutic benefit compared with both vehicle and anti-sTNF particles alone, based on higher average %BW, though this was not statistically significant. The triple combination of anti-sTNF plus anti-sTNFR1 plus anti-sTNFR2 particles showed significant benefit compared with both vehicle and anti-sTNF particles alone, supporting the same finding from the EAE scores. Efficacy of particles shown by histology: reduced inflammation and demyelination in particle- treated EAE mice EAE Disease Histology Endpoints Selection MS is an inflammatory neurodegenerative disease and all approved therapeutics act on one or both of those dimensions; biomarkers of inflammation and neurodegeneration measure efficacy. Inflammatory biomarkers in MS and EAE: two key inflammatory cell types of the CNS, astrocytes and microglia, are central to the pathogenic MS mechanisms and their presence is commonly analyzed to assess therapeutic interventions. In addition, histopathology analysis of inflammatory cell infiltrates is standard. Neurodegenerative biomarkers in MS and EAE: demyelination is a hallmark of MS and can be quantified by immunostaining for myelin basic protein (MBP); direct assessment of neuron axonal degeneration by immunostaining using the SMI-32 antibody, which binds to demyelinated axonal neurofilaments, is indicative of the progressive neurodegenerative outcome of demyelination and reflective of advancing severity of disease. The markers that were used are summarized below: 116 FoleyHoagUS13044684.14 Attorney Docket No. NIH-01625 Inflammatory markers: 1. Inflammatory cell infiltrates consisting of mixtures of leukocytes (primarily of lymphocytes and monocytes) were measured as # of foci (≥20 cells / focus) per field as visualized by hematoxylin / eosin (H / E) staining of spinal cord sections. 2. Activated / inflammatory microglial cells were enumerated in terms of frequency by Iba- 1+ biomarker status and expressed as % of total cells in spinal cord sections. 3. Activated / inflammatory astrocytes were enumerated in terms of frequency of GFAP+ biomarker and expressed as % of total cells in spinal cord sections. Neurodegeneration markers: 1. Demyelination was measured as lack of immunostaining for MBP in spinal cord sections using a 6-point scale (0: < 2% demyelinated area; 1: 2-5% demyelinated area; 2: 6-19% demyelinated area; 3: 20-29% demyelinated area; 4: 30-50% demyelinated area; 5: > 50% demyelinated area). 2. Axonal degeneration was measured by the area of tissue immunostained with SMI-32 antibody in the white matter area (the primary area of pathology) of spinal cord sections and expressed as % of the total tiss...

Claims

Attorney Docket No. NIH-01625 CLAIMS What is claimed is:

1. A method of treating a neurodegenerative disease or disorder in a subject in need thereof, comprising depleting one or more depletion targets selected from soluble tumor necrosis factor receptor 1 (sTNFR1), soluble tumor necrosis factor receptor 2 (sTNFR2), and soluble tumor necrosis factor (sTNF) from a body fluid of the subject.

2. A method of promoting neuron myelination in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject.

3. A method of inhibiting neuron demyelination in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject.

4. A method of enhancing the generation of oligodendrocytes in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject.

5. A method of increasing oligodendrocyte precursor cell proliferation in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject.

6. A method of increasing oligodendrocyte precursor cell differentiation to form oligodendrocytes in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject. 143 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 7. A method of maintaining or increasing the number of oligodendrocytes and / or oligodendrocyte precursor cells in a subject in need thereof, comprising depleting one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF from a body fluid of the subject.

8. The method of claim 1, wherein depleting the depletion targets has one or more of the following effects: promoting neuron myelination, inhibiting neuron demyelination, enhancing the generation of oligodendrocytes, increasing oligodendrocyte precursor cell proliferation, increasing oligodendrocyte precursor cell differentiation to form oligodendrocytes, and maintaining or increasing the number of oligodendrocytes and / or oligodendrocyte precursor cells in the subject.

9. The method of any one of claims 1-8, wherein the depletion target is sTNFR1.

10. The method of any one of claims 1-8, wherein the depletion target is sTNFR2.

11. The method of any one of claims 1-8, wherein the depletion target is sTNF.

12. The method of any one of claims 1-8, wherein the depletion targets are sTNFR1 and sTNF.

13. The method of any one of claims 1-8, wherein the depletion targets are sTNFR2 and sTNF.

14. The method of any one of claims 1-8, wherein the depletion targets are sTNFR1 and sTNFR2.

15. The method of any one of claims 1-8, wherein the depletion targets are sTNFR1, sTNFR2 and sTNF.

16. The method of any one of claims 1-15, wherein depleting the one or more depletion targets comprises administering to the subject a composition comprising a depletion particle.

17. The method of claim 9, wherein depleting sTNFR1 comprises administering to the subject a composition comprising a depletion particle. 144 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 18. The method of claim 10, wherein depleting sTNFR2 comprises administering to the subject a composition comprising a depletion particle.

19. The method of claim 11, wherein depleting sTNF comprises administering to the subject a composition comprising a depletion particle.

20. The method of claim 12, wherein depleting sTNFR1 and sTNF comprises administering to the subject a composition comprising a depletion particle.

21. The method of claim 13, wherein depleting sTNFR2 and sTNF comprises administering to the subject a composition comprising a depletion particle.

22. The method of claim 14, wherein depleting sTNFR1 and sTNFR2 comprises administering to the subject a composition comprising a depletion particle.

23. The method of claim 15, wherein depleting sTNFR1, sTNFR2 and sTNF comprises administering to the subject a composition comprising a depletion particle.

24. The method of any one of claims 16-23, wherein the depletion particle comprises one or more depletion agents, wherein the one or more depletion agents selectively bind to one of the depletion targets.

25. The method of claim 24, wherein the one or more depletion agents are disposed on the depletion particle such that the depletion agents are sterically inhibited from binding to a molecule on the surface of a cell.

26. The method of claim 25, wherein the molecule on the surface of the cell is a membrane form of the depletion target. 145 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 27. The method of claim 24, wherein the depletion particle further comprises one or more shielding moieties, wherein the one or more shielding moieties inhibit interactions between the depletion agent(s) and a membrane form of the depletion target(s).

28. The method of claim 24, wherein the depletion particle further comprises a coating, wherein the coating inhibits interactions between the depletion agent(s) and a membrane form of the depletion target(s).

29. The method of claim 28, wherein the coating comprises shielding moieties.

30. The method of any one of claims 24-29, wherein the one or more depletion agents comprise: a) an antibody or a target biomolecule-binding fragment of an antibody, b) a non-antibody scaffold protein, c) a nucleic acid, an aptamer, or a nucleic acid analog, d) a target-binding portion of a TNF family protein, e) a TNF mutein, or f) a target-binding portion of a TNF receptor family protein.

31. The method of claim 27 or 29, wherein the shielding moieties comprise a polymer.

32. The method of claim 31, wherein the polymer is hydrophilic.

33. The method of claim 31 or 32, wherein the polymer is selected from polyethylene glycol (PEG), a poly(amino acid), polylactate, polylactic acid, a sugar, a lipid, polyglutamic acid, polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyvinyl acetate (PVA), poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol) (PEG- PLGA-PEG), polycaprolactone-PEG (PCL-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), poly(lactic acid-co-PEG) (PLA-PEG), poly(methyl methacrylate)-PEG (PMMA-PEG), a polypeptoid, poly(sarcosine), and a combination thereof. 146 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 34. The method of any one of claims 1-8, wherein depleting the one or more depletion targets selected from sTNFR1, sTNFR2, and sTNF comprises administering to the subject a composition comprising a first depletion particle and a second depletion particle.

35. The method of claim 34, wherein: a) the first depletion particle comprises one or more of a first depletion agent that selectively binds to a first depletion target selected from sTNFR1, sTNFR2, and sTNF; and b) the second depletion particle comprises one or more of a second depletion agent that selectively binds to a second depletion target differing from the first depletion target.

36. The method of claim 35, wherein: a) the first depletion particle further comprises one or more of a first shielding moiety, wherein the one or more first shielding moieties inhibit interactions between the first depletion agent(s) and a membrane form of the first depletion target; and b) the second depletion particle further comprises one or more of a second shielding moiety, wherein the one or more second shielding moieties inhibit interactions between the second depletion agent(s) and a membrane form of the second depletion target.

37. The method of claim 35, wherein: a) the first depletion particle further comprises a first coating, wherein the first coating inhibits interactions between the first depletion agent(s) and a membrane form of the first depletion target; and b) the second depletion particle comprises a second coating, wherein the second coating inhibits interactions between the second depletion agent(s) and a membrane form of the second depletion target.

38. The method of any one of claims 35-37, wherein: a) the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNF; b) the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNFR2; or 147 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 c) the first depletion agent selectively binds to sTNFR2 and the second depletion agent selectively binds to sTNF.

39. The method of any one of claims 35-37, wherein the first depletion agent comprises: a) an antibody or a target biomolecule-binding fragment of an antibody, b) a non-antibody scaffold protein, c) a nucleic acid, an aptamer, or a nucleic acid analog, d) a target-binding portion of a TNF family protein, e) a TNF mutein, or f) a target-binding portion of a TNF receptor family protein.

40. The method of any one of claims 35-39, wherein the second depletion agent comprises: a) an antibody or a target biomolecule-binding fragment of an antibody, b) a non-antibody scaffold protein, c) a nucleic acid, an aptamer, or a nucleic acid analog, d) a target-binding portion of a TNF family protein, e) a TNF mutein, or f) a target-binding portion of a TNF receptor family protein.

41. The method of any one of claims 36-40, wherein the first shielding moiety or the first coating comprises a polymer.

42. The method of any one of claims 36-41, wherein the second shielding moiety or the second coating comprises a polymer.

43. The method of claim 41 or 42, wherein the polymer is hydrophilic.

44. The method of any one of claims 41-43, wherein the polymer is selected from polyethylene glycol (PEG), a poly(amino acid), polylactate, polylactic acid, a sugar, a lipid, polyglutamic acid, polyglycolic acid (PGA), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyvinyl acetate (PVA), poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol) (PEG- 148 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 PLGA-PEG), polycaprolactone-PEG (PCL-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), poly(lactic acid-co-PEG) (PLA-PEG), poly(methyl methacrylate)-PEG (PMMA-PEG), a polypeptoid, poly(sarcosine), and a combination thereof.

45. The method of any one of claims 34-44, wherein the composition further comprises a third depletion particle.

46. The method of claim 45, wherein the third depletion particle comprises one or more of a third depletion agent that selectively binds to a third depletion target differing from the first depletion target and the second depletion target.

47. The method of claim 46, wherein the third depletion particle further comprises one or more of a third shielding moiety, wherein the one or more third shielding moieties inhibit interactions between the third depletion agent(s) and a membrane form of the third depletion target.

48. The method of claim 46, wherein the third depletion particle comprises a third coating, wherein the third coating inhibits interactions between the third depletion agent(s) and a membrane form of the third depletion target.

49. The method of any one of claims 36-48, wherein the first depletion agent selectively binds to sTNFR1, the second depletion agent selectively binds to sTNF, and the third depletion agent selectively binds to sTNFR2.

50. The method of claim 16, wherein the depletion particle comprises: a) one or more of a first depletion agent; and b) one or more of a second depletion agent.

51. The method of claim 50, wherein the depletion particle further comprises one or more shielding moieties, wherein the shielding moieties inhibit interactions between the first depletion agent(s), the second depletion agent(s), and membrane forms of the depletion targets. 149 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 52. The method of claim 50, wherein the depletion particle further comprises a coating, wherein the coating inhibits interactions between the first depletion agent(s), the second depletion agent(s), and membrane forms of the depletion targets.

53. The method of any one of claims 50-52, wherein: a) the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNF; b) the first depletion agent selectively binds to sTNFR1 and the second depletion agent selectively binds to sTNFR2; or c) the first depletion agent selectively binds to sTNFR2 and the second depletion agent selectively binds to sTNF.

54. The method of any one of claims 50-53, wherein the depletion particle further comprises a third depletion agent.

55. The method of claim 54, wherein the first depletion agent selectively binds to sTNFR1, the second depletion agent selectively binds to sTNF, and the third depletion agent selectively binds to sTNFR2.

56. The method of any one of claims 1-10, 14, 16-18, or 22, further comprising administering a selective sTNF antagonist, wherein the sTNF antagonist comprises an antibody or a TNF mutein.

57. The method of any of claims 1-56, wherein the particles are magnetic and the method further comprises removing the particles from a body fluid of a subject by magnetic force.

58. The method of any one of claims 1-57, wherein the neurodegenerative disease or disorder is selected from Multiple Sclerosis (MS), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Mild Cognitive Impairment (MCI), Ataxia, Multiple System Atrophy (MSA), Progressive Supranuclear Palsy, Motor Neuron Diseases, Dementia, Spinocerebellar Ataxia, Spinal Muscular Atrophy, plaque related diseases, Peripheral Neuropathy and Traumatic Brain Injury (TBI). 150 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 59. The method of any one of claims 1-8, wherein the subject has a myelin-related disorder.

60. The method of claim 59, wherein the myelin-related disorder is multiple sclerosis (MS), neuromyelitis optica (NMO, Devic’s disease), optic neuritis, pediatric leukodystrophy, neonatal white matter injury, age-related dementia, progressive multifocal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelinolysis (CPM), leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy, Alexander's disease, Pelizaeus Merzbacher disease (PMD), Vanishing White Matter Disease, Wallerian Degeneration, transverse myelitis, amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson’s disease, spinal cord injury, traumatic brain injury-, post radiation injury, neurologic complications of chemotherapy, stroke, acute ischemic optic neuropathy, vitamin E deficiency, isolated vitamin E deficiency syndrome. Bassen-Kornzweig syndrome, Marchiafava-Bignami syndrome, trigeminal neuralgia, acute disseminated encephalitis, Guillain-Barre syndrome, Charcot-Marie-Tooth disease, Bell's palsy, radiation-induced demyelination, idiopathic inflammatory demyelinating disease, transverse myelitis, chronic inflammatory demyelinating polyneuropathy, autoimmune peripheral neuropathy, acute disseminated encephalomyelitis, adrenomyeloneuropathy, Leber's hereditary optic neuropathy, or human T-cell lymphotropic virus (HTLV)-associated myelopathy.

61. The method of any one of claims 1-57, wherein the neurodegenerative disease or disorder or the myelin-related disorder is MS.

62. The method of any one of claims 1-57, wherein the neurodegenerative disease or disorder or the myelin-related disorder is progression independent of relapse activity (PIRA) MS.

63. The method of any one of claims 1-57, wherein MS is primary progressive MS (PPMS).

64. The method of any one of claims 1-57, wherein MS is relapsing and remitting MS (RRMS).

65. The method of any one of claims 1-57, wherein MS is secondary progressive MS (SPMS). 151 FoleyHoagUS13044684.14Attorney Docket No. NIH-01625 66. The method of any one of claims 1-65, further comprising administering a therapeutically effective amount of a second therapeutic agent.

67. The method of claim 66, wherein the second therapeutic agent is a selective inhibitor of sTNF, optionally wherein the selective inhibitor of sTNF is a TNF mutein or a small molecule allosteric TNF inhibitor.

68. The method of claim 66, wherein the second therapeutic agent is selected from glatiramer acetate, ocrelizumab, alemtuzumab, fingolimod, dalfampridine, natalizumab, teriflunomide, interferon beta-1a, interferon beta-1b, peginterferon beta-1a, dimethyl fumarate, rituximab, daclizumab, ofatumymab, laquinimod, masitinib, siponimod, ozanimod, ponesimod, ibudilast, vatelizumab, minocycline, ibrutinib, tolebrutinib, cladripine, temelimab, daclizumab, and MD1003 (biotin), or a combination of any of them.

69. The method of any one of claims 1-68, wherein the second therapeutic agent and the depletion particle are administered simultaneously.

70. The method of any one of claims 1-68, wherein the second therapeutic agent and the depletion particle are administered sequentially.

71. The method of any one of claims 1-70, wherein the body fluid is the cerebrospinal fluid (CSF) or the circulation of the subject.

72. The method of any one of claims 16-71, wherein the depletion particle is administered to the circulation of the subject. 152 FoleyHoagUS13044684.14

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