EP4739705A1 - Targeting heterogeneous nuclear ribonucleoproteins for neuroprotection - Google Patents

Abstract

The disclosure relates to compositions and methods for providing neuroprotection in a subject and for treating neurodegenerative diseases and traumatic brain or spinal injuries. In embodiments, the disclosure provides agents that bind to cytoplasmic heterogeneous nuclear ribonucleoprotein (hnRNP) in neurons and that can inhibit neuronal cell death.

Description

DESCRIPTION TARGETING HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEINS FOR NEUROPROTECTION REFERENCE TO A SEQUENCE LISTING This application contains a Sequence Listing XML, which has been submitted electronically and is hereby incorporated by reference in its entirety. Said XML Sequence Listing, created on July 5, 2024, is named UTFDP4109WO.xml and is 33,844 bytes in size. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63/512,412, filed July 7, 2023, the entire contents of which are incorporated by reference. BACKGROUND I. Field The present disclosure relates to the fields of medicine, cell biology, neurology and neurodegenerative disease. More specifically, it relates to agents that bind to cytoplasmic heterogeneous nuclear ribonucleoprotein (hnRNP) in neurons and which can inhibit neuronal cell death, as well as methods of making such agents and uses therefor. II. Related Art Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), ischemic stroke, and others, are characterized by the loss of neurons. Affected neurons exhibit neuronal stress responses including ER stress, oxidative stress, mitochondrial dysfunction, impairment of the proteasome and protein aggregation. These stress responses cause disruption of normal neuronal function and can eventually lead to cell death. Neurons can also mount pro-survival responses to protect themselves from these deleterious effects. See Gorman AM, “Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling,” J Cell Mol Med.2008 Dec; 12(6a): 2263–2280. DB1/ 148791292.1 1 4879-8182-7022, v.1 RNA-binding proteins (RBPs) are a diverse class of intracellular proteins that have attracted attention specifically due to their roles in the progression of neurodegenerative diseases. Of the RBPs associated with diseases marked by neuronal loss is the heterogenous nuclear ribonucleoprotein “hnRNP” family of proteins. hnRNPs are canonically central to cellular RNA metabolism. hnRNP proteins are commonly known by a variety of names, including for example, Auf1 (hnRNP D), PCBP1 and 2 (hnRNP A1 and A2), RMBX (hnRNP G), PTB-1 (hnRNP I), FUS (hnRNP P2), and SYNCRIP (hnRNP Q). A core subset of six hnRNPs (A1, A2, B1, B2, C1, and C2) have been found to be expressed and consistently tightly associated with hnRNAs. See Thibault PA, et al., “hnRNP A/B Proteins: An Encyclopedic Assessment of Their Roles in Homeostasis and Disease,” Biology, Vol.10, No.712 (2021). Structurally, the hnRNP A/B subgroup, comprising hnRNPs A1, A2/B1, A3, and A0, share two N-terminal RNA recognition motifs (RRMs) and a C-terminal glycine-rich domain, referred to as a low- complexity domain (LCD), which includes an RGG motif (arginine-glycine-glycine), an M9 nuclear localization sequence, and an intrinsically-disordered core prion-like domain (PrLD). hnRNP A/B do not demonstrate appreciable enzymatic activity, rather, they function more like chaperone or scaffold proteins which promote, protect, and traffic RNAs, including during transcription, splicing, and translation. In particular, hnRNP A1 and A2/B1 are the most abundant proteins of the 40S ribonucleoprotein complex (see Thibault, 2021). hnRNP A/B are highly expressed in central nervous system (CNS) tissue. While hnRNP A/B generally localize to the nucleus, under stressed conditions hnRNP A/B translocate to the cytoplasm, forming RNA:protein granules (e.g., stress granules, (SG)). SGs and markers thereof have been found to be associated with a variety of neurodegenerative disease and pathologies marked by neuronal cell death. There remains a need for compositions and methods that reduce neuronal loss during neuronal injury, including to stop or slow progression of neurodegenerative diseases. Moreover, there remains a need for neuroprotective agents that target the hnRNP family of proteins and their role in neurol cell death. DB1/ 148791292.1 2 4879-8182-7022, v.1 SUMMARY OF THE DISCLOSURE In accordance with the present disclosure, there is provided a method for neuroprotection, comprising administering to a subject in need thereof an effective amount of an agent that binds to cytoplasmic heterogeneous nuclear ribonucleoprotein (hnRNP) in neurons, to thereby inhibit neuronal cell death. The hnRNP may comprise hnRNP A/B or may comprise hnRNP A2/B1, hnRNP C1/C2, hnRNP A1, hnRNP A3, and hnRNP D0. In embodiments, the hnRNP localizes in SGs. TGM-010, as described herein, is an antibody that binds neurons, and specifically interacts with cytoplasmic hnRNP targets. It is believed that TGM-010 functions to bind hnRNPs and prevent them from contributing to the SG, or removing them from the SG, reducing SG composition, size, and formation. Accordingly, the agent may be TGM-010 or an antigen-binding fragment or portion thereof, or another agent with similar hnRNP- binding properties, such as an agent that competes with the binding of TGM-010 to said hnRNP in an in vitro binding assay. The agent may be an antibody or antigen binding fragment thereof, including a monoclonal antibody (which may be a human antibody), a single chain variable fragment (scFv), or a single chain antibody. In some embodiments, the agent is selected from a Fab, a Fab', and a F(ab')2. The agent may be an IgG monoclonal antibody, which can be modified for improved pharmacodynamics (e.g., circulatory half-life), blood brain barrier (BBB) penetration, or neuronal entry. In embodiments, the agent may further comprise a cell penetrating peptide to enhance cellular internalization. The agent may be encapsulated or conjugated to the surface of liposomes, lipid nanoparticles, or polymeric particles. In embodiments, the agent is a polypeptide (e.g., scFv) that is expressed in neurons via gene or mRNA delivery. In embodiments, the agent internalizes into neurons and reduces intracellular SGs that contribute to neuronal apoptosis. The subject in need may have a neurodegenerative disease, such as Multiple Sclerosis (MS), clinically isolated syndrome (CIS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), Schizophrenia, Progressive supranuclear palsy, Friedreich ataxia, Lewy body disease, or Spinal muscular atrophy, or may have traumatic injury. In embodiments, the subject may be experiencing or recovering from ischemic or DB1/ 148791292.1 3 4879-8182-7022, v.1 hemorrhagic stroke, traumatic brain injury, or spinal injury. In embodiments, the subject is at risk to develop a neurodegenerative disease. In embodiments, the agent is administered systemically. The agent may be administered parenterally, such as by subcutaneous administration, intravenous administration, or intrathecal administration, among other routes. In embodiments, the agent may be administered intranasally to facilitate administration to the brain. The agent may be administered in a single dose, or a plurality of doses that are administered at a frequency of from about daily to about monthly, such as about daily, about twice weekly, about weekly, about twice monthly (e.g., once every two weeks), or about monthly. The therapy may be accompanied by methods to enhance blood brain barrier penetration including high frequency ultrasound. Therapy may be initiated upon symptoms of neuronal injury or attack of a neurodegenerative disease, or during or after recovery from the injury or attack. In embodiments, therapy is initiated for a subject at risk of neuronal injury or neurodegenerative disease, such as a subject considered at risk of developing a neurodegenerative disease. In aspects and embodiments, the disclosure provides compositions and methods for neuroprotection involving an antibody (or use thereof) having the following complementarity determining regions (CDRs) or an antigen-binding portion thereof: heavy chain CDR1 of SEQ ID NO: 2, heavy chain CDR2 of SEQ ID NO: 3, heavy chain CDR3 of SEQ ID NO: 4, light chain CDR1 of SEQ ID NO: 6, light chain CDR2 of SEQ ID NO: 7, and light chain CDR3 of SEQ ID NO: 8. The antibody may be an IgG antibody, which can be modified for improved pharmacodynamics (e.g., circulatory half-life), blood brain barrier (BBB) penetration, or neuronal entry. The antibody may be a scFv. The antibody or antigen binding fragment thereof may further comprise a cell penetrating peptide to improve cell entry. The antibody or antigen binding fragment thereof may be encapsulated or conjugated to the surface of liposomes, lipid nanoparticles, or polymeric particles. The antibody or antigen binding fragment thereof may be expressed in neurons via gene or mRNA delivery. The composition may be administered to subjects having a neurodegenerative disease, such as Multiple Sclerosis (MS), clinically isolated syndrome (CIS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), Schizophrenia, DB1/ 148791292.1 4 4879-8182-7022, v.1 Progressive supranuclear palsy, Friedreich ataxia, Lewy body disease, or Spinal muscular atrophy, or may have an acute or traumatic injury. The subject may be experiencing or recovering from ischemic or hemorrhagic stroke, traumatic brain injury, or spinal injury. In embodiments, the subject is at risk to develop a neurodegenerative disease. The antibody or antigen binding fragment thereof, or gene or mRNA encoding the same, may be administered systemically or parenterally. The antibody or antigen binding fragment thereof may be administered by subcutaneous administration, intravenous administration, or intrathecal administration, for example. The antibody or antigen binding fragment thereof, or gene or mRNA encoding the same, may be administered intranasally. The agent may be administered once or in a plurality of doses that are administered at a frequency of from about daily to about monthly, such as about daily, about twice weekly, about weekly, about twice monthly (e.g., once every two weeks), or about monthly. The therapy may be accompanied by methods to enhance blood brain barrier penetration including high frequency ultrasound. Therapy may be initiated upon suspicion of neurodegenerative disease diagnosis in the future, symptoms of neuronal injury or attack of neurodegenerative disease, or during or after recovery from the injury or attack. In aspects and embodiments, the disclosure provides a monoclonal antibody (and uses thereof in methods of neuroprotection), where the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 5, as well as variants thereof. The antibody may be an IgG antibody (e.g., IgG1), which can be modified for improved pharmacodynamics (e.g., circulatory half-life), blood brain barrier (BBB) penetration, or neuronal entry. In embodiments, the monoclonal antibody may further comprise a moiety that enhances cell penetration, such as a cell penetrating peptide. In aspects and embodiments, the disclosure provides an antigen binding fragment of an antibody (and uses thereof in methods of neuroprotection), wherein the antigen binding fragment comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain comprising the amino acid sequence of SEQ ID NO: 5. The fragment may be a scFv or a F(ab')2. The fragment may further comprise a moiety that enhances cell penetration, such as a cell penetrating peptide. DB1/ 148791292.1 5 4879-8182-7022, v.1 In aspects and embodiments, the disclosure provides a polynucleotide encoding the antibody or antigen binding fragment as described herein (and uses thereof in methods for neuroprotection). Also provided are pharmaceutical compositions comprising an effective amount of an antibody as described herein, an antigen binding fragment as described herein, or the polynucleotide as described herein, and a pharmaceutically acceptable carrier. Such pharmaceutical compositions are useful in methods for neuroprotection in a subject in need thereof. Also provided is a method for making a pharmaceutical composition for providing neuroprotection, comprising (a) identifying an agent that binds to cytoplasmic hnRNP in stress granules (or an epitope thereof, such as an RRM2 epitope), (b) evaluating whether the agent inhibits apoptosis in neurons in vitro, and/or determining whether the agent reduces or ameliorates symptoms of disease (e.g., neurodegenerative disease or neuronal loss) in an animal model. If the agent inhibits apoptosis in neurons and/or reduces or ameliorates symptoms of disease in an animal model, the agent is formulated for delivery to a human or animal. The hnRNP may comprise hnRNP A/B subgroups, and an agent may be selected that binds an RRM2 epitope thereof. In embodiments, the hnRNP may also comprise hnRNP A2/B1, hnRNP C1/C2, hnRNP A1, hnRNP A3, and hnRNP D0, and an agent may be selected that binds an RRM2 epitope thereof. The agent may be formulated for systemic or parenteral administration or for intranasal administration. The agent may be an antibody or antigen binding fragment thereof, or may be a peptide, an aptamer, an adnectin, or DARPin. The agent may be selected from a single- domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody, single chain variable fragment (scFv), a shark heavy-chain-only antibody (VNAR), a Tetranectin, an Affibody, a Transbody, an Anticalin, an Affilin, a Microbody, a phylomer, a stradobody, a fynomer, an avimer, a triomab, a Fv, a Fab, a Fab', and a F(ab')2. The agent may be a monoclonal antibody. The agent may be a scFv. The agent may be a F(ab')2. The agent may compete with the binding of TGM-010 to said hnRNP or RRM2 epitope using an in vitro binding assay. In embodiments, the agent is a TGM- 010 variant. DB1/ 148791292.1 6 4879-8182-7022, v.1 The agent may be a polypeptide that is delivered to the animal or human as a nucleic acid encoding the polypeptide, which is expressed in neurons via gene or mRNA delivery. Gene or mRNA delivery can be by lipid nanoparticle or viral vector. Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DB1/ 148791292.1 7 4879-8182-7022, v.1 BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1. Binding of TGM-010 in mouse brain tissue by immunofluorescence staining. FIG.2. Binding of TGM-010 in mouse corticohippocampal neurons and human motor neurons by immunofluorescence staining. FIG. 3. Binding of TGM-010 (top) and a control antibody (bottom) in primary mouse neuronal progenitor cells as shown by flow cytometry. FIG. 4. The binding capacities of TGM-010 in ALS-derived (C9orf72) human cortical neurons. FIG.5. Randomized antibody administration of TGM-010 to mice (EAE model). Figure shows cumulative EAE score data. FIG.6. Randomized antibody administration of TGM-010 to mice (Experimental Autoimmune Encephalitis, “EAE”, model) over a 2-week period by intraperitoneal (IP) injection beginning 1 day after recovery from the initial attack. Figure shows cumulative EAE score data. FIG. 7. Identification of potential targets for TGM-010 using a human protein array. FIG. 8. Immunoprecipitation studies with TGM-010 (TGM10) or control antibody JRR67 against Sy5y cell lysates as shown in SDS-PAGE gels. Cell lysate proteins were prepared and used for immunoprecipitation. FIG.9. Mass Spectrometry analysis of a trypsin digested 37/40 kDa doublet, 100 kDa band and 50 kDa doublet from FIG.8. FIG.10. Antibody cytotoxicity analysis of TGM-010 in comparison to a positive control antibody “DS14.” FIG. 11A. RRM2 alignment from hnRNP A2B1 (SEQ ID NO: 9), A1 (SEQ ID NO: 10), and AB (SEQ ID NO: 11). Bottom shows position of Peptide 1-8 (SEQ ID NO: 12), Peptide 1-9 (SEQ ID NO: 13), Peptide 1-10 (SEQ ID NO: 14), Peptide 1-11 (SEQ ID NO: 15); Peptide 3-8 (SEQ ID NO: 16), Peptide 3-9 (SEQ ID NO: 17), Peptide 3-10 (SEQ ID NO: 18), Peptide 3-11 (SEQ ID NO: 19), Peptide 6-11 (SEQ ID NO: 20), DB1/ 148791292.1 8 4879-8182-7022, v.1 Peptide 6-12 (SEQ ID NO: 21), Peptide 6-13 (SEQ ID NO: 22), and Peptide 6-14 (SEQ ID NO: 23). FIG.11B. ELISA results showing specificity for an RRM2 epitope. FIG. 12A. Confocal microscope fluorescence imaging of Sy5y human neuroblastoma cells demonstrating internalization of TGM-010 (scale bar = 20 μm). FIG.12B. Time-resolved quantification of TGM-010 internalization measured as mean fluorescence intensity in human neuroblastoma cells. FIG. 12C. Confocal microscope fluorescence imaging of mouse cortical neurons demonstrating cross-species cell internalization of TGM-010 (scale bar = 20 μm). FIG.12D. Time-resolved quantification of TGM-010 internalization measured as mean fluorescence intensity in mouse cortical neurons. FIG.13A. Schematic representation of pepsin cleavage of full-length IgG TGM- 010 to remove the Fc domain, where the resultant F(ab’)2 product was isolated for evaluating Fc-independent cellular internalization. FIG. 13B. Control antibody (e.g., JRR67) staining of Sy5y human neuroblastoma cells. FIG. 13C. Comparison of full- length (FL) TGM-010 and F(ab’)2 TGM-010 staining of Sy5y human neuroblastoma cells demonstrating that staining is Fc domain-independent. FIG. 14. TGM-010 neuroprotective effect in Sy5y neuroblastoma cells under cellular stress using a heat-shock neurotoxicity assay as measured by confocal microscopy and Caspase-3/7 fluorogenic substrate for cell lysis detection. Neuroprotection effect was compared to a neurotoxic control antibody, “DS14.” FIG.15A. Fluorescence confocal microscopy imaging of mouse cortical neurons under heat-induced stress granule (SG) formation. SG formation was visualized using stress granule assembly factor 1 (G3BP1) staining. FIG. 15B. Negative control non- specific antibody (JRR67) localization in mouse cortical neurons with heat stress induced SG formation visualized by fluorescence imaging. FIG. 15C. TGM-010 colocalization with stress granule condensation in heat stressed mouse cortical neurons visualized by fluorescence imaging. FIG.15D. Quantification of SG colocalization. FIG. 16A. Neuroprotective effects of TGM-010 demonstrated in an Experimental Autoimmune Encephalitis (EAE) mouse model. EAE was induced in SJL/j female mice by immunization with residues 139-151 of myelin proteolipid protein DB1/ 148791292.1 9 4879-8182-7022, v.1 (PLP_139-151). Mice with confirmed recovery from a first demyelination attack (n = 28) were blindly randomized to receive TGM-010 (5 µg) or a non-specific control antibody by intracerebroventricular (ICV) administration to the brain. Mice were scored for EAE severity. FIG. 16B. Subsequent blinded, EAE in vivo study performed in mice (n = 26) confirm neuroprotective effects of TGM-010 using systemic intraperitoneal (IP) administration. FIG. 17A. Quantification of TGM-010 staining in neurons compared to control antibody JRR67 with a statistically significant level of TGM-010 staining compared to JRR67. FIG.17B. Labeling of brain sections from the front, middle and end of the mouse brain Cortex Layer 1 at 24 hrs after drug administration, with strong staining of TGM- 010 observed in all parts of the cortex. FIG. 18. Time-resolved quantification of TGM-010 internalization into ALS- derived human cortical neurons measured as mean fluorescence intensity in human cortical neurons. DB1/ 148791292.1 10 4879-8182-7022, v.1 DETAILED DESCRIPTION In various embodiments, the present disclosure provides compositions and methods for providing neuroprotection in a subject in need thereof, including for use in treating neurodegenerative diseases and traumatic brain or spinal injuries. In some embodiments, the disclosure provides agents that bind to cytoplasmic heterogeneous nuclear ribonucleoprotein (hnRNP) in neurons, including hnRNPs involved in SG formation. hnRNP particles are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of hnRNPs bound to pre-mRNA serves as a signal that the pre-mRNA is not yet fully processed and therefore not ready for export to the cytoplasm. After splicing has occurred, hnRNPs remain bound to spliced introns and target them for degradation. hnRNPs are also integral to the 40S subunit of the ribosome and therefore important for the translation of mRNA in the cytoplasm. hnRNPs contain nuclear localization sequences (NLS) and are therefore found mainly in the nucleus, although some hnRNPs shuttle between the cytoplasm and nucleus. There are approximately 20 major hnRNPs (hnRNP A1 to hnRNP U), and the location and function of each member in various cell types are distinct. Several structural domains are shared between different family members. See Geuens T, et al., “The hnRNP family: insights into their roles in health and disease,” Hum Genet (2016) 135:851-867. The hnRNP A/B subgroup includes four gene products, A1, A2/B1, A3, and A0, and is involved in mRNA translation and splicing, and is a component of 40S hnRNP complexes. hnRNP A2/B1 plays an important role in oligodendrocytic and neuronal mRNA trafficking, and is also important for the correct localization of transcripts containing an A2 response element (A2RE) or A2RE-like sequences, such as the myelin basic protein (MBP) or Ca2+/calmodulin-dependent protein kinase II (CaMKII), activity-regulated cytoskeleton-associated protein (Arc) and neurogranin (NRGN) mRNA. hnRNP A1 has been reported to localize to Stress Granules (SG) during the cellular stress response. See Guil S, et al., “hnRNP A1 Relocalization to the Stress Granules Reflects a Role in the Stress Response,” Mol Cell Biol (2006) (15):5744-58. Post-transcriptional regulation of gene expression upon various stimuli, such as heat DB1/ 148791292.1 11 4879-8182-7022, v.1 shock, oxidative stress, and viral infection, is vital for cell survival. SGs represent cytoplasmic sites in which translationally stalled mRNAs and numerous RNA binding proteins are nucleated during the stress response, and this event allows the cell to reprogram gene expression. Thus, SGs allow mRNA triage take place to direct mRNAs to be degraded or translated. SGs and their dysregulation are believed to play a role in the pathophysiology of neurodegeneration. For example, cytoplasmic localization of hnRNPs and their association with stress granules (SG) are markers of neurodegeneration in MS tissues and may contribute to neurodegeneration in EAE and MS. See Salapa HE, et al, “Dysfunctional RNA-binding protein biology and neurodegeneration in experimental autoimmune encephalomyelitis in female mice.” J Neurosci Res 2020 Apr; 98(4):704-717. Abnormally persistent SG formation is pathogenic to cells, triggering apoptosis. The cytotoxic effects of SGs have been observed with anti-cancer agents. For example, the pan-kinase inhibitor, sorafenib, induces SG formation in hepatocarcinoma cells for cytotoxic effect, and additionally, 5-fluorouracil and vinca alkaloids elicit general anticancer effects associated with increased SG formation. Numerous neurodegenerative-associated mutations have been identified in hnRNPs known to associate with SGs that contribute to diseases, such as ALS, FTLD, and neuromuscular myopathies. See Protter and Parker, “Principles and Properties of Stress Granules,” Trends Cell Biol. Vol. 26, No. 9, (2016). Patient biopsies have contained aggregates of SG components mixed with sequestered RNA, where a pathogenic model has emerged indicating that SG formation leads to a series of events that ultimately result in cell death. In accordance with this disclosure, without intending to be bound by theory, it is believed that the human antibody TGM-010 disrupts hnRNP-SG interactions and/or sequestration in neurons and inhibits induction of neuronal apoptosis mediated by a mechanism involving SG biology. In embodiments, and without intending to be bound by theory, TGM-010 functions to bind hnRNPs and prevent them from contributing to the SG, or removing them from the SG, reducing SG composition, size, and formation. Thus, without intending to be bound by theory, TGM-010 antibodies and antigen-binding fragments thereof function to bind hnRNPs and to act as selective inhibitors of SG pathway-based neuronal cell death, and are believed to treat and/or slow the progression of diseases marked by neuron loss via these pathways. In some embodiments, TGM-010 and other modalities for inhibiting hnRNP-SG interactions are candidates for DB1/ 148791292.1 12 4879-8182-7022, v.1 neuroprotection in various neurodegenerative conditions including but not limited to Multiple Sclerosis (MS), stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease, among others. In some embodiments, TGM-010 and other modalities for inhibiting hnRNP-SG interactions are candidates for treating brain or spinal injuries including stroke, TBI, and spinal injury. “TGM-010” refers to the antibody having the following complementarity determining regions (CDRs) as well as antigen-binding portions or fragments thereof: heavy chain CDR1 of SEQ ID NO: 2, heavy chain CDR2 of SEQ ID NO: 3, heavy chain CDR3 of SEQ ID NO: 4, light chain CDR1 of SEQ ID NO: 6, light chain CDR2 of SEQ ID NO: 7, and light chain CDR3 of SEQ ID NO: 8. TGM-010 can comprise a heavy chain variable sequence comprising SEQ ID NO: 1 and a light chain sequence comprising SEQ ID NO: 5. In some embodiments, the TGM-010 antibody has cell penetration activity, e.g., allowing binding to cytoplasmic targets such as hnRNPs. In one aspect, the disclosure provides a method for neuroprotection. The method comprises administering to a subject in need thereof an effective amount of an agent that binds to cytoplasmic heterogeneous nuclear ribonucleoprotein (hnRNP) in neurons, to thereby inhibit neuronal cell death (including but not limited to neuronal apoptosis). In embodiments, the agent comprises TGM-010 or an antigen-binding portion or fragment thereof. According to the present disclosure, TGM-010 is shown to bind to an antigen in neurons, demonstrates neuroprotection in the EAE model, and shown to specifically bind to hnRNPs, including hnRNPs in SGs. Thus, the present disclosure identifies cytoplasmic hnRNPs as targets for neuroprotection, e.g., during abnormal or chronic stress response. In some embodiments, TGM-010 antibodies and antibody fragments thereof and variants thereof are capable of penetrating neurons in an Fc-independent manner where they bind hnRNP intracellularly. The present disclosure further identifies TGM-010 and its derivatives (including fragments and antigen-binding portions thereof) as candidate neuroprotective agents. In embodiments, the agent is an antibody or antigen-binding fragment or portion thereof that comprises a heavy chain variable domain comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 1, and a light chain variable domain comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 5. In embodiments, the antibody or antigen-binding fragment or portion thereof DB1/ 148791292.1 13 4879-8182-7022, v.1 comprises the six CDR sequences of TGM-010. In embodiments, the antibody or antigen-binding fragment or portion thereof comprises a heavy chain variable domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 1, and a light chain variable domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 5. In embodiments, the antibody or antigen- binding fragment or portion thereof comprises a heavy chain variable domain comprising an amino acid sequence having at least 98% sequence identity to SEQ ID NO: 1, and a light chain variable domain comprising an amino acid sequence having at least 98% sequence identity to SEQ ID NO: 5. In embodiments, the antibody or antigen-binding fragment or portion thereof comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 5. In various embodiments, the hnRNP targeted by the agent (e.g., a binding agent) comprises hnRNP A/B (UniProtKB - Q99729). hnRNP A/B is localized in cytoplasmic mRNP granules containing untranslated mRNAs. ALS type 20 is caused by mutations in the hnRNPA1 gene. Krebs BB and De Mesquita JF, “Amyotrophic Lateral Sclerosis Type 20 – In Silico Analysis and Molecular Dynamics Simulation of hnRNPA1.” PLoS One (2016 Jul 14;11(7):e0158939). Autoantibodies against these proteins have also been detected. Dangli A, et al. “Recognition of subsets of the mammalian A/B-type core heterogeneous nuclear ribonucleoprotein polypeptides by novel autoantibodies.” Biochem. J. 320, 761-767. Antibodies against hnRNP A1 have been described as contributing to neuronal cell loss in an animal model of multiple sclerosis (MS). See Libner CD et al., J Comp Neurol 2020 Jul;528(10):1704-1724. Cytoplasmic localization of hnRNPs and their association with stress granules (SG) are markers of neurodegeneration in MS tissues and may contribute to neurodegeneration. See Salapa HE, et al. “Dysfunctional RNA-binding protein biology and neurodegeneration in experimental autoimmune encephalomyelitis in female mice.” J Neurosci Res 2020 Apr;98(4):704-717. Cytoplasmic hnRNP A1 was reported to be substantially higher in EAE mice as compared to naïve mice, and directly correlated with neuronal cell death and clinical score in animal models. In some embodiments, the hnRNP targeted by the agent comprises hnRNP A/B (UniProtKB - Q99729), hnRNP A2/B1 (UniProtKB - P22626), hnRNP C1/C2 (UniProtKB - P07910), hnRNP A1 (UniProtKB - P09651), hnRNP A3 (UniProtKB - DB1/ 148791292.1 14 4879-8182-7022, v.1 P51991), or hnRNP D0 (UniProtKB - Q14103). In some embodiments, the agent binds any hnRNP protein family member that comprises an RNA recognition motif (RRM) (e.g., RRM2), including for example, hnRNP A, hnRNP A/B, hnRNP C, hnRNP G, hnRNP I, hnRNP L, hnRNP M, hnRNP P, hnRNP Q, and/or hnRNP R. See Geuens et al., 2016. For example and as described herein, in embodiments the antibodies and agents bind to hnRNP A1 including peptides comprising the amino acid sequence of SEQ ID NO: 24, SEQ ID NO: 16, and/or SEQ ID NO: 19; and/or hnRNP A/B including peptides comprising the amino acid sequence of SEQ ID NO: 25, SEQ ID NO: 20, and/or SEQ ID NO: 23. SEQ ID NOS: 24 and 25 have about 40% sequence identity to one another. RRM2 epitopes of antibodies and agents described herein are summarized in Table 1. In embodiments, these RRM2 epitopes compete for hnRNP binding by the antibodies and agents described herein. Table 1. hnRNP protein RRM2 domain epitope regions. All amino acid numbering is relative to the canonical UniProtKB sequences. hnRNP protein Epitope amino acid sequence G DB1/ 148791292.1 15 4879-8182-7022, v.1 (SEQ ID NO: 20) The agent may be a binding agent that is optionally an antibody or an antigen- binding portion thereof, or an antibody mimetic. The term “antibody” includes antibodies comprising heavy and light chains, or an antigen binding fragment or an antigen binding portion thereof. In some embodiments, the antibody is a human antibody. Antibody fragments include F(ab')2, Fab, Fab', Fv, and Fd fragments, as well as single domain antibodies and single-chain antibodies. Other antibody platforms that find use include nanobodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v- NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology, 23(9):1126- 1136 (2005)). In some embodiments, the binding agent is a peptide, an aptamer, an adnectin, or DARPin. In some embodiments, the agent is selected from a single-domain antibody, a recombinant heavy-chain-only antibody (VHH) (“nanobody”), a single-chain antibody, single chain variable fragment (scFv), a shark heavy-chain-only antibody (VNAR), a Tetranectin, an Affibody, a Transbody, an Anticalin, an Affilin, a Microbody, a phylomer, a stradobody, a fynomer, an avimer, or a triomab. Various binding agent platforms that may be used are described in the following U.S. Patents and U.S. published patent applications: U.S. 7,417,130, U.S. 2004/132094, U.S. 5,831,012, U.S. 2004/023334, U.S. 7,250,297, U.S. 6,818,418, U.S. 2004/209243, U.S. 7,838,629, U.S. 7,186,524, U.S. 6,004,746, U.S. 5,475,096, U.S. 2004/146938, U.S. 2004/157209, U.S. 6,994,982, U.S. 6,794,144, U.S. 2010/239633, U.S. Pat. No. 7,803,907, U.S. 2010/119446, and U.S. 7,166,697, the contents of which are hereby incorporated by reference in their entireties. See also, Storz MAbs. 2011 May-June; 3(3): 310-317. In embodiments, the binding agent is selected according to this disclosure, as one that binds the hnRNP RRM2 epitopes described herein. In embodiments, the binding agent binds to the hnRNP target (or epitope described herein) with a dissociation constant (K_D) of less than about 1 µM, or a KD of less than about 100 nM, or a KD of less than about 10 nM, or a K_D of less than about 1 nM, which can be determined using known methods, such as ELISA, surface plasmon resonance (SPR, e.g., BIACORE assay), and biolayer interferometry (BLI). DB1/ 148791292.1 16 4879-8182-7022, v.1 In some embodiments, the agent is or is derived from a VH4 antibody (e.g., a human antibody) that satisfies the antibody gene signature (AGS) codons described in U.S. Patent 8,394,583, which is hereby incorporated by reference. In some embodiments, the agent is an antibody that binds selectively to neurons or selectively to neurons and astrocytes. Exemplary antibodies cloned from CSF B cells isolated from patients having clinically isolated syndrome optic neuritis (ON-CIS), clinically isolated syndrome transverse myelitis (TM-CIS) or clinically definite MS, and which contain AGS codons, are described in U.S. Patent Publication 2021/0214423, which is hereby incorporated by reference in its entirety. In some embodiments, the agent is TGM-010, or a derivative or antigen binding fragment thereof, as described herein. TGM-010 antibody can comprise the heavy chain variable sequence of SEQ ID NO: 1 and the light chain sequence of SEQ ID NO: 5. In some embodiments, the agent blocks or competes with the binding of TGM- 010 to the hnRNP target (e.g., hnRNP A1, hnRNP A/B, or hnRNPA2/B1, or RRM2 epitope thereof) according to an in vitro binding assay. Any of the known binding assays and instrumentations can be used to determine whether the agent and TGM-010 bind to the same epitope or an overlapping epitope. For example, the agent may bind the selected hnRNP (or RRM2 epitope thereof) with an affinity of less than or equal to 1 x 10^-7 M, or less than or equal to 1 x 10^-8 M, less than or equal to 1 x 10^-9 M, less than or equal to 1 x 10^-10 M, less than or equal to 1 x 10^-11 M, or less than or equal to 1 x 10^-12 M. Binding affinity as well as binding competition with TGM-010 may be determined by an ELISA or surface plasmon resonance (SPR, e.g., BIACORE assay), biolayer interferometry (BLI), as well as other techniques known in the art. In exemplary embodiments, the agent is a human or humanized monoclonal antibody, that is, comprising heavy and light chains, including but not limited to TGM- 010 and variants thereof. The antibody can be of any isotype, such as IgG, IgD, IgA, or IgM isotype. In some embodiments, the antibody is an IgG antibody (e.g., IgG1, IgG2, IgG3, or IgG4). In some embodiments, the antibody is IgG4 isotype. IgG4 is a poor inducer of Fc-mediated effector functions, and therefore is preferable in some embodiments. In embodiments, the antibody is IgG1 isotype, which is optionally modified to reduce or eliminate one or more effector functions and/or to increase DB1/ 148791292.1 17 4879-8182-7022, v.1 circulatory half-life and/or to increase penetration of the BBB and/or retention in the brain. In some embodiments, the antibody (including but not limited to TGM-010) comprises an Fc domain (e.g., IgG1, IgG2, or IgG4 isotype). In some embodiments, one or more amino acid substitutions, insertions, or deletions in the Fc domain attenuate Fc- mediated effector functions, and/or improves pharmacokinetic (PK) and/or pharmacodynamic (PD) properties. Among these properties include increased half-life (e.g., circulating or serum half-life), improved blood-brain barrier (BBB) penetration, and/or reduced off-target or non-specific uptake. In various embodiments, the antibodies described herein, and antigen-binding fragments thereof, do not appreciably accumulate (relative to neurons in the brain) in cells comprising the BBB, including endothelial cells (ECs), pericytes (PCs), capillary basement membrane, and astrocyte end-feet. In some embodiments, the agent (including but not limited to TGM-010) does not comprise an Fc domain. For example, the agent can be F(ab')2, Fab, Fab', Fv, or Fd fragment. In some embodiments, the agent is a single chain variable fragment (scFv), which can be a scFv of TGM-010. scFv is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of the antibody, connected with a short linker peptide of ten to about 25 amino acids. These smaller formats can be engineered for increased tissue or cell penetration in some embodiments, as well as for non-parenteral administration routes such as intranasal, which may allow for better CNS penetration. In some embodiments, the antigen-binding portion (e.g., scFv or other antibody mimetic) is multimerized to enhance antigen binding. In some embodiments, the agent is F(ab´)2 (including but not limited to a TGM-010 F(ab´)₂). In some embodiments, the agent is modified or formulated to enhance CNS delivery and/or intracellular delivery of the binding agent. For example, the agent can be modified or formulated to enhance delivery through the blood-brain barrier (BBB). One of the most selective barriers surrounding the CNS is the BBB formed by endothelial cells with tight junctions (TJ) and adherence junctions (AJ). The BBB excludes large molecules. Further, the FcRn expressed in the BBB and the blood–cerebrospinal fluid (CSF) barrier contributes to elimination of full-length IgGs from the brain. Thus, in some embodiments, smaller binding agents, such as nanobodies and antibody derivatives without an Fc domain (e.g., as described herein), are used for better CNS penetration and DB1/ 148791292.1 18 4879-8182-7022, v.1 half-life. In other embodiments, the binding agent comprises a fusion, conjugation, or particle formulation with a ligand that facilitates active transport. The active transport of molecules, such as proteins and peptides, through the BBB is mediated by three mechanisms: adsorptive-mediated transcytosis (AMT), transporter-mediated transcytosis, and receptor-mediated endocytosis (RMT). For example, the human insulin receptor is known to shuttle insulin over the BBB by transcytosis. Antibodies binding this receptor have been shown to be shuttled to the CNS. Accordingly, antibodies or antigen-binding portions thereof against receptors at the BBB, such as the insulin or low- density lipoprotein (LDL) receptors, can be presented by liposomes or other nano/microparticles to target and guide an encapsulated binding agent past the BBB. In some embodiments, paratopes or binding moieties for facilitating BBB transport or for neuronal targeting replace the Fc domain of an antibody or are fused to the Fc domain (or portion thereof) (e.g., of TGM-010 or variant thereof). In some embodiments, the agent is modified or formulated to improve intracellular delivery. Potential approaches to improve cellular delivery include direct intracellular expression, the use of protein-transduction domains or their mimics, and the use of various nanoparticle carriers (including inorganic nanoparticles, liposomes, polymeric particles, and viral envelopes). In some embodiments, the agent comprises a fusion to a protein transduction domain (i.e., a cell penetrating peptide or CPP). Exemplary CPP fusions comprise HIV 1 trans-activating (TAT) protein, or peptides derived therefrom. In some embodiments, the agent is a cell penetrating TransMabs (Muller et al., 2005) or transbody. Muller, S., et al. (2005). “TransMabs: cell-penetrating antibodies, the next generation.” Expert Opin. Biol. Ther.5, 237–241. Also see Slastnikoval AV, et al., “Targeted Intracellular Delivery of Antibodies: The State of the Art,” Front. Pharmacol., 24 October 2018. One or more cell penetrating peptides can be engineered into or on the ends of antibody sequences (including but not limited to TGM-010 and its variants), to improve cell penetration. In various embodiments, the CPP is fused or conjugated at the N- terminus or C-terminus of a heavy chain and/or a light chain, or the N- and/or C-terminus of a scFv or single chain antibody. In some embodiments, one or more CPPs are fused directly before or after an antibody hinge region. Exemplary CPPs include Pep1 (KETWWETWWTEWSQPKKKRKV, SEQ ID NO: 27), TAT (YGKKRRQRRR, SEQ DB1/ 148791292.1 19 4879-8182-7022, v.1 ID NO: 28), PEPth (VKKKKIKAEIKI, SEQ ID NO: 29), aurein 1,2 (GLFDIIKKIAESF, SEQ ID NO: 30), MTS (KGEGAAVLLPVLLAAPG, SEQ ID NO: 31), and GFWFG (SEQ ID NO: 32), and derivatives thereof. See Gaston J, et al., “Intracellular delivery of therapeutic antibodies into specific cells using antibody-peptide fusions.” Scientific Reports (2019) 9:18688. In various embodiments, the CCP is any of the known TAT derivatives. In some embodiments, the antibody or agent (including but not limited to TGM- 010) is conjugated to a phosphorothioate (PS) DNA oligonucleotide to enhance cell penetration. See Herrmann A., et al. “An effective cell-penetrating antibody delivery platform,” JCI Insight 2019;4(14):e127474. In some embodiments, the agent is encapsulated by or conjugated to the surface of inorganic particles, liposomes, lipid nanoparticles, or polymeric particles. In some embodiments, the polymeric particles comprise poly(lactic acid)-polyethylene glycol (PLA-PEG) or poly(lactic acid-co-glycolic acid)-polyethylene glycol (PLGA-PEG) copolymers and one or more polypeptide ligands conjugated to PEG through a functional group, such as a thioether bond. In such embodiments, a neuronal targeting agent can be conjugated to PEG as a targeting ligand. Particles can be sized to improve penetration through the BBB, such as a size of less than about 200 nm or a size of less than about 150 nm, or a size less than about 100 nm. Alternative polymers that can be used include cyclodextrin-containing polymers, cationic cyclodextrin-containing polymers, poly(D,L-lactic acid-co-glycolic acid) (PLGA), poly(caprolactone) (PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(L-lactic acid- co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(L-Lactide) (PLLA), PLGA-b-poly(ethylene glycol)-PLGA (PLGA-bPEG-PLGA), PLLA-bPEG-PLLA, PLGA-PEG-maieimide (PLGA-PEG-mal), PLA-PEG-maleimide, poly(D,L-lactide-co- caprolactone), poly(D,L-Lactide-co-caprolactone-co-glycolide), poly(D,L-lactide-co- PEO-co-D,L-lactide), poly(D,L-lactide-co-PPO.about.co-D,L-lactide), polyalkylcyanoacralate, polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA), polyethyleneglycol, poly-L-glutamic acid, poly(hydroxy acids), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers), polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene DB1/ 148791292.1 20 4879-8182-7022, v.1 glycols such as poly(ethylene glycol) (PEG), polyalkylene oxides (PEO), polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters such as poly(vinyl acetate), polyvinyl haiides such as poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS), polyurethanes, derivatized celluloses such as alkyl celluloses, hydroxy alkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, hydroxypropylcellulose, carboxymethylcellulose, polymers of acrylic acids, such as polymethylmethacrylate) (P MA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly (isobutyl (meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), polyiisobutyl acrylate), poly(octadecyl acrylate) (poly acrylic acids), and copolymers and mixtures thereof, polydioxanone and its copolymers, polyhydroxyalkanoates, polypropylene fumarate), polyoxymethylene, poloxamers, poly(ortho)esters, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), trimethylene carbonate, polyvinylpyrrolidone, polyorthoesters, polyphosphazenes, and polyphosphoesters, dendrimers and derivatives thereof, and blends and/or block copolymers of two or more such polymers. In other embodiments, the particles are lipid nanoparticles comprising a PEG- conjugated lipid. Exemplary PEG lipids are selected from one or more of a PEG- modified phosphatidylethanolamine, a PEG- modified phosphatidic acid, a PEG- modified ceramide, a PEG-modified dialkylamine, a PEG- modified diacylglycerol, and a PEG-modified dialkylglycerol. A PEG lipid may be selected from PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, PEG-Cholesterol, PEG tocopherol, or a PEG- DSPE lipid. In some embodiments, the lipid nanoparticles further comprise a cationic or ionizable lipid, a neutral lipid or phospholipid, and a structural lipid. Exemplary structural lipids can be selected from one or more of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, and tocopherols (e.g., alpha tocopherol). In some embodiments, the structural lipid is cholesterol. In some embodiments, the LNP comprises one or more phospholipids. Exemplary phospholipids are selected from the group consisting of cardiolipins, sterol modified lipids (modified with a cholesterol moiety attached at the sn-2 carbon of the DB1/ 148791292.1 21 4879-8182-7022, v.1 glycerol backbone), mixed-acyl glycerophospholipids, and symmetrical acyl glycerophospholipids. Head groups for acyl glycerophospholipids include, for example, phosphatidic acid, lysophosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphoinositides, and phosphatidylserine. Exemplary phospholipids are selected from 1,2-dilinoleoyl-sn- glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn- glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3- phosphocholine (18:0 Diether PC), 1-oleoyl—2-cholesterylhemisuccinoyl-sn-glycero-3- phosphocholine (OChemsPC), l-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3- phosphocholine, l,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, l,2-dioleoyl-sn- glycero-3-phosphoethanol amine (DOPE), l,2-diphytanoyl-sn-glycero-3- phosphoethanolamine (ME 16.0 PE), l,2-distearoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinolenoyl-sn-glycero-3- phosphoethanolamine, l,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, l,2- didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, l,2-dioleoyl-sn-glycero-3- phospho-rac-(l -glycerol) sodium salt (DOPG), and sphingomyelin. In some embodiments, the agent is a polypeptide encoded and expressed by one or more nucleic acids. In some embodiments, the nucleic acid is DNA (e.g., a gene or gene cassette) or mRNA. In some embodiments, the polypeptide is expressed in neurons via DNA or mRNA delivery. In some embodiments, the agent is expressed using a neuron-specific promoter, such a synapsin 1 promoter. An exemplary agent to be encoded by the gene or mRNA is a single chain antibody or scFv based on TGM-010, or a derivative thereof as described herein. Gene or mRNA delivery can employ lipid nanoparticles as described above or known gene delivery techniques including viral vectors (e.g., AAV9, lentiviral vectors, etc.). TGM-010 and its variants and other hnRNP-binding agents described herein can be used in methods for treating subject having or at risk of neuronal injury or neurodegenerative disease. In various embodiments, the subject in need has a DB1/ 148791292.1 22 4879-8182-7022, v.1 neurodegenerative disease or traumatic injury to one or more tissues of the central nervous system (CNS). In embodiments, the subject is at risk for developing a neurodegenerative disease, for example, may be deemed asymptomatic or pre- symptomatic. Exemplary neurodegenerative diseases include Multiple Sclerosis (MS), clinically isolated syndrome (CIS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS), Progressive supranuclear palsy, frontotemporal dementia (FTD), Schizophrenia, Friedreich ataxia, Lewy body disease, and Spinal muscular atrophy. In some embodiments, the subject in need is experiencing or recovering from ischemic or hemorrhagic stroke, traumatic brain injury, or spinal injury. In embodiments, the subject is at risk to develop a neurodegenerative disease (e.g., progress from an asymptomatic or pre-symptomatic state). In another aspect, the invention provides an antibody known as TGM-010, variants thereof, and polynucleotides encoding the same, and their use in methods for providing neuroprotection. Exemplary subjects include those suffering from neurodegenerative disease, stroke, or traumatic brain or spinal injury as described herein. In some embodiments, the TGM-010 antibody or variant is an IgG antibody, such as an IgG4 isotype. In embodiments, the TGM-010 antibody or variant thereof is an IgG1 isotype, which can be modified as described herein. In some embodiments, the TGM- 010 antibody does not have an Fc domain. In some embodiments, the TGM-010 antibody derivative or variant is a single chain antibody, scFv, or nanobody, or other antibody format described herein (such as those that lack an Fc domain). In some embodiments, the TGM-010 antibody derivative may further comprise a cell penetrating peptide fusion, as described herein. The penetrating peptide fusion may be fused at the N-terminus and/or C-terminus in embodiments. TGM-010 derivatives (i.e., TGM-010 variants) include antibodies or portions thereof having from one to four (e.g., 1, 2, 3, or 4) amino acid substitutions in the six CDRs (i.e., collectively). Amino acid substitutions in the CDRs can be selected from those that increase binding to the hnRNP target, such as hnRNP A1 or hnRNP A/B (or an RRM2 epitope thereof), or which increase cell penetration, antibody stability, or which enhance neuroprotection (e.g., in vitro or in an animal model, such as a mouse EAE model). In addition, or alternatively, from one to ten amino acid modifications (e.g., DB1/ 148791292.1 23 4879-8182-7022, v.1 substitutions) can be made in TGM-010 framework regions. For example, from one to eight or from one to five amino acid substitutions can be made within the framework regions. Amino acid substitutions in the framework regions can be selected from those that increase binding to the hnRNP target (such as hnRNP A/B or hnRNP A1, or an RRM2 epitope thereof), or which increase cell penetration, improve antibody stability, or which enhance neuroprotection (e.g., in vitro or in an animal model such as a mouse EAE model). In some aspects and embodiments, TGM-010 antibody variants can be employed that bind hnRNP (including an RRM2 epitope as described), including hnRNP targets that form SGs as described herein (e.g., hnRNPA1 and/or hnRNPA/B). In some aspects and embodiments, the method of preparing the variant comprises introducing from one to four (e.g., 1, 2, 3, or 4) amino acid substitutions in one or more of the six CDRs of TGM-010 (i.e., SEQ ID NOs: 2-8), and/or introducing 1, 2, 3, 4, 5, or 6 or more amino acid substitutions, deletions, or insertions within the framework regions of the VH (SEQ ID NO: 1) and/or VL (SEQ ID NO: 5). In embodiments, the TGM-010 variant is prepared or further prepared by modifying the Fc domain, including as described herein. In some embodiments, the method of preparing the variant comprises screening such antibody variants by measuring binding against one or more peptides from a target hnRNP protein. In non-limiting examples, the peptides comprise an RRM2 domain epitope, or at least 20 amino acids of an RRM2 domain epitope, or at least 25 amino acids of an RRM2 domain epitope, or at least 40 amino acids of an RRM2 domain epitope, including an RRM2 epitope of Table 1. In embodiments, the peptide comprises an amino acid sequence of Table 1, or an epitope thereof having at least about 80%, at least about 90%, or at least about 95%, or 100% amino acid sequence identity to one or more regions of at least 20 amino acids, or at least 25 amino acids, or at least 40 amino acids of an amino acid sequence listed in Table 1. In embodiments, the method includes performing one or more techniques for measuring binding between antibody variants and peptides, including for example, ELISA, surface plasmon resonance (SPR, e.g., BIACORE assay), and biolayer interferometry (BLI), as well as other techniques known in the art. In embodiments, the agent (including but not limited to TGM-010, its variants, and/or antigen-binding fragments or portions) or pharmaceutical composition thereof is administered systemically. In embodiments, the agent or composition may be DB1/ 148791292.1 24 4879-8182-7022, v.1 administered parenterally, such as by subcutaneous administration, intravenous administration, intracerebroventricular administration, intraparenchymal administration, or intrathecal administration. In embodiments, the agent or composition may be administered intranasally for more direct administration to the brain. In some embodiments, the agent or composition is administered once. In some embodiments, the agent or composition is administered in a plurality of doses that are administered at a frequency (e.g., administration schedule) of from about daily to about monthly, such as about daily, about twice weekly, about weekly, about twice monthly (e.g., once every two weeks), or about monthly. In embodiments, the administration frequency can be varied. In embodiments, the agent or composition is administered as needed once the subject experiences symptoms of neurodegenerative disease or neuronal injury. For example, therapy may be initiated upon symptoms of neuronal injury or attack of the neurodegenerative disease, or during or after recovery from the injury or attack. In embodiments, the subject is at risk for developing a neurodegenerative disease or at risk of disease progression. In embodiments, the agent or pharmaceutical composition thereof is administered to an asymptomatic or pre-symptomatic subject. In some aspects, the disclosure provides pharmaceutical compositions comprising an effective amount of an antibody or agent of this disclosure, or a polynucleotide of this disclosure, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that can be used in accordance with this disclosure are known in the art. In some embodiments, the pharmaceutically acceptable carrier is a physiological solution, e.g., saline or other pharmacologically acceptable solvent or a buffered solution, and may optionally comprise a surfactant. Pharmaceutically acceptable carriers include water, saline, and glycerol. In some embodiments, the formulation may comprise fixed oils, polyethylene glycol, propylene glycol or other solvents. The pharmaceutical compositions of the disclosure may be conveniently presented in unit dose forms containing a predetermined amount of the active agent of the disclosure per dose. Auto-injectors such as an “injection pen” are spring-loaded syringes designed to deliver a dose of a particular drug. By design, injection pens are easy to use and are intended for self-administration by patients, or administration by untrained personnel. Injection pens are designed to overcome the hesitation associated DB1/ 148791292.1 25 4879-8182-7022, v.1 with self-administration of the needle-based drug delivery device. The injection pen keeps the needle tip shielded prior to injection and also has a passive safety mechanism to prevent accidental firing (injection). Injection depth can be adjustable or fixed and a function for needle shield removal may be incorporated. By pressing a button, the syringe needle is automatically inserted into the subcutaneous tissue and the drug is delivered. Once the injection is completed some injection pens have a visual or audible indication to confirm that the full dose has been delivered. In some embodiments, the injection pen contains from one to ten unit doses or from one to five unit doses. In some embodiments, the unit doses are no more than about 1.5 mL or about 1 mL in volume (whether or not contained or delivered by an injection pen). The injection pen may contain at least four unit doses (e.g., at least about 5, at least about 8, or at least about 10 unit doses). In other aspects, the disclosure provides a method for making a pharmaceutical composition for providing neuroprotection. The method comprises: identifying an agent that binds to cytoplasmic hnRNP in stress granules (including variants of TGM-010 as described), determining whether the agent reduces or inhibits apoptosis in neurons (e.g., stressed neurons), and/or reduces or ameliorates neurodegenerative disease or neuronal loss in an animal model. Where the agent reduces or inhibits apoptosis in neurons (e.g., stressed neurons), and/or reduces or ameliorates neurodegenerative disease or neuronal loss in an animal model, the agent is formulated for delivery to a human or animal. In embodiments, the agent competes for the binding of TGM-010 to the hnRNP or an RRM2 domain epitope thereof (as already described) according to an in vitro binding assay (as already described). In various embodiments, the agent employs a binding agent format described herein including but not limited to antibodies (e.g., scFv or single chain antibody), and may comprise one or more cell penetrating peptides (e.g., as described herein). In various embodiments, the binding agent may bind the selected hnRNP or RRM2 domain epitope (e.g., see Table 1) with an affinity of less than or equal to 1 x 10^-7 M, or less than or equal to 1 x 10^-8 M, less than or equal to 1 x 10^-9 M, less than or equal to 1 x 10^-10 M, or less than or equal to 1 x 10^-11 M, or less than or equal to 1 x 10^-12 M. Binding affinity as well as binding competition with TGM-010 may be determined by an ELISA assay, or surface plasmon resonance (SPR, e.g., BIACORE assay), biolayer interferometry (BLI), as well as other techniques known in the art. DB1/ 148791292.1 26 4879-8182-7022, v.1 In some embodiments, the agent is a VH4 antibody that satisfies the antibody gene signature (AGS) codons described in U.S. Patent 8,394,583, which is hereby incorporated by reference. In some embodiments, the agent is an antibody that binds selectively to neurons or selectively to neurons and astrocytes. In some embodiments, neuroprotection is determined in vitro using a mouse and/or human neuronal cell line (e.g., as described herein), and/or is determined in vivo using a suitable animal model, such as the EAE mouse model. In embodiments, internalization in neurons is quantified in vitro or using an in vivo animal model. In some embodiments, the identified agent is expressed in neurons of a subject, via gene or mRNA delivery as described. In some embodiments, the agent is formulated for parenteral administration or non-parenteral administration as described (e.g., intranasal administration). As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. As used herein, the term “about” means ±10% of an associated numerical value. Embodiments of the disclosure are now described with reference to the following examples. EXAMPLES The following examples are included to demonstrate preferred embodiments. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of embodiments, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. DB1/ 148791292.1 27 4879-8182-7022, v.1 Example 1: TGM-010 Staining Pattern TGM-010 is a recombinant human IgG antibody described in U.S. Patent Publication 20210214423, which is hereby incorporated by reference in its entirety. TGM-010 includes the variable heavy and light chains cloned from a single CSF B cell isolated from a patient having clinically isolated syndrome optic neuritis (ON-CIS). TGM- 010 is a VH4 antibody that satisfies the antibody gene signature (AGS) codons described in U.S. Patent 8,394,583, which is hereby incorporated by reference. The staining characteristics of TGM-010 on mouse brain sections and cell cultures were evaluated. TGM-010 robustly stains injured mouse brain tissue (stroke and EAE brain tissue), as compared to mouse wild type brain tissue using Diaminobenzidine (DAB)-immunohistochemistry. Immunofluorescence (IFC) staining shows that TGM- 010 stains neurons but not astrocytes in mouse brain tissue. As shown in FIG. 2, TGM-010 stains mouse corticohippocampal neurons and human motor neurons as shown by immunofluorescence staining. TGM-010 stains mouse neuronal progenitor cells as shown by flow cytometry in FIG.3. Accordingly, the cellular target of TGM-010 is identified as neurons. The binding capacity of TGM-010 was tested in ALS-derived (C9orf72) human cortical neurons. ALS-derived (C9orf72) human cortical neurons were incubated overnight at 4°C with primary antibodies, diluted in blocking buffer: rhAbs (20 μg/mL), anti-ChAT, and anti-MAP2. Choline acetyltransferase (ChAT) was used as a neuron marker, and microtubule-associated protein 2 (MAP2) was used to delineate neuron cell boundaries. Cells were visualized using a confocal fluorescent microscope. As shown in FIG. 4, TGM-010 exhibited superior binding in comparison to the non-specific control antibody, as evidenced by fluorescence intensity within the boundaries of the human cells (scale bars = 20 μm). Example 2: TGM-010 Prevents Relapse in EAE Mouse Model The experimental autoimmune encephalomyelitis (EAE) mouse model was employed to assess neuroprotection with TGM-010. The EAE model is described in Robinson, AP, et al. “The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment”, Handb Clin Neurol. 2014; 122: 173-189. EAE was induced in SJL/j female mice by immunization with 100µg PLP139-151 with 2 µg complete Freund’s adjuvant (CFA). The first attack DB1/ 148791292.1 28 4879-8182-7022, v.1 typically emerges around day 10 and resolves around day 17. Mice that have a confirmed recovery were administered TGM-010 (5 µg) or control antibody by intracerebroventricular (ICV) administration. The location of ICV administration was recorded. Mice were scored for EAE for 20 days or until they develop and recover from a subsequent attack. Immunohistochemistry can be used to evaluate demyelination and inflammation in treated and control mice. In these studies, TGM-010 was evaluated alongside control antibodies HD10-15 and G11 and no antibody control (PBS). TGM- 007 (also known as AJL7) antibody was also evaluated, which is a human recombinant AGS antibody that binds neurons and astrocytes. As shown in FIG.5, cumulative EAE scores were comparable between groups in the first attack. After randomization and antibody administration, mice that received TGM-010 had a striking decrease in their cumulative EAE scores. The cumulative EAE score data indicate that 6 of 10 mice receiving TGM-010 demonstrated no evidence of disease activity following TGM-010 injection compared to controls. In a further experiment, TGM-010 was delivered over a 2-week period by intraperitoneal (IP) injection beginning 1 day after recovery from the initial attack. Mice that had a confirmed first attack were randomized to receive either placebo or TGM-010 at either 200 ug or 100 ug by intraperitoneal (IP) injection for a total of 6 injections per mouse. The mice were scored for an additional 20 days, and the EAE scores which track disease severity are recorded each day. The cumulative EAE score data indicate that TGM-010 injected at 200 ug per dose reduced the cumulative EAE score significantly compared to the placebo (HOLO). TGM-010 at 100 ug per dose had an intermediate effect on cumulative EAE score demonstrating a dose effect. Cumulative EAE score data indicate that all mice had similar severity of the first attack. See FIG.6. These studies demonstrate that TGM-010 has neuroprotective properties in vivo. Example 3: TGM-010 specifically recognizes hnRNP targets, suggesting potential mechanisms for TGM-010 neuroprotection Potential targets for TGM-010 were identified using a human protein array (CDI Laboratories, Inc.). Non-specific hits that directly bind the secondary antibody were eliminated from the analysis. CDI software was used to quantify the specificity of each individual sample to specific proteins on the array based on Z scores. The Z score is the average of the duplicate spots of a given protein (each protein is printed in duplicate on DB1/ 148791292.1 29 4879-8182-7022, v.1 the array). The Z score of each spot on the array is calculated according to the algorithm: Z=[F635-5635(avg)]/F635(std) where F635(avg) and F635(std) are the average and standard deviation of the F635 values of all spots on the array. The results of the protein array investigation are shown in FIG.7. The top hit was heterogeneous nuclear protein A/B (hnRNPAB), with a Z-Score of 79.65. Because the protein arrays were limited in representation of brain antigen targets and do not necessarily present proteins in their physiological state, antigen targets for TGM-010 were also evaluated by immunoprecipitation studies. For immunoprecipitation studies, Sy5y cell lysates were prepared and used for immunoprecipitation with TGM-010 or control antibody JRR67. Immunoprecipitated protein was separated by SDS-PAGE, followed by trypsin digestion of individual bands and Mass Spectrometry analysis of the individual peptides. SDS-PAGE gels are shown in FIG. 8, with bands submitted for Mass Spec. analysis, which include a doublet of around 37/40 kDa, as well as a 100 kDa band and a 50 kDa doublet. Mass Spec. results are shown in FIG. 9 for the 37/40 kDa band. Most of the sequences (6 of the top 10) correspond to heterogeneous nuclear ribonucleoproteins, including the top CDI array hit (heterogeneous nuclear ribonucleoprotein A/B). Based on these studies, it is believed that TGM-010 has high specificity for hnRNPs, particularly subgroups of the hnRNP A/B family. hnRNP particles are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of the proteins bound to a pre-mRNA molecule serves as a signal that the pre-mRNA is not yet fully processed and therefore not ready for export to the cytoplasm. After splicing has occurred, the hnRNPs remain bound to spliced introns and target them for degradation. hnRNPs are also integral to the 40S subunit of the ribosome and therefore important for the translation of mRNA in the cytoplasm. hnRNPs have their own nuclear localization sequences (NLS) and are therefore found mainly in the nucleus, although some hnRNPs shuttle between the cytoplasm and nucleus. There are approximately 20 major hnRNPs (hnRNP A1 to hnRNP U), and the location and function of each member in various cell types are distinct. Several structural domains are shared between different family members. See Geuens T, et al., “The hnRNP DB1/ 148791292.1 30 4879-8182-7022, v.1 family: insights into their roles in health and disease,” Hum Genet (2016) 135:851-867. hnRNP A/B includes 4 subgroups, A1, A2/B1, A3, and A0, and is involved in mRNA translation and splicing, and are components of 40S hnRNP complexes. hnRNP A2/B1 plays an important role in oligodendrocytic and neuronal mRNA trafficking. hnRNP A2/B1 is important for the correct localization of transcripts containing an A2 response element (A2RE) or A2RE-like sequences, such as the myelin basic protein (MBP) or Ca2+/calmodulin-dependent protein kinase II (CaMKII), activity-regulated cytoskeleton-associated protein (Arc) and neurogranin (NRGN) mRNA. hnRNP A1 has been reported to localize to Stress Granules (SG) during the cellular stress response. See Guil S, et al., “hnRNP A1 Relocalization to the Stress Granules Reflects a Role in the Stress Response,” Mol Cell Biol (2006) (15):5744-58. Interestingly, ALS type 20 is caused by mutations in the hnRNPA1 gene. Krebs BB and De Mesquita JF, “Amyotrophic Lateral Sclerosis Type 20 – In Silico Analysis and Molecular Dynamics Simulation of hnRNPA1.” PLoS One (2016 Jul 14;11(7):e0158939). Antibodies against hnRNP A1 have been described as contributing to neuronal cell loss in an animal model of multiple sclerosis. See Libner CD et al., J Comp Neurol 2020 Jul;528(10):1704-1724. In fact, mislocalization hnRNP A1 was reported to be substantially higher in EAE mice as compared to naïve mice, and directly correlated with neuronal cell death and clinical score in these models. Post-transcriptional regulation of gene expression upon various stimuli, such as heat shock, oxidative stress, and viral infection, is vital for cell survival. SGs represent cytoplasmic sites in which translationally stalled mRNAs and numerous RNA binding proteins are nucleated upon stresses, and this event allows the cell to reprogram gene expression. SGs may be sites where mRNA triage takes place to direct mRNAs to be degraded or translated. Example 4: TGM-010 in vitro antibody toxicity evaluation This study focused on evaluating the possible neurotoxicity of the antibody, TGM-010. A positive control antibody was created by sequencing B cells from a patient with autoimmune encephalitis and cloning an anti-neuronal antibody, e.g., “DS14.” Sy5y cells were incubated with the antibodies at 37°C for 3 hr. Cells were then incubated with 6 μM Caspase-3/7 Green Detection Reagent (INVITROGEN C10423, DB1/ 148791292.1 31 4879-8182-7022, v.1 fluorogenic substrate for cell lysis detection) for the last 30 min of the incubation period. Cells were then fixed with 4% (v/v) paraformaldehyde (PFA) and stained for immunocytochemistry with the following antibodies: mouse anti-G3BP1 (1:100 BD BIOSCIENCES 611126), goat anti-human conjugated ALEXAFLUOR 568 (1:1000 THERMO FISHER A-21090), and goat anti-mouse conjugated ALEXAFLUOR 647 (1:500 ABCAM ab150115). Coverslips were mounted and cells were visualized using spinning disk confocal microscopy. As shown in FIG. 10, TGM-010 did not induce any appreciable neuronal apoptosis, similarly to the vehicle control, in comparison to the positive control, DS14, which caused a statistically significant degree of apoptosis (~35%). These data demonstrated, inter alia, that neuron-targeted antibody, TGM-010, possesses no appreciable in vitro neurotoxicity. Example 5: TGM-010 hnRNP binding domain studies and epitope mapping To evaluate the binding location of TGM-010, an enzyme-linked immunosorbent assay (ELISA) was performed against an hnRNP peptide array. Peptide arrays were generated at 24 amino acid length (24-mer) using an 8-mer overlap. Select hnRNP family protein members were tested: hnRNP A2B1, hnRNP A1, and hnRNP AB, using a standard ELISA protocol, comparing between TGM-010 against a non-specific, control antibody (e.g., JRR7). NUNC-IMMUNO MAXISORP 96-well plates (SIGMA ALDRICH) were incubated overnight at 4°C with hnRNP peptides at 5 µg/ml, in 0.1 M sodium carbonate buffer (pH 9.5). Coated plates were probed with TGM-010 or JRR67 at 20 µg/mL in assay diluent. After several washes, the plates were subsequently incubated with horseradish peroxidase-conjugated goat anti-human IgG secondary antibodies (CHEMICON). Colorimetric readings were obtained using an ELISA microplate reader (λ = 450). Positive antibody reactivity was defined as values that were greater than the mean of the control plus 2 standard errors. As shown in FIGS. 11A, B, ELISA signal indicated that peptides 3-8 and 3-11 (SEQ ID NOS: 16 and 19, Table 1) were bound by TGM-010 antibody with more than 2 standard errors over the control antibody. These peptides are located within the RRM2 domain of hnRNP A1. Additionally, peptides 6-11 and 6-14 (SEQ ID NOs: 20 and 23, Table 1) of hnRNP A/B bound the TGM-010 antibody with more than 2 standard errors DB1/ 148791292.1 32 4879-8182-7022, v.1 over the control antibody. These peptides are located within the RRM2 domain of hnRNP A/B. These data indicated, inter alia, that the antibody has specificity within the RRM2 domain of select hnRNP proteins with homology within this region. The data demonstrate, inter alia, that TGM-010 binds to the conserved RRM2 region of hnRNP proteins that are implicated in a variety of neurological and neurodegenerative conditions characterized by the loss of neurons. Example 6: TGM-010 live cell internalization As an overview, the Sy5y human neuroblastoma cell line was used to evaluate the internalization capabilities of TGM-010 in vitro. Sy5y cells were cultured to confluency, incubated with either a non-specific negative control antibody or TGM-010, and then fixed, stained, and imaged using fluorescence confocal microscopy at various time points. Staining was performed with anti-tubulin monoclonal antibody (e.g., Tub) to visualize neuronal cell bodies, DAPI blue staining for visualizing nuclei, and control or TGM-010 antibody staining (e.g., rhAb). As shown in FIGs. 12A-12B, there was a statistically significant internalization of TGM-010 into Sy5y neuroblastoma cells as evidenced by fluorescence intensity in comparison to the control antibody at 2 hr., 6 hr., and 24 hr. post-exposure (scale bars = 20 μm). Moreover, internalization kinetics, as shown in shown in FIG. 12B, illustrates that TGM-010 rapidly enters into the cytoplasm at 60 min post-exposure, whereas control antibody did not appreciably enter the cells. A mouse cortical neuron model was also used to evaluate and confirm the in vitro internalization of TGM-010 performed as substantially described above for Sy5y cells. As shown in FIGs.12C, 12D, there was a statistically significant internalization of TGM- 010 in mouse cortical neurons in comparison to the non-specific, control antibody at 30 min, 2 hr., and 6 hr. post-exposure (scale bars = 20 μm). These data demonstrated, inter alia, that TGM-010 adequately internalizes into neurons (cross-species) at an increased total amount and increased rate in comparison non-specific antibodies. These results reflect in part the conserved nature of the RRM2 epitope across species. DB1/ 148791292.1 33 4879-8182-7022, v.1 Example 7: Evaluation of TGM-010 Fc domain binding Next, the presence of the Fc domain was evaluated for its impact on binding of TGM-010. Full-length IgG TGM-010 underwent pepsin cleavage to remove the Fc domain, where the resultant F(ab’)2 product was isolated, e.g., as shown in FIG.13A. A Sy5y human neuroblastoma cell line was used to evaluate the effect of the Fc domain on binding of TGM-010. Sy5y cells were cultured to confluency, incubated with either a non-specific negative control antibody, full-length IgG TGM-010, or a F(ab’)2 TGM- 010, and then fixed, stained, and imaged using fluorescence confocal microscopy at various time points. Staining was performed with DAPI blue for visualizing nuclei, with antibody staining (e.g., rhAb) in green, such that overlapping fluorescence from internalization of antibody or antigen-binding fragment would result in a neuron color shift to cyan. As shown in FIG. 13B, the full-length, non-specific, control antibody (JRR67) demonstrated no appreciable staining. By contrast, as shown in FIG.13C, both the full- length IgG TGM-010 and antigen-binding fragment, F(ab’)2 TGM-010, resulted in significant neuronal binding as evidenced by the color shift in fluorescence intensity. Example 8: TGM-010 in vitro neuroprotective effect under stressed conditions To evaluate the potential neuroprotective effects of TGM-010 in neurons under stressed conditions, a modification of the toxicity assay used in Example 4 was employed. Toxicity was compared to a positive control anti-neuronal antibody, DS14, which is an antibody cloned from a B cell obtained from a patient with autoimmune encephalitis. Sy5y cells were incubated with antibodies for 6 hr. prior to either a heat shock treatment at 43°C for 2 hrs, or remaining at 37°C for 1.5 hr. Cells were then incubated with 6 μM Caspase-3/7 Green Detection Reagent (INVITROGEN C10423, fluorogenic substrate for cell lysis detection) for the last 30 min. of each incubation period. Cells were fixed with 4% (v/v) paraformaldehyde (PFA), coverslips were then mounted and cells were visualized for Caspase-3/7 fluorescence using spinning disk confocal microscopy. As shown in FIG. 14, TGM-010 treatment resulted in a statistically significant degree of neuroprotection from heat-induced neuronal apoptosis in comparison to vehicle alone and the neurotoxic antibody, DS14. TGM-010 replicates showed approximately DB1/ 148791292.1 34 4879-8182-7022, v.1 60%+ non-apoptotic cells in culture, demonstrating about 10-fold decrease in the presence of apoptotic neurons. These data demonstrated, inter alia, that TGM-010 possesses appreciable in vitro neuroprotective effects from cellular stress (e.g., heat-induced stress). Example 9: TGM-010 co-localization with stress granule condensation To further examine the neuroprotective mechanism of TGM-010, an assessment of the antibody’s colocalization with stress granule assembly factor 1 (G3BP1) in stress granules (SGs) was evaluated. G3BP1 is a known core protein of stress granules (SGs) and is used as a marker to evaluate SG condensation, for example, as described in Fang et al., Neuron 2019. Here, isolated mouse cortical neurons underwent heat-induced SG formation, were subsequently fixed, stained, and then imaged using fluorescence confocal microscopy. Staining was performed with an anti-G3BP1 monoclonal antibody to visualize SGs, DAPI blue to visualize the nuclei, MAP2 staining to visualize neuronal bodies, and an anti-human secondary antibody to visualize either a non-specific control antibody or TGM-010 antibody. As shown in FIG.15A, heat treatment at 45°C for 2 hr. without antibody resulted in significant SG formation, with G3BP1 staining appearing in granules under heat- treated conditions (e.g., as denoted by white arrows). A non-specific, negative control antibody (e.g., JRR67) was then compared to TGM-010 to analyze the antibody’s ability to colocalize with SGs. As shown in FIG. 15B, the control antibody did not show colocalization with SGs, whereas as shown in FIGs. 15C-15D, qualitative and quantitative analyses demonstrated that TGM-010 treatment resulted in a statistically significant colocalization with SG formation under heat-stress conditions. These data demonstrated, inter alia, that TGM-010 colocalizes with stress granules (SG) in neurons under cellular stress. Example 10: Neuroprotective effects of TGM-010 in an Experimental Autoimmune Encephalitis (EAE) mouse model Experimental autoimmune encephalitis (EAE) animals have classically been utilized to screen neuroprotective agents. EAE was induced in SJL/j female mice by immunization with 100 µg of residues 139-151 of myelin proteolipid protein (PLP_139-151) DB1/ 148791292.1 35 4879-8182-7022, v.1 with 2 µg complete Freund’s adjuvant (CFA). The first “attack” or manifestation of disease severity due to demyelination typically emerges around day 10 and resolves around day 17 (e.g., as shown as the peak in disease severity in FIGs. 16A-16B). Mice that have a confirmed recovery from a first attack (n = 28) were blindly randomized to receive either TGM-010 (5 µg) or a non-specific control antibody on day 15 by intracerebroventricular (ICV) administration. Mice were scored for EAE for 20 days or until they develop and recover from a subsequent attack. They were followed for 39 days and sacrificed. As shown in FIG.16A, there was a statistically significant improvement in mean EAE scores. TGM-010 antibody showed a statistically significant reduction in disease severity relative to the control antibody immediately following administration, where the improvement lasted for at least about 2 weeks after injection. A subsequent blinded, EAE in vivo study was performed in mice (n = 26) to confirm the results using systemic intraperitoneal (IP) administration with 6 administrations, e.g., on day 19, 21, 23, 25, 27, and 29. As seen in FIG. 16B, TGM-010 achieved a statistically significant reduction in disease severity in comparison to control antibody, even when administered systemically. In order to confirm that TGM-010 can penetrate the intact BBB and access its cellular target, WT mice were injected with TGM-010 or control antibody JRR67 intravenously and brains were harvested from mice 24 hours post injection. Serial fixed sections were then made from the brains of treated mice. The administered antibodies detected in sequential brain sections by immunofluorescence staining with goat anti- human AlexaFluor 488 secondary antibody. Neurons are labeled with mouse anti-NeuN primary antibody followed by goat anti-Ms AlexaFluor 647 labeled secondary antibody. Images were captured on a Zeiss Axioscope.A1 fluorescent microscope with a 20x/0.45NA lens. As shown in FIG 17A, TGM-010 shows strong BBB penetration and labeling of neurons at 24 hrs after administration whereas the control antibody does not. Punctate labeling observed in both slides is non-specific background autofluorescence. FIG.17A further shows the quantification of TGM-010 staining in neurons compared to control antibody JRR67 with a statistically significant level of TGM-010 staining compared to JRR67. DB1/ 148791292.1 36 4879-8182-7022, v.1 FIG. 17B shows labeling of brain sections from the front, middle and end of the mouse brain Cortex Layer 1 at 24 hrs after drug administration, with strong staining of TGM-010 observed in all parts of the cortex. FIG. 17B shows quantitation of signal intensity with a significant increase in TGM-010 staining at 24 hrs over control antibody and compared to 8 hrs post administration. These data demonstrated, inter alia, that TGM-010 exhibits neuroprotective effects in vivo and is capable of traversing the blood-brain barrier (BBB) in vivo through a variety of local and systemic administration modes. Example 11: TGM-010 internalization into ALS-derived human cortical neurons ALS-derived human cortical neurons were used to evaluate the internalization capabilities of TGM-010 in vitro. Human cortical neuron cells were cultured to confluency, incubated with either a non-specific negative control antibody (JR667) or TGM-010 for 2 hrs, and then fixed, stained, and imaged using fluorescence confocal microscopy at various time points. Staining was performed with anti-MAP2 monoclonal antibody to visualize neuronal cell boundaries, DAPI blue staining for visualizing nuclei, and control or TGM-010 antibody staining (e.g., rhAb). As shown in FIG.18, there was a statistically significant internalization of TGM- 010 into human cortical neurons as evidenced by fluorescence intensity in comparison to the vehicle at 0 and 30 min post-exposure, and a significant increase over JRR67 at 30 min, illustrating that TGM-010 rapidly enters into the cytoplasm, whereas control antibody did not appreciably enter the cells. These data demonstrate, inter alia, that TGM-010 adequately internalizes into ALS-derived cortical neurons at an increased total amount and increased rate in comparison to non-specific antibodies. All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method DB1/ 148791292.1 37 4879-8182-7022, v.1 described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims. DB1/ 148791292.1 38 4879-8182-7022, v.1 TGM-010 SEQUENCES SEQ ID NO: 1 -- TGM10 Heavy Chain Variable Amino Acid Sequence (CDRs underlined QVQLQESGPGLVKPSETLSLTCSVSGGAVSNYYWSWIRQSAGKGLEWLGRIYINGTTYYNPSLR SRVSMSVDTSKGQFSLRLTSVTAADTAIYYCARWGALLGDYYYGLDVWGQGTTVTVSS SEQ ID NO: 2 – TGM10 HC CDR1 GGAVSNYY SEQ ID NO: 3 – TGM10 HC CDR2 IYINGTT SEQ ID NO: 4 – TGM HC CDR3 ARWGALLGDYYYGLDV SEQ ID NO: 5 – TGM10 Light Chain Amino Acid Sequence (CDRs underlined) DIVMTQSPLSLPVTPGEPASISCRSTQSLLHSNEYIYLDWYVQKPGQSPQLLIFLASNRASGVP DRFSGSASGTDFTLKISRVEAEDVGVYYCMQALEAPWTFGQGTRLEIK SEQ ID NO: 6 – TGM10 LC CDR1 QSLLHSNEYIY SEQ ID NO: 7 – TGM10 LC CDR2 LAS SEQ ID NO: 8 – TGM10 LC CDR3 MQALEAPWT DB1/ 148791292.1 39 4879-8182-7022, v.1

Claims

WHAT IS CLAIMED: 1. A method for neuroprotection, comprising administering to a subject in need thereof an effective amount of an agent that binds to cytoplasmic heterogeneous nuclear ribonucleoprotein (hnRNP) in neurons, to thereby inhibit neuronal cell death. 2. The method of claim 1, wherein the hnRNP comprises hnRNP A1 or hnRNP A/B. 3. The method of claim 1, wherein the hnRNP comprises one or more of hnRNP A2/B1, hnRNP C1/C2, hnRNP A1, hnRNP A3, and hnRNP D0. 4. The method of any one of claims 1 to 3, wherein the agent binds an RRM2 epitope in Table 1. 5. The method of any one of claims 1 to 4, wherein the agent is an antibody or antigen binding fragment or portion thereof. 6. The method of claim 5, wherein the agent is an IgG monoclonal antibody. 7. The method of claim 5, wherein the agent is a scFv. 8. The method of claim 5, wherein the agent is a F(ab')2. 9. The method of any one of claims 1 to 8, wherein the agent is a polypeptide expressed in neurons via delivered nucleic acid. 10. The method of claim 9, wherein the nucleic acid is DNA or mRNA. 11. The method of claim 9 or 10, wherein the nucleic acid is delivered by lipid nanoparticle or are encoded in a viral vector. 12. The method of any one of claims 1 to 11, wherein the agent is a TGM-010 antibody or antigen-binding fragment or portion thereof, or a variant thereof. 13. The method of claim 12, wherein the antibody or antigen-binding fragment or portion thereof comprises the following complementarity determining regions (CDRs) of heavy chain CDR1 of SEQ ID NO: 2, heavy chain CDR2 of SEQ ID NO: 3, heavy chain CDR3 of SEQ ID NO: 4, light chain CDR1 of SEQ ID NO: 6, light chain CDR2 of SEQ ID NO: 7, and light chain CDR3 of SEQ ID NO: 8. 14. The method of claim 13, wherein the antibody or antigen-binding fragment or portion thereof comprises a heavy chain variable domain comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 1, and a light chain DB1/ 148791292.1 40 4^{879-8182-7022, v. 1} variable domain comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 5. 15. The method of claim 13, wherein the antibody or antigen-binding fragment or portion thereof comprises a heavy chain variable domain comprising the amino acid sequence having of SEQ ID NO: 1, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 5. 16. The method of any one of claims 1 to 15, wherein the subject has or is at risk of a neurodegenerative disease or traumatic injury. 17. The method of claim 16, wherein the neurodegenerative disease is Multiple Sclerosis (MS), clinically isolated syndrome (CIS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Progressive supranuclear palsy, Friedreich ataxia, Lewy body disease, or Spinal muscular atrophy. 18. The method of any one of claims 1 to 15, wherein the subject is at risk or experiencing or recovering from ischemic or hemorrhagic stroke, traumatic brain injury, or spinal injury. 19. The method of any one of claims 1 to 18, wherein the agent is administered systemically. 20. The method of any one of claims 1 to 18, wherein the agent is administered parenterally, optionally by subcutaneous administration, intravenous administration, intracerebroventricular administration, intraparenchymal administration, or intrathecal administration. 21. The method of any one of claims 1 to 18, wherein the agent is administered intranasally. 22. The method of claim 20 or 21, wherein the agent is administered once, or is administered a plurality of times optionally at a frequency of from about daily to about monthly. 23. The method of claim 22, wherein the agent is administered upon symptoms of neuronal injury or attack of a neurodegenerative disease, or during or after recovery from the injury or attack. DB1/ 148791292.1 41 4^{879-8182-7022, v. 1}

24. A method for neuroprotection, comprising administering to a subject in need thereof an effective amount of an antibody, or an antigen-binding portion thereof, having the following complementarity determining regions (CDRs): heavy chain CDR1 of SEQ ID NO: 2, heavy chain CDR2 of SEQ ID NO: 3, heavy chain CDR3 of SEQ ID NO: 4, light chain CDR1 of SEQ ID NO: 6, light chain CDR2 of SEQ ID NO: 7, and light chain CDR3 of SEQ ID NO: 8. 25. The method of claim 24, wherein the antibody, or an antigen-binding portion thereof, binds one or more cytoplasmic heterogeneous nuclear ribonucleoprotein (hnRNP) in neurons. 26. The method of claim 25, wherein the hnRNP comprises hnRNP A/B. 27. The method of claim 25, wherein the hnRNP comprises hnRNP A1. 28. The method of any one of claims 24 to 27, wherein the antibody is an IgG antibody, optionally selected from IgG1, IgG2, IgG3, and IgG4. 29. The method of any one of claims 24 to 28, wherein the antibody is a scFv or F(ab')2. 30. The method of any one of claims 24 to 29, wherein the antibody or antigen binding fragment thereof is expressed in neurons via DNA or mRNA delivery. 31. The method of claim 30, wherein the antibody or antigen binding fragment thereof is delivered using lipid nanoparticles. 32. The method of claim 30, wherein the antibody or antigen binding fragment thereof is encoded in a viral vector. 33. The method of any one of claims 24 to 32, wherein the antibody or antigen- binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 1, and a light chain variable domain comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 5. 34. The method of claim 33, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 1, and a light chain variable domain comprising an amino acid sequence having at least 95% sequence identity to SEQ ID DB1/ 148791292.1 42 4^{879-8182-7022, v. 1} NO: 5. 35. The method of claim 33, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence having of SEQ ID NO: 1, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 5. 36. The method of any one of claims 24 to 35, wherein the subject has or is at risk of a neurodegenerative disease or acute or traumatic injury. 37. The method of claim 36, wherein the neurodegenerative disease is Multiple Sclerosis (MS), clinically isolated syndrome (CIS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), Schizophrenia, Progressive supranuclear palsy, Friedreich ataxia, Lewy body disease, or Spinal muscular atrophy. 38. The method of claim 36, wherein the subject is at risk, experiencing, or recovering from ischemic or hemorrhagic stroke, traumatic brain injury, or spinal injury. 39. The method of any one of claims 24 to 38, wherein the antibody or antigen binding fragment thereof is administered parenterally. 40. The method of claim 39, wherein the antibody or antigen binding fragment thereof is administered by subcutaneous administration, intravenous administration, intracerebroventricular administration, intraparenchymal administration, or intrathecal administration. 41. The method of any one of claims 24 to 38, wherein the antibody or antigen binding fragment thereof, or DNA or mRNA encoding the same, is administered intranasally. 42. The method of claim 40 or 41, wherein the antibody or antigen binding fragment thereof is administered at a frequency of from about daily to about monthly. 43. The method of any one of claims 34 to 42, wherein the antibody or antigen binding fragment thereof is administered upon symptoms of neuronal injury or attack of neurodegenerative disease, or during or after recovery from the injury or attack. 44. A pharmaceutical composition comprising a monoclonal antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and DB1/ 148791292.1 43 4^{879-8182-7022, v. 1} a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5, and a pharmaceutically acceptable carrier; the monoclonal antibody further comprising one or more selected from: a moiety that enhances cell penetration, a modification that attenuates Fc-mediated effector functions, and an Fc modification that improves pharmacodynamic (PD) properties. 45. The pharmaceutical composition of claim 44, wherein the monoclonal antibody comprises one or more modifications that increase circulating or serum half-life, increase blood-brain barrier (BBB) penetration, increase neuronal uptake, and reduce off-target or non-specific uptake. 47. A pharmaceutical composition comprising an antigen binding fragment of an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5, or a polynucleotide encoding the same, and a pharmaceutically acceptable carrier. 48. The pharmaceutical composition of claim 47, wherein the fragment is a scFv or F(ab')2. 49. The pharmaceutical composition of claim 47 or 48, wherein the fragment further comprises a moiety that enhances cell penetration. 50. The pharmaceutical composition of claim 49, wherein the moiety comprises a cell penetrating peptide. 51. The pharmaceutical composition of claim 47, comprising a polynucleotide encoding a scFv, optionally further comprising a peptide for enhancing cell penetration. 52. The pharmaceutical composition of claim 51, wherein the polynucleotide is DNA or mRNA. 53. The pharmaceutical composition of claim 51, wherein the polynucleotide is encapsulated by lipid nanoparticles. 54. The pharmaceutical composition of claim 52, wherein the DNA or mRNA is encoded or expressed from a viral vector. 55. A method for making a pharmaceutical composition for providing neuroprotection, comprising: DB1/ 148791292.1 44 4^{879-8182-7022, v. 1} identifying an agent that binds to one or more cytoplasmic heterogeneous nuclear ribonucleoprotein (hnRNP) in stress granules or an RRM2 epitope thereof, determining whether the agent reduces or inhibits apoptosis in neurons, and/or reduces or ameliorates neurodegenerative disease or neuronal loss in an animal model, and formulating the agent for delivery to a human or animal. 56. The method of claim 55, wherein the one or more hnRNP comprises an RNA recognition motif 2 (RRM2). 57. The method of claim 55 or 56, wherein the hnRNP comprises hnRNP A/B or hnRNP A1. 58. The method of claim 55 or 56, wherein the one or more hnRNP comprises hnRNP A2/B1, hnRNP C1/C2, hnRNP A1, hnRNP A3, and hnRNP D0. 59. The method of any one of claims 55 to 58, wherein the agent blocks the binding of TGM-010 to said hnRNP or an RRM2 epitope, as measured by an in vitro binding assay. 60. The method of any one of claims 55 to 59, wherein the agent binds the hnRNP or RRM2 epitope with an affinity of less than or equal to 1 x 10^-7 M, or less than or equal to 1 x 10^-8 M, less than or equal to 1 x 10^-9 M, less than or equal to 1 x 10^-10 M, less than or equal to 1 x 10^-11 M, or less than or equal to 1 x 10^-12 M. 61. The method of claim 59 or 60, wherein the agent is an antibody or antigen binding fragment thereof. 62. The method of claim 59 or 60, wherein the agent is a peptide, an aptamer, an adnectin, or DARPin. 63. The method of claim 59 or 60, wherein the agent is selected from a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody, single chain variable fragment (scFv), a shark heavy-chain-only antibody (VNAR), a Tetranectin, an Affibody, a Transbody, an Anticalin, an Affilin, a Microbody, a phylomer, a stradobody, a fynomer, an avimer, a triomab, a Fv, a Fab, a Fab', and a F(ab')2. 64. The method of claim 59 or 60, wherein the agent is an antibody, and optionally a DB1/ 148791292.1 45 4^{879-8182-7022, v. 1} human antibody, and is optionally a TGM-010 variant. 65. The method of claim 64, wherein the agent is a VH4 antibody that binds selectively to neurons or selectively to neurons and astrocytes. 66. The method of claim 64, wherein the TGM-010 variant is prepared by introducing from one to four amino acid substitutions in one or more of the TGM-010 CDRs (SEQ ID NOs: 2-5 or 6-8), and/or introducing from 1 to 6 amino acid substitutions, deletions, or insertions within the framework regions of the TGM-010 VH (SEQ ID NO: 1) and/or VL (SEQ ID NO: 5) chains. 67. The method of claim 64, wherein the TGM-010 variant is prepared by modifying the Fc domain. 68. The method of any one of claims 55 to 67, comprising screening candidate agents for binding against one or more peptides from an RRM2 domain epitope. 69. The method of claim 68, wherein the RRM2 domain epitope comprises at least 20 amino acids, or at least 25 amino acids, or at least 40 amino acids. 70. The method of claim 69, wherein the RRM2 domain epitope comprises an amino acid sequence of Table 1 or a portion thereof. 71. The method of claim 69, wherein the RRM2 domain epitope has at least about 80%, at least about 90%, or at least about 95%, or 100% amino acid sequence identity to at least 20 amino acids, or at least 25 amino acids, or at least 40 amino acids of an amino acid sequence listed in Table 1. 72. The method of any one of claims 66 to 71, further comprises measuring binding between candidate binding agents and RRM2 epitope by ELISA, surface plasmon resonance (SPR), and biolayer interferometry (BLI). 73. The method of any one of claims 55 to 72, wherein inhibition of apoptosis in neurons is determined in vitro using a mouse or human neuronal cell line. 74. The method of any one of claims 55 to 73, wherein inhibition of apoptosis in neurons is determined in vitro. 75. The method of any one of claims 55 to 74, wherein reduction or amelioration of neurodegenerative disease or neuronal loss is determined in an animal model, which is optionally an EAE mouse model. DB1/ 148791292.1 46 4^{879-8182-7022, v. 1}

75. The method of any one of claims 55 to 74, further comprising quantifying internalization in neurons in vitro or using an in vivo animal model. 76. The method of any one of claims 55 to 75, wherein the agent is a polypeptide and is formulated so as to be expressed in neurons via gene or mRNA delivery. 77. The method of any one of claims 55 to 75, comprising formulating the agent for parenteral administration or intranasal administration. DB1/ 148791292.1 47 4^{879-8182-7022, v. 1}