Methods and compositions for the treatment of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and learning disabilities

Abstract

Methods and compositions are provided for the treatment of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and learning disabilities.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 476,331, filed December 20, 2022, and U.S. Provisional Application No. 63 / 504,860, filed May 30, 2023, all of which are incorporated herein by reference. [Background technology]

[0002] Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and learning disabilities all affect cognitive and behavioral processes, and treatments are needed to ameliorate the symptoms of these disorders.

[0003] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0004] There is an urgent unmet need to develop effective treatments for neurological diseases associated with synapse and neuron loss, harmful neuroinflammation (e.g., microgliosis, astrogliosis), and increased H3K9me3 epigenetic repression (e.g., associated with heterochromatin epigenetic silencing) to preserve neuromotor and cognitive function. Histone hypermethylation leads to gene silencing and reduced brain and synaptic plasticity, which can affect motor, cognitive, and visual function. The methods and compositions described herein may involve inhibiting or targeting enzymes involved in excessive histone methylation that can occur in the brain in neurodegenerative disorders. This may be advantageous in the treatment of various neuromuscular and neurological disorders, such as Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), which results in CNS-neuron preservation and promotes the new formation of neurons and synapses. Described herein are methods and compositions for reversing H3K9me3 epigenomic gene repression and inducing the transcription and translation of proteins with important functions in promoting neuronal survival and synaptic regeneration.

[0005] In certain aspects, described herein are methods for treating Parkinson's disease, Huntington's disease, ALS, or a learning disability in a subject in need thereof, the methods comprising administering to the subject a compound comprising an inhibitor of histone 3, lysine 9 (H3K9) trimethylation. In some embodiments, the compound comprises an inhibitor of SUV39H1. In some embodiments, the compound comprises an inhibitor of SUV39H2. In some embodiments, the compound has Formula (I):

[0006] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 2, 3, or 4; and R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 16 and R 18 are independently hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —CI3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. In some embodiments, the compound comprises (Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile) (ETP69) or a pharmaceutically acceptable salt thereof. In some embodiments, administration improves locomotor activity in the subject. In some embodiments, administration reduces neuroinflammation in the subject. In some embodiments, administration increases or improves a neuroprotective phenotype. In some embodiments, administration activates brain-derived neurotrophic factor (BDNF) or VGF-nerve growth factor-induced (VGF) signaling in the subject. In some embodiments, administration reduces or improves a phenotype associated with Parkinson's disease, Huntington's disease, ALS, or a learning disability in the subject. In some embodiments, the subject has or has been diagnosed with Parkinson's disease. In some embodiments, the subject has or has been diagnosed with Huntington's disease. In some embodiments, the subject has or has been diagnosed with ALS. In some embodiments, the subject has or has been diagnosed with a learning disability.

[0007] In certain aspects, described herein are methods of inhibiting an enzyme selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H1, and SUV39H2, the method comprising inhibiting the enzyme with a compound represented by formula (I):

[0008] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 2, 3, or 4; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 and R 18are independently hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —CI3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. In some embodiments, the compound comprises (Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile) (ETP69) or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in a neuron of a subject. In some embodiments, the contacting is in a human subject. In some embodiments, the method further comprises assessing the activity of the enzyme during or after contacting the enzyme with the compound. In some embodiments, the activity of the enzyme is reduced by at least 75% after contacting the enzyme with the compound. [Brief explanation of the drawings]

[0009] [Figure 1A] FIG. 1A shows Golgi-Cox staining in the cingulate cortex (cc) of mice treated with DMSO (upper panel) and ETP69 (lower panel). [Figure 1B] FIG. 1B shows Golgi-Cox staining in the hippocampus. [Figure 1C] FIG. 1C shows individual neurons from DMSO-treated and ETP69-treated neurons. [Figure 1D] Figure 1D shows a schematic diagram of the different types of dendritic spines that were quantified. [Figure 1E]FIG. 1E shows quantification of thin spines in the cingulate cortex and hippocampus. [Figure 1F] Figure 1F shows the correlation between the number of thin spines in the hippocampus and the number of errors and the number of seconds of freezing. [Figure 1G] FIG. 1G shows quantification of dendritic spines in the cingulate cortex and hippocampus. [Figure 1H] Figure 1H shows the correlation between the ratio of mushroom spines to dendritic spines in the hippocampus and the number of errors and the number of seconds of freezing. [Figure 2A] Figure 2A shows the experimental setup. [Figure 2B] Figure 2B shows the brain regions isolated for further analysis. [Figure 2C] FIG. 2C shows H3K9me3 staining in layers of the cingulate cortex. [Figure 2D] FIG. 2D shows H3K9me3 staining in DMSO-treated brains (upper panel) and ETP69-treated brains (lower panel). [Figure 2E] Figure 2E shows the correlation between the percentage of alternations and H3K9me3 irradiance in the study. [Figure 2F] FIG. 2F shows a blot showing H3K9me3 in DMSO- and ETP69-treated AD+ mice. [Figure 2G] FIG. 2G shows H3K9me3 staining in DMSO- and ETP69-treated brains. [Figure 2H] Figure 2H shows quantification of H3K9me3 irradiance. [Figure 2I] Figure 2I shows representative images of H3K9me3 immunofluorescence. [Figure 2J] Figure 2J shows quantification of H2K9me3 in the cingulate cortex of DMSO- and ETP69-treated animals. [Figure 2K] Figure 2K shows the levels of H3K9me3 levels normalized to actin levels in mice treated with DMSO and ETP69. [Figure 2L]FIG. 2L shows quantification of H2K9me3 in the hippocampus of DMSO- and ETP69-treated animals. [Figure 2M] Figure 2M shows the correlation between H3K9me3 staining and the number of errors or seconds of freezing. [Figure 3] FIG. 3 shows genes activated in the BDNF and VGF protective pathways. [Figure 4A] Figure 4A shows the genes activated and inactivated by ETP69. [Figure 4B] FIG. 4B shows quantification of PLTP in DMSO- and ETP69-treated mice. [Figure 4C] FIG. 4C shows quantification of Annexin 2 in DMSO- and ETP69-treated mice. [Figure 4D] FIG. 4D shows Annexin 2 and PLTP staining in DMSO- and ETP69-treated mice. [Figure 4E] FIG. 4E shows quantification of PLTP irradiance in DMSO- and ETP69-treated mice. [Figure 4F] FIG. 4F shows quantification of annexin 2 irradiance in DMSO- and ETP69-treated mice. [Figure 4G] Figure 4G shows quantification of BDNF irradiance in DMSO and ETP69+AD+ mice. [Figure 4H] FIG. 4H shows quantification of VGF irradiance in the hippocampus of DMSO- and ETP69-treated mice. [Figure 4I] FIG. 41 shows BDNF, VGF, and Thio-S staining in DMSO- and ETP69-treated mice. [Figure 4J] Figure 4J shows quantification of TTC3 in DMSO- and ETP69-treated mice (left panel), TRKB in DMSO- and ETP69-treated mice (middle panel), and VGF in DMSO- and ETP69-treated mice (right panel). [Figure 4K]Figure 4K shows the correlation between VGF irradiance and H3K9me3 irradiance in the hippocampus. [Figure 4L] Figure 4L shows quantification of VGF irradiance in the cingulate cortex of DMSO- and ETP69-treated mice. [Figure 4M] Figure 4M shows the correlation between the number of errors on day 2 and the level of VGF irradiance in the cingulate cortex. [Figure 5] FIG. 5 shows the experimental protocol used to test the effects of ETP69 on mice. [Figure 6A] Figure 6A shows the total number of entries into the Y-maze. [Figure 6B] FIG. 6B shows the percentage of alternations in the Y-maze. [Figure 6C] Figure 6C shows a schematic diagram of the visual stimulus X-maze and the total number of inputs to the visual stimulus X-maze. [Figure 6D] FIG. 6D shows the percentage of alternations in the visual stimulation X-maze. [Figure 6E] FIG. 6E shows percent transitions in the visual stimulation X-maze. [Figure 6F] FIG. 6F shows the percentage of alternations in the visual stimulation X-maze. [Figure 6G] Figure 6G shows a schematic of the high contrast visual stimulus X-maze as well as the total number of entries. [Figure 6H] FIG. 6H shows the percentage of alternations in the high-contrast visual stimulus X-maze. [Figure 7A] FIG. 7A shows a schematic diagram of the Barnes maze. [Figure 7B] FIG. 7B shows the number of errors in the Barnes maze for mice administered ETP69 or DMSO during training on day 10. [Figure 7C] FIG. 7C shows the number of errors in the reversal phase of the Barnes maze test. [Figure 7D] FIG. 7D shows a schematic diagram of the fear conditioning test. [Figure 7E] FIG. 7E shows the results of the fear conditioning test. [Figure 8A]FIG. 8A shows representative images of AD+ mouse brains stained with H3K9me3 and DAPI. [Figure 8B] Figure 8B shows the relationship between the levels of H3K9me3 irradiance in the cingulate cortex and different treatment conditions at 5 days post-treatment (left panel) and 15 days post-treatment (right panel). [Figure 8C] FIG. 8C shows H3K9me3 and DAPI staining in the hippocampus of AD+ mice treated with DMSO or ETP69. [Figure 8D] FIG. 8D shows the levels of H3K9me3 irradiance in the hippocampus of mice treated with DMSO and ETP69. [Figure 8E] Figure 8E shows the relationship between the number of errors in the reverse phase of the Barnes test at day 15 H3K9me3 irradiance with DG and the relationship between seconds to freezing in the fear conditioning test and day 15 H3K9me3 irradiance. [Figure 9A] Figure 9A shows representative images of H3K9me2, 6E10, and GFAP staining in mice administered DMSO and ETP69. [Figure 9B] FIG. 9B shows quantification of GFAP staining in the cingulate cortex of mice administered DMSO and ETP69 after 4 days (left panel) and 15 days (right panel) of treatment. [Figure 9C] FIG. 9C shows quantification of 6E10 staining in the cingulate cortex of mice administered DMSO and ETP69 after 4 days (left panel) and 15 days (right panel) of treatment. [Figure 10A] FIG. 10A shows a representative image of Golgi-Cox stained cingulate cortex from a mouse treated with DMSO. [Figure 10B] FIG. 10B shows a representative image of the Golgi-Cox stained hippocampus of a mouse treated with DMSO. [Figure 10C] FIG. 10C shows a representative image of Golgi-Cox stained neurons from a mouse administered DMSO. [Figure 10D] FIG. 10D shows a representative image of Golgi-Cox stained cingulate cortex from a mouse administered ETP69. [Figure 10E] FIG. 10E shows representative images of Golgi-Cox stained hippocampi from mice administered ETP69. [Figure 10F] FIG. 10F shows representative images of Golgi-Cox stained neurons from mice administered ETP69. [Figure 10G] FIG. 10G shows quantification of dendritic spines in the cingulate cortex and hippocampus. [Figure 10H] FIG. 10H shows quantification of PSD95 irradiance. [Figure 11A] FIG. 11A shows representative images of H3K9me3, NeuN, and DAPI staining in AD+ mice administered DMSO or ETP69. [Figure 11B] FIG. 11B shows quantification of neurons in mice administered DMSO or ETP69. [Figure 11C] FIG. 11C shows representative images of neurons stained for H3K9 and GFAP in AD+ mice treated with DMSO or ETP69. [Figure 11D] FIG. 11D shows quantification of neurons stained for H3K9 and GFAP in AD+ mice treated with DMSO or ETP69. [Figure 11E] FIG. 11E shows representative images of neurons stained with H3K9, CD45, Ilba-1, 6E10, and DAPI in AD+ mice administered DMSO or ETP69. [Figure 11F] FIG. 11F shows quantification of microglia macrophages in AD+ mice treated with DMSO or ETP69. [Figure 12A] FIG. 12A shows a principal component analysis of the proteomic data. [Figure 12B] FIG. 12B shows a plot showing the inverse relationship of FC in protein expression of overlapping significant DEPs in AD+ mice (vs. WT mice) and ETP69-treated AD+ mice (vs. DMSO-treated AD+ mice). [Figure 12C]FIG. 12C shows a volcano plot comparing protein levels in ETP69- and DMSO-treated mice. [Figure 12D] FIG. 12D shows pathway analysis of the proteomic data. [Figure 13A] FIG. 13A shows genes inactivated and activated by ETP69 administration. [Figure 13B] FIG. 13B shows representative images of BDNF, VGF, and Thio-S in mice administered DMSO and ETP69. [Figure 13C] FIG. 13C shows representative images of immunofluorescence of BDNF, VGF, and Thio-S in mice administered ETP69 or DMSO. [Figure 13D] FIG. 13D shows quantification of BDNF in mice administered ETP69. [Figure 13E] FIG. 13E shows quantification of VGF in mice administered ETP69. [Figure 13F] FIG. 13F shows the relationship between the levels of VGF and H3K9me3 staining in the hippocampus. [Figure 13G] FIG. 13G shows the relationship between VGF expression and the number of errors in the reverse phase of the test. [Figure 14] FIG. 14 shows a chart of differentially expressed proteins between ETP69 and DMSO. [Figure 15A] Figure 15A shows the percentage of alternations in color mode of the ViS4M test. #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001: DMSO-treated WT mice vs. DMSO-treated AD+ mice; ★p<0.05, ★★p<0.01, ★★★p<0.001, and ★★★★p<0.0001: DMSO-treated mice vs. ETP69-treated mice; one-way ANOVA followed by Fisher's LSD post-hoc test or unpaired Student's t-test. [Figure 15B]Figure 15B shows the density of dendritic spines as counts per 100 μm of dendrites. #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001: DMSO-treated WT mice vs. DMSO-treated AD+ mice; ★p<0.05, ★★p<0.01, ★★★p<0.001, and ★★★★p<0.0001: DMSO-treated mice vs. ETP69-treated mice; one-way ANOVA followed by Fisher's LSD post-hoc test or unpaired Student's t-test. [Figure 15C] FIG. 15C shows the Pearson coefficients between cortical and hippocampal thin spine density and behavioral performance in the Barnes maze and context-specific fear conditioning tests. [Figure 15D] Figure 15D shows the ratios of thin spines to total spines and mushroom spines to total spines. #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001: DMSO-treated WT mice vs. DMSO-treated AD+ mice; ★p<0.05, ★★p<0.01, ★★★p<0.001, and ★★★★p<0.0001: DMSO-treated mice vs. ETP69-treated mice; one-way ANOVA followed by Fisher's LSD post-hoc test or unpaired Student's t-test. [Figure 15E] FIG. 15E shows the Pearson correlation between the ratio of cortical thin spines and hippocampal mushroom spines and performance during the retention phase of the Barnes maze test. [Figure 16A] Figure 16A shows representative images of H3K9me3 IR in the cortex, showing the regions used for measurement (layers II / III and VI) and quantification of cortical H3K9me3 IR. #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001: DMSO-treated WT mice vs. DMSO-treated AD+ mice; ★p<0.05, ★★p<0.01, ★★★p<0.001, and ★★★★p<0.0001: DMSO-treated mice vs. ETP69-treated mice; one-way ANOVA followed by Fisher's LSD post-hoc test or unpaired Student's t-test. [Figure 16B]Figure 16B shows the Pearson coefficient between cortical H3K9me3 IR and performance in color mode of the ViS4M test. [Figure 16C] Figure 16C shows representative images of H3K9me3 IR in the hippocampus, showing the cornu ammonis (CA) and dentate gyrus (DG) regions used for measurement of H3K9me3 IR and corresponding quantification. #p<0.05, ##p<0.01, ###p<0.001, and ####p<0.0001: DMSO-treated WT mice vs. DMSO-treated AD+ mice; ★p<0.05, ★★p<0.01, ★★★p<0.001, and ★★★★p<0.0001: DMSO-treated mice vs. ETP69-treated mice; one-way ANOVA followed by Fisher's LSD post-hoc test or unpaired Student's t-test. [Figure 16D] Figure 16D shows quantification of Iba-1 IR (red; indicating activated microglia) in the cerebral cortex. Group means, SEM, and individual data points are shown. *p<0.05, *p<0.01, *p<0.001, and *p<0.0001: DMSO-treated mice vs. ETP69-treated mice; one-way ANOVA followed by Fisher's LSD post-hoc test or unpaired Student's t-test. [Figure 17A] Figure 17A shows the inverse correlation of FC in protein expression of 162 overlapping significant DEPs in AD+ mice (vs. WT mice) and ETP69-treated AD+ mice (vs. DMSO-treated AD+ mice). In cluster 1, the expression of 89 proteins was upregulated in AD+ mice and downregulated after ETP69 treatment. In cluster 2, the expression of 70 proteins was downregulated in AD+ mice and upregulated after ETP69 treatment. [Figure 17B] Figure 17B shows a heatmap comparing activation z-scores for biological processes related to behavior and neuroplasticity in AD+ mice (vs. WT mice) and ETP69-treated AD+ mice (vs. DMSO-treated AD+ mice) as determined by IPA (Qiagen). [Figure 17C]Figure 17C shows the STRING v11.5 protein association network showing overlapping proteins involved in "learning," "quantity of neurons," and "dendritic growth / branching" by IPA. Red nodes: upregulated. Green nodes: downregulated. Edge thickness: medium (0.7) to high confidence (0.9) protein associations. [Figure 17D] FIG. 17D shows a heatmap comparing IPA activation z-scores for upstream regulators in AD+ mice (vs. WT mice) and ETP69-treated AD+ mice (vs. DMSO-treated AD+ mice). DETAILED DESCRIPTION OF THE INVENTION

[0010] There is an urgent unmet need to develop effective treatments for neurological diseases that may be commonly associated with synapse and neuron loss, harmful neuroinflammation (e.g., microgliosis, astrogliosis), and increased H3K9me3 epigenetic repression (e.g., associated with heterochromatin epigenetic silencing) to preserve neuromotor and cognitive function. Described herein are methods for reversing H3K9me3 epigenetic gene repression and inducing the transcription and translation of proteins that may have important functions in promoting neuronal survival and synaptic regeneration. Without being limited by theory, inhibition of enzymes responsible for excessive histone methylation may occur in the aging brain and in neurodegenerative disorders. Histone hypermethylation can lead to gene silencing, which can reduce brain and synaptic plasticity, which may be important for motor, cognitive, and visual function.

[0011] In some embodiments, described herein is the use of epipolythiodioxopiperazine (ETP) as an ETP69 or analog (or any histone trimethylation inhibitor) for treating Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and other neurological disorders. In some embodiments, described herein is the use of histone methyltransferase SUV39H1 inhibitors for treating Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and other neurological disorders.

[0012] In the examples described herein, ETP69 administration in aged and middle-aged wild-type (WT) and neurodegenerative mice protected against or reversed locomotor, cognitive, and behavioral impairments. Along with substantially enhancing neuronal dendrite formation (especially newly formed thin dendrites) and synaptic markers, ETP69 activated brain proteins associated with neurotrophic support, immunoregulation, and homeostatic balance. Neurotrophic factors (NTFs) are molecules that enhance neuronal growth and survival. Indeed, ETP69 activated BDNF and increased VGF neuroinducer and levodopa (dopaminergic neuron) levels in the brain. In addition to activating BDNF, the data described herein demonstrate substantial increases in VGF neuroinducer and other factors in the cortex and hippocampus by ETP69, which may preserve the structure and function of neurons and their connections (synapses). The poor delivery efficacy and diffusion of some NTFs into the brain through the blood-brain barrier are considered to be major issues behind their modest efficacy in clinical trials. ETP69 was found to have good delivery to the brain and causes a significant increase in NTFs.

[0013] In some embodiments, the methods and compositions described herein provide benefits in the treatment of various neuromuscular and neurological disorders, such as Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Administration of these methods may result in CNS neuron preservation and promotion of new neuron and synapse formation. Furthermore, without being limited by theory, ETP69 has shown protective effects on microglia and astrocytes (supporting cells of the CNS that are important for repairing abnormal proteins / cancer cells / pathogens, maintaining tissue homeostasis, and / or phagocytosis).

[0014] In some embodiments, administration of ETP69 may comprise disease-modifying therapy. Without being limited by theory, administration of ETP69 may reverse the biological aging clock of neurons, provide neurotrophic support to the central nervous system, and rejuvenate non-neuronal glial cells. Administration of ETP69 may preserve neuromuscular and cognitive behavioral functions.

[0015] Methylation of histone tails typically occurs at specific lysine residues, such as H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20, and can activate or repress transcription. H3K9me3 can be a repressive histone mark and is typically involved in gene silencing. Some embodiments involve the role of histone H3K9me3 and its histone methyltransferase (SUV39H1) in mediating hippocampal memory function and in influencing the progression or development of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or learning disabilities. Pharmacological inhibition of SUV39H1 using selective inhibitors can reduce H3K9me3 levels in the hippocampus of treated subjects and / or improve performance in object location memory tasks, fear conditioning tasks, or complex spatial environment learning tasks. Inhibition of SUV39H1 by ETP69 or another compound disclosed herein can induce an increase in spine density of thin, short, and thick spines, rather than mushroom-shaped spines, in the hippocampus of treated subjects, and can increase the level of GluR1-containing AMPA receptors on the spine surface, a useful indicator of long-term potentiation (LTP). The establishment of H3K9me3 may depend on the activity of the histone methyltransferase SUV39H1, which regulates H3K9 trimethylation in pericentric heterochromatin. Therefore, modulating the function of enzymes that contribute to histone methylation may be a powerful means to counteract cognitive impairment.

[0016] In some embodiments, described herein are methods for treating cognitive impairment by inhibiting an enzyme selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Set1b complex, SMYD2, SMYD3, SUV39H1, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2. In some embodiments, described herein are methods for treating cognitive impairment by inhibiting histone methyltransferases. In some embodiments, the histone methyltransferase includes SUV39H1. In some embodiments, described herein are methods for treating cognitive impairment by inhibiting histone methyltransferases other than SUV39H1. In some embodiments, the cognitive impairment includes Parkinson's disease, Huntington's disease, ALS, or a learning disability.

[0017] A. Compound Provided herein are compounds for use in methods for treating, preventing, or delaying the onset of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or learning disabilities. In some embodiments, the compounds inhibit histone methyltransferase. In some embodiments, the compounds inhibit SUV39H1. In some embodiments, the compounds inhibit trimethylation of H3K9 (H3K9me3). For example, some embodiments include the use of H3K9me3 modulation for enhancing cognitive function or treating disorders such as Parkinson's disease, Huntington's disease, ALS, or learning disabilities.

[0018] In some embodiments, the compound comprises ETP69 (Rac-(3S,6S,7S,8aS)-6-(benzo[d][l,3]dioxol-5-yl)-2,3,7-trimethyl-l,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[l,2-a]pyrazine-7-carbonitrile). In some embodiments, the compound consists of ETP69. The structure of ETP69 is shown in Figure 1. In some embodiments, the compound comprises ETP69 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound consists of ETP69 or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound comprises an analog of ETP69. In some embodiments, the compound is an analog of ETP69. In some embodiments, the compound comprises or consists of an analog of ETP69 or a pharmaceutically acceptable salt thereof. In some embodiments, the analog of ETP69 is a compound having the formula:

[0020] [ka]

[0021] The symbol p can be 2, 3, or 4. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0022] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , and / or R 18each independently can be hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0023] In some embodiments, R 1 is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0024] In some embodiments, R 2 is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0025] In some embodiments, R 3is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0026] In some embodiments, R 4 is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0027] In some embodiments, R 5 is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0028] In some embodiments, R 6is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0029] In some embodiments, R 16 is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0030] In some embodiments, R 18 is hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —Cl3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0031] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 16 , or R 18 is hydrogen. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is halogen. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -N3. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -CF3. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —CCl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —CBr. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -Cl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R 16 , or R 18 is -CN. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -CHO. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —OH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -NH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —COOH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -CONH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —NO. In some embodiments, R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 16 , or R 18 is -SH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -SO. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —SO2Cl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —SO3H. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —SO4H. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —SO 2 NH 2 . In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is -NHNH. In some embodiments, R 1 , R 2 , R 3 , R4 , R 5 , R 6 , R 16 , or R 18 is -ONH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is —NHC(O)NHNH. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is substituted or unsubstituted alkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is substituted or unsubstituted heteroalkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is a substituted or unsubstituted cycloalkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is a substituted or unsubstituted heterocycloalkyl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18is substituted or unsubstituted aryl. In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , or R 18 is a substituted or unsubstituted heteroaryl.

[0032] In some embodiments, the compound inhibits a methyltransferase that is not SUV38H1, and the compound is not ETP69. In some embodiments, the compound is an siRNA. In some embodiments, the compound is a peptide. In some embodiments, the compound is an antibody. In some embodiments, the methyltransferase is selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Set1b complex, SMYD2, SMYD3, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2.

[0033] In some embodiments, the compounds are used in the manufacture of a medicament for the treatment of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, the compounds are used in the manufacture of a medicament for the prevention of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, the compounds are used in the manufacture of a medicament for delaying the onset of Parkinson's disease, Huntington's disease, ALS, or a learning disability.

[0034] B. Preparation In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration.

[0035] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is sterile. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0036] In some embodiments, the pharmaceutically acceptable carrier comprises water. In some embodiments, the pharmaceutically acceptable carrier comprises a buffer. In some embodiments, the pharmaceutically acceptable carrier comprises saline. In some embodiments, the pharmaceutically acceptable carrier comprises water, a buffer, or saline. In some embodiments, the composition comprises a liposome. In some embodiments, the pharmaceutically acceptable carrier comprises a liposome, a lipid, a nanoparticle, a protein, a protein-antibody complex, a peptide, cellulose, a nanogel, or a combination thereof.

[0037] C. Disease Treatment and Prevention The compositions and methods described herein include methods for treating, preventing, or delaying the onset of neurodegenerative diseases such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). Also described herein are methods and compositions for treating disorders other than Parkinson's disease, Huntington's disease, and disorders affecting cognition, including learning disorders, that affect cognition and learning. The compositions and methods reduce neuroinflammation, increase neuroprotection, reverse motor impairments, and activate pathways related to neuromodulatory function.

[0038] In some embodiments, methods are disclosed herein for treating, preventing, or delaying the onset of Parkinson's disease, Huntington's disease, ALS, or a learning disorder in a subject in need thereof. Some embodiments include treating Parkinson's disease, Huntington's disease, ALS, or a learning disorder. Some embodiments include preventing Parkinson's disease, Huntington's disease, ALS, or a learning disorder. Some embodiments include delaying the onset of Parkinson's disease, Huntington's disease, ALS, or a learning disorder. Some embodiments include treating or delaying the onset of Parkinson's disease, Huntington's disease, ALS, or a learning disorder. Some embodiments include administering a composition described herein to a subject. For example, the composition may include ETP69 or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, a method for improving cognition in a subject is disclosed herein. In some embodiments, the subject is at risk of developing Parkinson's disease, Huntington's disease, ALS, or learning disability. Some embodiments include improving cognition in a subject at risk of developing Parkinson's disease, Huntington's disease, ALS, or learning disability. Some embodiments include administering a composition described herein to a subject. For example, the composition can include ETP69 or a pharmaceutically acceptable salt thereof.

[0040] 1. Parkinson's disease Parkinson's disease is a neurodegenerative disease that affects the motor system and has motor and cognitive symptoms.Motor symptoms include unintentional or uncontrollable movements, such as trembling, stiffness, difficulty walking, difficulty speaking, and difficulty with balance and coordination.Cognitive symptoms include mental and behavioral changes, sleep problems, depression, memory difficulties, and fatigue.

[0041] In some embodiments, disclosed herein are methods for treating, preventing, or delaying the onset of Parkinson's disease in a subject in need thereof. Some embodiments include treating Parkinson's disease. Some embodiments include preventing Parkinson's disease. Some embodiments include delaying the onset of Parkinson's disease. Some embodiments include treating or delaying the onset of Parkinson's disease. Some embodiments include administering to the subject a composition described herein. For example, the composition may include ETP69 or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, a method for improving cognition in a subject is disclosed herein. In some embodiments, the subject is at risk of developing Parkinson's disease. Some embodiments include improving cognition in a subject at risk of developing Parkinson's disease. Some embodiments include administering a composition described herein to the subject. For example, the composition may include ETP69 or a pharmaceutically acceptable salt thereof.

[0043] 2. Huntington's disease Huntington's disease is a neurodegenerative disorder caused by a defect in the Huntington gene. Mutant forms of huntingtin result in an increased rate of neuronal decay, including neurons in the basal ganglia. Symptoms include lack of coordination, cognitive changes, movement abnormalities including chorea (hyperkinetic movement disorder), and dementia. Cognitive deficits include deficits in executive function, cognitive flexibility, abstract thinking, rule acquisition, and memory deficits.

[0044] In some embodiments, disclosed herein are methods for treating, preventing, or delaying the onset of Huntington's disease in a subject in need thereof. Some embodiments include treating Huntington's disease. Some embodiments include preventing Huntington's disease. Some embodiments include delaying the onset of Huntington's disease. Some embodiments include treating or delaying the onset of Huntington's disease. Some embodiments include administering to the subject a composition described herein. For example, the composition may include ETP69 or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, a method for improving cognition in a subject is disclosed herein. In some embodiments, the subject is at risk of developing Huntington's disease. Some embodiments include improving cognition in a subject at risk of developing Huntington's disease. Some embodiments include administering a composition described herein to the subject. For example, the composition can include ETP69 or a pharmaceutically acceptable salt thereof.

[0046] 3. Amyotrophic lateral sclerosis (ALS) Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons. Symptoms of ALS include stiff muscles, muscle spasms, muscle weakness, muscle wasting, difficulty speaking or swallowing, frontotemporal dementia, and cognitive and behavioral impairments. Cognitive and behavioral deficits include phrase repetition, loss of inhibition, language dysfunction, executive dysfunction, social cognition deficits, and verbal memory deficits.

[0047] In some embodiments, methods for treating, preventing, or delaying the onset of ALS in a subject in need thereof are disclosed herein. Some embodiments include treating ALS. Some embodiments include preventing ALS. Some embodiments include delaying the onset of ALS. Some embodiments include treating or delaying the onset of ALS. Some embodiments include administering a composition described herein to a subject. For example, the composition may include ETP69 or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, a method for improving cognition in a subject is disclosed herein. In some embodiments, the subject is at risk of developing ALS. Some embodiments include improving cognition in a subject at risk of developing ALS. Some embodiments include administering a composition described herein to the subject. For example, the composition can include ETP69 or a pharmaceutically acceptable salt thereof.

[0049] 4. Learning disabilities Learning disabilities affect the brain's ability to send, receive, and process information. Learning disabilities can exist at birth or due to injuries that occur after birth, including head injuries. Learning disabilities include, but are not limited to, reflex disorders, cognitive impairment, dysgraphia, auditory processing disorders, language processing disorders, nonverbal learning disorders, and visual perceptual / visual motor disorders.

[0050] In some embodiments, disclosed herein are methods for treating, preventing, or delaying the onset of a learning disorder in a subject in need thereof. Some embodiments include treating the learning disorder. Some embodiments include preventing the learning disorder. Some embodiments include delaying the onset of the learning disorder. Some embodiments include treating or delaying the onset of the learning disorder. Some embodiments include administering a composition described herein to the subject. For example, the composition may include ETP69 or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, a method for improving cognition in a subject is disclosed herein. In some embodiments, the subject is at risk of developing a learning disability. Some embodiments include improving cognition in a subject at risk of developing a learning disability. Some embodiments include administering a composition described herein to the subject. For example, the composition can include ETP69 or a pharmaceutically acceptable salt thereof.

[0052] D. Administration In some embodiments, administering a compound (e.g., ETP69) to a subject comprises administering an effective amount of the compound sufficient to inhibit a methyltransferase in the subject. In some embodiments, administering a compound comprises administering an effective amount of the compound sufficient to inhibit SUV39H1. In some embodiments, administering a compound comprises administering an effective amount of the compound sufficient to inhibit ASH1L. In some embodiments, administering a compound comprises administering an effective amount of the compound sufficient to inhibit the MLL1 complex. In some embodiments, administering a compound comprises administering an effective amount of the compound sufficient to inhibit the MLL4 complex. In some embodiments, administering a compound comprises administering an effective amount of the compound sufficient to inhibit NSD3. In some embodiments, administering a compound comprises administering an effective amount of the compound sufficient to inhibit the SET1b complex. In some embodiments, administering a compound comprises administering an effective amount of the compound sufficient to inhibit SMYD2. In some embodiments, administering a compound comprises administering an effective amount of the compound sufficient to inhibit SMYD3. In some embodiments, administering the compound comprises administering an effective amount of the compound sufficient to inhibit SUV39H2. In some embodiments, administering the compound comprises administering an effective amount of the compound sufficient to inhibit a methyltransferase selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Set1b complex, SMYD2, SMYD3, SUV39H1, and SUV39H2. In some embodiments, administering the compound comprises administering an effective amount of the compound sufficient to inhibit a methyltransferase selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Set1b complex, SMYD2, SMYD3, SUV39H1, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2.

[0053] In some embodiments, administration of the compound inhibits methyltransferase by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more than 95%. In some embodiments, administration of the compound inhibits methyltransferase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more than 95%. In some embodiments, the methyltransferase is selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2. In some embodiments, SUV39H1 is not inhibited.

[0054] In some embodiments, the compound is administered at a dose that inhibits a methyltransferase selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2. In some embodiments, the compound is administered at a dose that does not inhibit SUV39H1.

[0055] In some embodiments, the route of administration is intravenous, oral, subcutaneous, intraperitoneal, ophthalmic, intraocular, intramuscular, interstitial, or intracranial administration. In some embodiments, the administration is systemic administration. In some embodiments, the administration is intravenous administration. In some embodiments, the administration is oral administration. In some embodiments, the administration comprises injection. In some embodiments, the administration is subcutaneous administration. In some embodiments, the administration is intraperitoneal administration. In some embodiments, the administration is ophthalmic administration. In some embodiments, the administration is intraocular administration. In some embodiments, the administration is intramuscular administration. In some embodiments, the administration is interstitial administration. In some embodiments, the administration is intracranial administration.

[0056] In some embodiments, administering the compound comprises administering a single dose. In some embodiments, administering the compound comprises administering multiple doses (e.g., two doses). For example, administering can comprise multiple administrations at separate times. Multiple doses can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more doses, or a dose range defined by any two of the foregoing dose numbers. In some embodiments, administering comprises administering 11 doses.

[0057] E. Subject Some embodiments of the methods described herein involve administering a compound to a subject. Non-limiting examples of subjects include vertebrates, animals, mammals, dogs, cats, cows, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a vertebrate. In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. In some embodiments, the subject is a cow. In some embodiments, the subject is a mouse. In some embodiments, the subject is a rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a monkey. In some embodiments, the subject is an animal, mammal, dog, cat, cow, rodent, mouse, rat, primate, or monkey. In some embodiments, the subject is a human. In some embodiments, the subject is male. In some embodiments, the subject is female.

[0058] In some embodiments, the subject is 90 years of age or older. In some embodiments, the subject is 85 years of age or older. In some embodiments, the subject is 80 years of age or older. In some embodiments, the subject is 70 years of age or older. In some embodiments, the subject is 60 years of age or older. In some embodiments, the subject is 50 years of age or older. In some embodiments, the subject is 40 years of age or older. In some embodiments, the subject is 30 years of age or older. In some embodiments, the subject is 20 years of age or older. In some embodiments, the subject is 10 years of age or older. In some embodiments, the subject is 1 year of age or older. In some embodiments, the subject is 0 years of age or older. In some embodiments, the subject is asymptomatic of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or a learning disability. In some embodiments, the subject is at least about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, or about 70 years of age.

[0059] In some embodiments, the subject is 100 years old or younger. In some embodiments, the subject is 90 years old or younger. In some embodiments, the subject is 85 years old or younger. In some embodiments, the subject is 80 years old or younger. In some embodiments, the subject is 70 years old or younger. In some embodiments, the subject is 60 years old or younger. In some embodiments, the subject is 50 years old or younger. In some embodiments, the subject is 40 years old or younger. In some embodiments, the subject is 30 years old or younger. In some embodiments, the subject is 20 years old or younger. In some embodiments, the subject is 10 years old or younger. In some embodiments, the subject is 1 year old or younger. In some embodiments, the subject is about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, or about 70 years old or younger.

[0060] In some embodiments, the subject is 0-100 years old. In some embodiments, the subject is 20-90 years old. In some embodiments, the subject is 30-80 years old. In some embodiments, the subject is 40-75 years old. In some embodiments, the subject is 50-70 years old. In some embodiments, the subject is 40-85 years old.

[0061] In some embodiments, the subject has Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, the subject is at risk of developing Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, the subject has symptoms of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, the subject does not have symptoms of Parkinson's disease, Huntington's disease, ALS, or a learning disability.

[0062] F. Patient Selection In some embodiments, the method includes selecting a subject for treatment, wherein a methyltransferase is dysregulated in the subject's tissue. In some embodiments, the methyltransferase is ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2. In some embodiments, the methyltransferase is not SUV39H1.

[0063] In some embodiments, the method comprises inhibiting a methyltransferase in a patient in need thereof. In some embodiments, the methyltransferase is ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2. In some embodiments, the methyltransferase is not SUV39H1.

[0064] In some embodiments, the method includes selecting a target for methyltransferase inhibition. In some embodiments, the methyltransferase is ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2. In some embodiments, the methyltransferase is not SUV39H1.

[0065] In some embodiments, the subject has, has been diagnosed with, or is suspected of having a cognitive impairment. In some embodiments, the cognitive impairment is Parkinson's disease, Huntington's disease, ALS, or a learning disability.

[0066] G. Baseline Characteristics Some embodiments of the methods described herein include obtaining a baseline measurement from a subject. For example, in some embodiments, the baseline measurement is obtained from the subject before treating the subject. In some embodiments, the baseline measurement is a symptom of a learning disorder, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or a condition described herein. Non-limiting examples of baseline measurements include a baseline memory measurement, a baseline learning measurement, a baseline locomotor activity measurement, a baseline neuroarchitecture measurement, a baseline neuroinflammation measurement, a baseline locomotor activity measurement, or a baseline biomarker measurement.

[0067] In some embodiments, the baseline measurement comprises a mental state examination. In some embodiments, the mental state examination is the Mini-Mental State Examination (MMSE), Mini-Cog, Cantab Mobile, CogniGram, CogniVue, or Cognitive and Automated Neuropsychological Assessment Metrics (ANAM). In some embodiments, the mental state examination is the Mini-Mental State Examination (MMSE). In some embodiments, the mental state examination is the Mini-Cog. In some embodiments, the mental state examination is the Cantab Mobile. In some embodiments, the mental state examination is the CogniGram. In some embodiments, the mental state examination is the CogniVue. In some embodiments, the mental state examination is the Cognitive and Automated Neuropsychological Assessment Metrics (ANAM). In some embodiments, the baseline measurement comprises a neuroimaging examination. In some embodiments, the neuroimaging examination is magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, the neuroimaging examination is an MRI examination. In some embodiments, the neuroimaging examination is a CT examination.

[0068] In some embodiments, the baseline measurements are obtained directly from the subject. In some embodiments, the baseline measurements are obtained by observation, for example, by observation of the subject or tissues of the subject. In some embodiments, the baseline measurements are obtained non-invasively using an imaging device. In some embodiments, the baseline measurements are obtained on a sample from the subject. In some embodiments, the baseline measurements are obtained on one or more histological tissue sections. In some embodiments, the baseline measurements are obtained by performing an assay, such as an immunoassay, a colorimetric assay, or a fluorescent assay, on a sample obtained from the subject. In some embodiments, the baseline measurements are obtained by an immunoassay, a colorimetric assay, or a fluorescent assay. In some embodiments, the baseline measurements are obtained by PCR.

[0069] In some embodiments, the baseline measurement is a baseline memory measurement. In some embodiments, the baseline memory measurement is a baseline spatial memory measurement. In some embodiments, the baseline memory measurement is a baseline hippocampal-based spatial memory measurement. In some embodiments, the baseline spatial memory measurement comprises a fear-based test. In some embodiments, the baseline spatial memory measurement comprises a fear conditioning test.

[0070] In some embodiments, the baseline measure is a baseline learning measure. In some embodiments, the baseline learning measure is a baseline visual recognition memory and learning measure. In some embodiments, the baseline visual recognition memory and learning measure comprises a color memory and learning measure. In some embodiments, the baseline visual recognition memory and learning measure comprises a contrast memory and learning measure. In some embodiments, the baseline visual recognition memory and learning measure comprises a transition memory and learning measure. In some embodiments, the baseline visual recognition memory and learning measure comprises a spatial memory and learning measure. In some embodiments, the baseline measure is a baseline spontaneous activity measure.

[0071] In some embodiments, the baseline measurement is a baseline neuronal architecture measurement. In some embodiments, the baseline neuronal architecture measurement includes a baseline spine integrity measurement. In some embodiments, the baseline neuronal architecture measurement includes a baseline dendritic spine measurement. In some embodiments, the baseline dendritic spine measurement evaluates elongated filopodia spines, elongated spines, thin spines, short and thick spines, broad-headed mushroom-shaped spines, and / or branching spines. In some embodiments, the baseline neuronal architecture measurement includes a baseline spine density measurement. In some embodiments, the baseline neuronal architecture measurement includes a number of synapses. In some embodiments, the baseline neuronal architecture measurement is determined on a biopsy. In some embodiments, the baseline neuronal architecture measurement is determined using a stain, such as a Golgi-Cox stain. In some embodiments, the baseline neuronal architecture measurement is determined using photography. In some embodiments, the baseline neuronal architecture measurement is determined using a microscope.

[0072] In some embodiments, the baseline measurement comprises a baseline neuroinflammation measurement. In some embodiments, the baseline neuroinflammation measurement comprises a baseline activated or baseline reactive immune activation measurement. In some embodiments, the baseline neuroinflammation measurement comprises a baseline activated or baseline reactive immune cell measurement. In some embodiments, the baseline neuroinflammation measurement comprises a baseline reactive astrocyte measurement. In some embodiments, the baseline neuroinflammation measurement comprises a baseline activated microglia measurement. In some embodiments, the baseline neuroinflammation measurement comprises a baseline macrophage measurement. In some embodiments, the baseline neuroinflammation measurement is obtained in a tissue or fluid sample. In some embodiments, the baseline neuroinflammation measurement is obtained from a biopsy. In some embodiments, the baseline neuroinflammation measurement is obtained by an assay such as an immunoassay, by fluorescence-activated cell sorting (FACS), or by histological evaluation.

[0073] In some embodiments, the baseline measurement is a baseline ambulatory measurement. In some embodiments, the baseline ambulatory measurement is a measurement of respiratory muscle function. In some embodiments, the baseline measurement of respiratory muscle function is a forced vital volume measurement, a maximum inspiratory pressure measurement, or a maximum expiratory pressure measurement. In some embodiments, the baseline ambulatory measurement is a functional speed measurement. In some embodiments, the functional assessment scale is the Appel ALS Rating Scale, the ALS Functional Rating Scale, the Unified Huntington's Disease Rating Scale (UHDRS), a Total Functional Capacity (TFC) scale, or a Total Motor Score (TMS).

[0074] In some embodiments, the baseline measurement is a baseline molecular marker measurement. In some embodiments, the baseline molecular marker measurement is a baseline histone trimethylation (H3K9me3) measurement. In some embodiments, the baseline molecular measurement is a baseline nucleosome methylation measurement. In some embodiments, the baseline measurement is a baseline core histone methylation measurement. In some embodiments, the baseline measurement is a histone H4 methylation measurement. In some embodiments, the baseline measurement is a MEKK2 methylation measurement. In some embodiments, the baseline molecular measurement is a measurement of an enzyme from Table 1. In some embodiments, the baseline molecular measurement is a measurement of ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2. In some embodiments, the baseline molecular marker measurement is a baseline protein measurement. In some embodiments, the baseline molecular marker measurement is a baseline biomarker measurement. In some embodiments, the baseline molecular marker measurement is determined in a biopsy. In some embodiments, the baseline molecular marker measurement is determined using an immunoassay such as an ELISA.

[0075] Some embodiments of the methods described herein include obtaining a sample from a subject. In some embodiments, a baseline measurement is obtained in the sample obtained from the subject. In some embodiments, the sample is obtained from the subject prior to administration or treatment of the subject with a composition described herein. In some embodiments, the baseline measurement is obtained in the sample obtained from the subject prior to administration of the composition to the subject.

[0076] In some embodiments, the sample comprises a fluid. In some embodiments, the sample is a fluid sample. In some embodiments, the sample is a blood, plasma, or serum sample. In some embodiments, the sample comprises blood. In some embodiments, the sample is a blood sample. In some embodiments, the sample is a whole blood sample. In some embodiments, the blood is fractionated or centrifuged. In some embodiments, the sample comprises plasma. In some embodiments, the sample is a plasma sample. In some embodiments, the sample comprises serum. In some embodiments, the sample is a serum sample. In some embodiments, the sample comprises cerebrospinal fluid (CSF).

[0077] In some embodiments, the sample comprises tissue. In some embodiments, the sample is a tissue sample. In some embodiments, the sample comprises neural tissue. In some embodiments, the sample is a brain sample. In some embodiments, the sample is a hippocampal sample. In some embodiments, the sample comprises neurons.

[0078] In some embodiments, the sample comprises cells. The cells may comprise neuronal cells. The cells may comprise brain cells. The cells may comprise brain macrophages, microglia, or astrocytes. In some embodiments, the cells comprise neurons. In some embodiments, the cells comprise macrophages. In some embodiments, the cells comprise microglia. In some embodiments, the cells comprise astrocytes.

[0079] H. Treatment Effects In some embodiments, the composition or administration of the composition affects a measurement, such as a memory measurement, a learning measurement, a spontaneous activity measurement, a neuronal architecture measurement, a neuroinflammation measurement, or a biomarker measurement, compared to a baseline measurement. In some embodiments, the measurement is related to symptoms of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), or a learning disability.

[0080] Some embodiments of the methods described herein include obtaining a measurement from a subject. For example, the measurement can be obtained from the subject after the subject has been treated. In some embodiments, the measurement is obtained in a second sample (such as a body fluid or tissue sample as described herein) obtained from the subject after the composition has been administered to the subject. In some embodiments, the measurement is an indication that the disorder has been treated.

[0081] In some embodiments, the measurements are obtained directly from the subject. In some embodiments, the measurements are obtained non-invasively using an imaging device. In some embodiments, the measurements are obtained in a second sample from the subject. In some embodiments, the measurements are obtained in one or more histological tissue sections. In some embodiments, the measurements are obtained by performing an assay on the second sample obtained from the subject. In some embodiments, the measurements are obtained by an assay such as an assay described herein. In some embodiments, the assay is an immunoassay, a colorimetric assay, a fluorescent assay, or a PCR assay. In some embodiments, the measurements are obtained by an assay such as an immunoassay, a colorimetric assay, or a fluorescent assay. In some embodiments, the measurements are obtained by PCR. In some embodiments, the measurements are obtained by histology. In some embodiments, the measurements are obtained by observation. In some embodiments, additional measurements are made in a third, fourth, fifth, or other sample.

[0082] In some embodiments, measurements are obtained within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after administration of the composition. In some embodiments, measurements are obtained within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the composition. In some embodiments, measurements are obtained within 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition. In some embodiments, measurements are obtained 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours after administration of the composition. In some embodiments, measurements are obtained 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after administration of the composition. In some embodiments, measurements are obtained 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years after administration of the composition.

[0083] In some embodiments, the composition reduces the measurement relative to a baseline measurement. In some embodiments, the reduction is measured in a second tissue sample obtained from the subject after administering the composition to the subject. In some embodiments, the reduction is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement is reduced by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline measurement. In some embodiments, the measurement is reduced by about 10% or more relative to the baseline measurement. In some embodiments, the measurement is reduced by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more relative to the baseline measurement. In some embodiments, the measurement is reduced by about 2.5% or less, about 5% or less, or about 7.5% or less relative to the baseline measurement. In some embodiments, the measurement is reduced by about 10% or less relative to the baseline measurement. In some embodiments, the measurement is decreased by about 20% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less, or about 100% or less compared to the baseline measurement, hi some embodiments, the measurement is decreased by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or a range defined by either of the two aforementioned percentages.

[0084] In some embodiments, the composition increases the measurement relative to a baseline measurement. In some embodiments, the increase is measured in a second tissue sample obtained from the subject after administering the composition to the subject. In some embodiments, the increase is measured directly in the subject after administering the composition to the subject. In some embodiments, the measurement increases by about 2.5% or more, about 5% or more, or about 7.5% or more relative to the baseline measurement. In some embodiments, the measurement increases by about 10% or more relative to the baseline measurement. In some embodiments, the measurement increases by about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more relative to the baseline measurement. In some embodiments, the measurement increases by about 100% or more, about 250% or more, about 500% or more, about 750% or more, or about 1000% or more relative to the baseline measurement. In some embodiments, the measurement increases by about 2.5% or less, about 5% or less, or about 7.5% or less relative to the baseline measurement. In some embodiments, the measurement increases by about 10% or less relative to the baseline measurement. In some embodiments, the measurement increases by about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or less relative to the baseline measurement. In some embodiments, the measurement increases by about 100%, 250%, 500%, 750%, or 1000% or less relative to the baseline measurement. In some embodiments, the measurement increases by 2.5%, 5%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 250%, 500%, 750%, or 1000%, or a range defined by either of the two aforementioned percentages.

[0085] In some embodiments, the measurement comprises a mental status test. In some embodiments, the mental status test is the Mini-Mental State Examination (MMSE), Mini-Cog, Quanta Mobile, CogniGram, Cogniview, or Cognitive and Automated Neuropsychological Assessment Metrics (ANAM) test. In some embodiments, the measurement comprises a neuroimaging test. In some embodiments, the neuroimaging test is magnetic resonance imaging (MRI) or computed tomography (CT).

[0086] In some embodiments, the measurement is a memory measurement. In some embodiments, the memory measurement is a spatial memory measurement. In some embodiments, the memory measurement is a hippocampal-based spatial memory measurement. In some embodiments, the spatial memory measurement comprises a fear-based test. In some embodiments, the spatial memory measurement comprises a fear conditioning test. In some embodiments, the memory measurement is improved. In some embodiments, the memory measurement is increased.

[0087] In some embodiments, the measure is a learning measure. In some embodiments, the learning measure is a visual cognitive memory and learning measure. In some embodiments, the visual cognitive memory and learning measure comprises a color memory and learning measure. In some embodiments, the visual cognitive memory and learning measure comprises a contrast memory and learning measure. In some embodiments, the visual cognitive memory and learning measure comprises a transition memory and learning measure. In some embodiments, the visual cognitive memory and learning measure comprises a spatial memory and learning measure. In some embodiments, the learning measure is improved. In some embodiments, the learning measure is increased. In some embodiments, the measure is a spontaneous activity measure. In some embodiments, the spontaneous activity measure is improved. In some embodiments, the spontaneous activity measure is increased.

[0088] In some embodiments, the measurement is a neuronal architecture measurement. In some embodiments, the neuronal architecture measurement includes a spine integrity measurement. In some embodiments, the neuronal architecture measurement includes a dendritic spine measurement. In some embodiments, the dendritic spine measurement evaluates elongated filopodia, long thin, thin, short thick, broad-headed mushroom-shaped, and / or branched spines. In some embodiments, the neuronal architecture measurement includes a spine density measurement. In some embodiments, the neuronal architecture measurement includes a number of synapses. In some embodiments, the neuronal architecture measurement is determined in a biopsy. In some embodiments, the neuronal architecture measurement is determined using a stain, such as a Golgi-Cox stain. In some embodiments, the neuronal architecture measurement is determined using photography. In some embodiments, the neuronal architecture measurement is determined using microscopy. In some embodiments, the neuronal architecture measurement is improved. In some embodiments, the neuronal architecture measurement (e.g., number of synapses) is increased.

[0089] In some embodiments, the measurement comprises a neuroinflammation measurement. In some embodiments, the neuroinflammation measurement comprises an activated or reactive immune activation measurement. In some embodiments, the neuroinflammation measurement comprises an activated or reactive immune cell measurement. In some embodiments, the neuroinflammation measurement comprises a reactive astrocyte measurement. In some embodiments, the neuroinflammation measurement comprises an activated microglia measurement. In some embodiments, the neuroinflammation measurement comprises a macrophage measurement. In some embodiments, the neuroinflammation measurement is obtained in a tissue or fluid sample. In some embodiments, the neuroinflammation measurement is obtained from a biopsy. In some embodiments, the neuroinflammation measurement is obtained by an assay such as an immunoassay, by fluorescence activated cell sorting (FACS), or by histological evaluation.

[0090] In some embodiments, the measurement is a motor measurement. In some embodiments, the motor measurement is a measurement of respiratory muscle function. In some embodiments, the measurement of respiratory muscle function is a forced vital volume measurement, a maximum inspiratory pressure measurement, or a maximum expiratory pressure measurement. In some embodiments, the motor measurement is a functional heart rate measurement. In some embodiments, the functional assessment scale is the Appel ALS Rating Scale, the ALS Functional Rating Scale, the Unified Huntington's Disease Rating Scale (UHDRS), a Total Functional Capacity (TFC) scale, or a Total Motor Score (TMS). In some embodiments, the motor measure is improved relative to the baseline motor measure.

[0091] In some embodiments, the measurement is a molecular marker measurement. In some embodiments, the molecular marker measurement is histone trimethylation (H3K9me3) measurement. In some embodiments, the molecular marker measurement is nucleosome methylation measurement. In some embodiments, the molecular marker measurement is core histone methylation measurement. In some embodiments, the molecular marker measurement is histone H4 methylation measurement. In some embodiments, the molecular marker measurement is MEKK2 methylation measurement. In some embodiments, the molecular measurement is measurement of an enzyme from Table 1. In some embodiments, the molecular measurement is measurement of ASH1L, MLL1 complex, MLL4 complex, NSD3, SetIb complex, SMYD2, SMYD3, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2. In some embodiments, the molecular marker measurement is a protein measurement. In some embodiments, the molecular marker measurement is a biomarker measurement. The measurement may be increased relative to a baseline measurement. The measurement may be decreased relative to a baseline measurement. In some embodiments, the molecular marker measurement is determined in a biopsy. In some embodiments, the molecular marker measurement is determined using an immunoassay such as an ELISA. In some embodiments, the molecular marker measurement is increased. For example, BDNF measurement may be increased after treatment with a compound. In some embodiments, the molecular marker measurement is decreased. For example, H3K9me3 measurement may be decreased after treatment with a compound.

[0092] In some embodiments, administration ameliorates symptoms of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, administration alleviates symptoms of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, administration prevents symptoms of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, administration delays symptoms of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, administration slows the progression of symptoms of Parkinson's disease, Huntington's disease, ALS, or a learning disability.

[0093] Methods for delaying the onset of Parkinson's disease, Huntington's disease, ALS, or a learning disability are described herein. In some embodiments, the delayed onset of Parkinson's disease, Huntington's disease, ALS, or a learning disability comprises a delayed onset of at least one symptom of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, the delayed onset of at least ON symptoms is at least about 6 months, about 12 months, about 18 months, about 2 years, about 3 years, about 5 years, about 10 years, about 15 years, or about 20 years. In some embodiments, the delayed onset of at least onset symptoms is at least 6 months. In some embodiments, the delayed onset of at least onset symptoms is at least 12 months. In some embodiments, the delayed onset of at least onset symptoms is at least 18 months. In some embodiments, the delayed onset of at least onset symptoms is at least 2 years. In some embodiments, the delayed onset of at least onset symptoms is at least 3 years. In some embodiments, the delayed onset of at least onset symptoms is at least 5 years. In some embodiments, the delay in onset of at least onset symptoms is at least 10 years. In some embodiments, the delay in onset of at least onset symptoms is at least 15 years. In some embodiments, the delay in onset of at least onset symptoms is at least 20 years.

[0094] In some embodiments, the delay in onset of Parkinson's disease, Huntington's disease, ALS, or a learning disability comprises a delay in onset of one or less symptoms of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, the delay in onset of symptoms before onset is about 6 months, about 12 months, about 18 months, about 2 years, about 3 years, about 5 years, about 10 years, about 15 years, or about 20 years or less. In some embodiments, the delay in onset of symptoms before onset is 6 months or less. In some embodiments, the delay in onset of symptoms before onset is 12 months or less. In some embodiments, the delay in onset of symptoms before onset is 18 months or less. In some embodiments, the delay in onset of symptoms before onset is 2 years or less. In some embodiments, the delay in onset of symptoms before onset is 3 years or less. In some embodiments, the delay in onset of symptoms before onset is 5 years or less. In some embodiments, the delay in onset of symptoms before onset is 10 years or less. In some embodiments, the delay in onset of symptoms before onset is 15 years or less. In some embodiments, the delay in onset is 20 years or less.

[0095] Described herein are methods for delaying the onset of at least one symptom of Parkinson's disease, Huntington's disease, ALS, or a learning disability. In some embodiments, the symptom comprises memory loss, difficulty concentrating, difficulty completing familiar tasks, confusion in time or place, difficulty understanding visual images and spatial relationships, language difficulties, misplacing items, poor or impaired judgment, social withdrawal, and / or mood or personality changes. In some embodiments, the symptom comprises memory loss. In some embodiments, the symptom comprises difficulty concentrating. In some embodiments, the symptom comprises difficulty completing familiar tasks. In some embodiments, the symptom comprises confusion in time or place. In some embodiments, the symptom comprises difficulty understanding visual images and spatial relationships. In some embodiments, the symptom comprises language difficulties. In some embodiments, the symptom comprises incorrect items. In some embodiments, the symptom comprises poor or impaired judgment. In some embodiments, the symptom comprises social withdrawal. In some embodiments, the symptom comprises mood or personality changes.

[0096] In some embodiments, the method improves a subject's memory loss, difficulty concentrating, difficulty completing known tasks, confusion in time or place, difficulty understanding visual images and spatial relationships, language difficulties, misplacement of items, poor or poor judgment, social withdrawal, and / or mood or personality changes. In some embodiments, the method improves memory loss. In some embodiments, the method improves concentration difficulties. In some embodiments, the method improves difficulty completing known tasks. In some embodiments, the method improves confusion in time or place. In some embodiments, the method improves difficulty understanding visual images. In some embodiments, the method improves difficulty understanding spatial relationships. In some embodiments, the method improves difficulty understanding visual images and spatial relationships. In some embodiments, the method improves language difficulties. In some embodiments, the method improves misplacement of items. In some embodiments, the method improves poor or poor judgment. In some embodiments, the method improves social withdrawal. In some embodiments, the method improves mood or personality changes.

[0097] In some embodiments, the treatment results in an improvement in a mental state examination and / or a neuroimaging test. In some embodiments, the treatment results in an improvement in the mental state examination. In some embodiments, the mental state examination is the Mini-Mental State Examination (MMSE), Mini-Cog, Cantab Mobile, CogniGram, CogniVue, or Cognitive and Automated Neuropsychological Assessment Metrics (ANAM). In some embodiments, the mental state examination is the Mini-Mental State Examination (MMSE). In some embodiments, the mental state examination is the Mini-Cog. In some embodiments, the mental state examination is the Cantab Mobile. In some embodiments, the mental state examination is the CogniGram. In some embodiments, the mental state examination is the CogniVue. In some embodiments, the mental state examination is the Cognitive and Automated Neuropsychological Assessment Metrics (ANAM). In some embodiments, the improvement comprises an improved score compared to the score obtained before administration of the composition.

[0098] In some embodiments, the treatment results in an improvement in a neuroimaging study. In some embodiments, the neuroimaging study is magnetic resonance imaging (MRI) or computed tomography (CT). In some embodiments, the neuroimaging study is an MRI study. In some embodiments, the neuroimaging study is a CT study.

[0099] I. Definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is generally understood in the art.

[0100] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to have all possible subranges specifically disclosed, as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0101] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "sample" includes multiple samples, mixtures thereof.

[0102] The terms "determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present or not (e.g., detecting). These terms can include quantitative, qualitative, or quantitative and qualitative determinations. Evaluation can be relative or absolute. "Detecting the presence" can include determining the amount of something present in addition to determining whether it is present or absent, depending on the context.

[0103] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0104] "Pharmaceutically acceptable acid addition salt" refers to salts that retain the biological effectiveness and properties of the free base and are biologically or otherwise undesirable and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, etc. Salts of amino acids such as alginate, gluconate, and galacturonate are also contemplated. Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those of ordinary skill in the art.

[0105] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid, which is not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,7V-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins, and the like.

[0106] The terms "subject" and "patient" may be used interchangeably herein. A "subject" may be a biological entity that contains expressed genetic material. The biological entity may be, for example, a plant, an animal, or a microorganism, including bacteria, viruses, fungi, and protozoa. The subject may be a mammal. The mammal may be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for a disease.

[0107] As used herein, the term "about" refers to a number plus or minus 10% of that number. The term "about" refers to a range minus 10% of the lowest value and plus 10% of the highest value.

[0108] As used herein, the terms "treatment" or "treating" refer to a pharmaceutical or other intervention regimen to obtain a beneficial or desired result in a recipient. Beneficial or desired results include, but are not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit may refer to the eradication or amelioration of the condition or underlying disease being treated. Therapeutic benefit may also be achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in a subject, even though the subject may still be afflicted with the underlying disorder. Prophylactic benefit includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, subjects at risk of developing a particular disease or reporting one or more physiological symptoms of a disease may receive treatment even if a diagnosis of the disease has not been made.

[0109] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0110] J. Embodiment In certain aspects, the following embodiments are disclosed herein: 1. A method for treating Parkinson's disease, Huntington's disease, ALS, or a learning disability in a subject in need of such treatment, comprising administering to the subject a compound comprising an inhibitor of histone 3, lysine 9 (H3K9) trimethylation. 2. The method of embodiment 1, wherein the compound comprises an inhibitor of SUV39H1. 3. The method of embodiment 1, wherein the compound comprises an inhibitor of SUV39H2. 4. The compound is represented by formula (I)

[0111] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 2, 3, or 4; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 and R 18 are independently hydrogen, halogen, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2, -SO2Cl, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. 5. The method of any one of embodiments 1-4, wherein the compound comprises (Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile) (ETP69) or a pharmaceutically acceptable salt thereof. 6. The method of any one of embodiments 1-5, wherein administering improves locomotor activity in the subject. 7. The method of any one of embodiments 1-6, wherein administering reduces neuroinflammation in the subject. 8. The method of any one of embodiments 1-7, wherein administering increases or improves a neuroprotective phenotype. 9. The method of embodiment 7, wherein the administration activates brain-derived neurotrophic factor (BDNF) or VGF nerve growth factor-induced (VGF) signaling in the subject. 10. The method of any of embodiments 1-9, wherein administering reduces or ameliorates a phenotype associated with Parkinson's disease, Huntington's disease, ALS, or a learning disability in the subject. 11. The method of embodiment 10, wherein the subject has or has been diagnosed with Parkinson's disease. 12. The method of embodiment 10, wherein the subject has or has been diagnosed with Huntington's disease. 13. The method of embodiment 10, wherein the subject has or has been diagnosed with ALS. 14. The method of embodiment 10, wherein the subject has or has been diagnosed with a learning disability. 15. A method for inhibiting an enzyme selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H1, and SUV39H2, comprising: inhibiting the enzyme with a compound represented by formula (I):

[0112] [ka] or a pharmaceutically acceptable salt thereof, wherein p is 2, 3, or 4; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 16 , and R 18are independently hydrogen, halogen, —N3, —CF3, —CCl3, —CBr3, —CI3, —CN, —CHO, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO2, —S02Cl, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. 16. The method of embodiment 15, wherein the compound comprises (Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile) (ETP69) or a pharmaceutically acceptable salt thereof. 17. The method of embodiment 15 or 16, wherein the contacting is in vitro. 18. The method of embodiment 15 or 16, wherein the contacting is in vivo. 19. The method of embodiment 18, wherein the contact is in a neuron of the subject. 20. The method of embodiment 18 or 19, wherein the contacting is in a human subject. 21. The method of any one of embodiments 15-21, further comprising assessing the activity of the enzyme during or after contacting the enzyme with the compound. 22. The method of embodiment 21, wherein the activity of the enzyme is reduced by at least 75% after contacting the enzyme with the compound. [Example]

[0113] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0114] Example 1: ETP69 Inhibition of Methyltransferases The ability of ETP69 to inhibit methyltransferases was tested. The results are shown in Table 1. ASH1L, MLL1 complex, MLL4 complex, NSD3, SET1B complex, SMYD2, SMYD3, SUV39H1, SUV39H2, G9a, MLL2 complex, MLL3 complex, NSD1, NSD2, NSD2(E1099K), NSD2(T1150A), PRDM9, PRMT7, SETDB1, and SETD2 all showed at least 75% inhibition compared to the DMSO control.

[0115] [Table 1]

[0116] Example 2: Restoration of brain synaptic density by treatment with ETP69 Brains from 18-month-old mice were stained using the Golgi-Cox method to detect neuronal cytoarchitecture and morphology. Figure 1A shows representative images of the cingulate cortex (cc) of mice administered DMSO or ETP69. Figure 1B shows a representative hippocampus. Figure 1C shows representative neurons from DMSO-treated and ETP69-treated hippocampi. Figure 1D is a schematic diagram of neuronal spine quantification. Mice treated with ETP69 showed an increase in both thin spines and dendritic spines in both the cc and hippocampus (Figures 1E-1H).

[0117] Example 3: Reduction of epigenomic histone methylation and disease-associated gene silencing by treatment with ETP69 The experimental protocol is shown in Figure 2A. Mice were treated with ETP69 or DMSO. Two days later, they were tested in the color X-maze. On day 12, they were tested in the Barnes maze. On day 14, they were tested for fear conditioning. Brain tissue was isolated as shown in Figures 2B-2D for analysis of H3K9me3 staining on days 4 and 15. The level of H3K9me3 correlated with the percentage of alternations on day 4, as shown in Figure 2E. On day 15, H3K9me3 was reduced in mice treated with ETP69 compared to mice treated with DMSO. H3K9me3 levels were reduced in both the cingulate cortex and hippocampus on days 4 and 15 (Figures 2J-2M).

[0118] Gene expression was measured in mice treated with ETP69 and DMSO. As shown in Figure 3, genes in the BDNF and VGF pathways were activated. These pathways are consistent with protective neurotrophic support. This pathway correlates with reduced H3K9me3 and improved cognition. Figure 4A shows genes in the BDNF pathway that were inhibited (left) and activated (right) by ETP69. Inactivated genes are quantified in Figures 4B-4F. Activated genes are quantified in Figures 4G-4M.

[0119] Example 4: Treatment of mice with ETP69 The effects of single and repeated ETP69 injections in mice were tested. The experimental timeline is shown in Figure 5. Three parallel injection conditions were tested: a single ETP69 condition, a booster ETP69 injection, and repeated ETP69 injections. Single-injection mice received one injection of ETP69 or DMSO on day 0. Booster-injection mice received one injection of ETP69 or DMSO on day 0 and one injection on day 9. Repeat-injection mice received 11 injections of ETP69 or DMSO on day 0 or day 9. Both wild-type and AD model (APP / PS1-transgenic) mice were tested.

[0120] Treatment with ETP69 restored CNS-related locomotor, visual, and cognitive functions (Figures 6A-6H). First, the effects of ETP69 on cognitive and visual protection were tested using the Y-maze test. Wild-type and AD mice treated with ETP69 were compared. + Both mice showed a decrease in total entries (Figure 6A) and decreased motor activity. The percentage of alternations, a proxy for cognition, was significantly higher in the DMSO-treated AD group. + Mice showed a significant reduction compared to wild-type mice treated with DMSO. + When mice were treated with ETP69, there was a significant increase in the rate of alternation (Fig. 6B).

[0121] Figures 6C-6F show the results of the visual stimulation X-maze test in color mode. The percentage of alternations, a proxy for cognition, was examined in mice treated with DMSO. + Mice showed a significant reduction compared to wild-type mice treated with DMSO. + When mice were treated with ETP69, there was a significant increase in the percentage of alternations and bidirectional movements (Figures 6C-6F). Figures 6G-6H show the results of the contrast mode of the visual stimulation X-maze test. The percentage of alternations was significantly higher in the AD mice treated with DMSO. + Mice showed a significant reduction compared to wild-type mice treated with DMSO. + When mice were treated with ETP69, there was a significant increase in the rate of alternation.

[0122] ETP69 treatment restored cognitive and behavioral functions (Figures 7A-7E). The results of the open-field Barnes maze test demonstrate hippocampal-based spatial memory. Figure 7A shows a schematic diagram of the Barnes maze test. AD treated with ETP69 + Mice were treated with DMSO and + The results of the fear conditioning test showed improved memory retention compared to AD mice treated with ETP69 (Figures 7A-7C). + Mice showed increased freezing time, indicating memory protection (Figures 7D-7E).

[0123] ETP69 treatment resulted in a reduction in the repression of epigenetic H3K9me3 marks (Figures 8A-8E). + Brains were stained for neuronal H3K9me3 and DAPI. Representative images of the cingulate cortex and hippocampus from DMSO- and ETP69-treated mice are shown in Figures 8A and 8C, respectively. Neuronal H3K9me3 irradiance in the cingulate cortex is quantified in Figure 8B. Wild-type and AD-treated mice treated with ETP69 + Both mice showed a decrease in H3K9me3 irradiance at day 4 (27% and 40%, respectively). + Mice showed a 40% decrease in H3K9me3 irradiance at day 14. In the hippocampus, DMSO-treated AD mice + Mice were treated with DMSO and + Mice exhibited a 47% reduction in irradiance compared to control mice (Figure 8E). H3K9me3 staining in the DG correlated with performance in the Barnes test, whereas K3K9me3 staining in the hippocampus correlated with performance in the fear conditioning test.

[0124] ETP69 administration reduced AD-related brain pathology (Figures 9A-9C). Brain sections were stained for H3K9me3, 6E10, and GFAP. Representative images are shown in Figure 9A. + Mice showed a 6.8-fold increase in GFAP levels compared to wild-type mice treated with DMSO (Figure 9B). + This resulted in a significant decrease in GFAP and 6E10 in mice at both days 4 and 15 (FIGS. 9B-9C).

[0125] Brains were stained using the Golgi-Cox method to detect neuronal cytoarchitecture and morphology. Representative images of mice treated with DMSO (Figures 10A-10C) and ETP69 (Figures 10D-10F) are shown. The number of dendritic spines was quantified. ETP69 administration significantly increased the number of dendritic spines in both the cingulate cortex and hippocampus (Figure 10G). ETP69 administration also resulted in increased expression of PSD95 irradiance (Figure 10H). Furthermore, ETP69 administration reduced the epigenetic H3K9me3 repressive mark in a cell-specific manner. H3K9 expression was reduced in neurons (Figures 11A-11B), astrocytes (Figures 11C-11D), and microglia-macrophages (Figures 11E-11F).

[0126] Proteome signatures revealed that ETP69 induces protein homeostasis with enrichment of learning and memory pathways and increased NTFs (Figures 12A-12D). Results included levodopa (L-dopa), a natural product that is also a drug for the management of Parkinson's motor symptoms.

[0127] Furthermore, in the proteosome signature, ETP69 induced the expression of brain neurotrophic factors (NTFs), including BDNF, VGF, and levodopa (Figures 13A-13G). Differentially expressed proteins were enriched for conserved pathways in spines and dendritic cells (Figure 14).

[0128] Example 5: ETP69 administration is neuroprotective in aged mice in both neurodegenerative mouse models and wild-type mice ETP69 was administered to aged (18-month-old) mice. + Both aged WT mice and wild-type siblings were tested. Mice were treated with intraperitoneal injections of ETP69 [E; 10 mg / kg dissolved in dimethyl sulfoxide (DMSO)]. A series of behavioral tests were performed to assess motor, cognitive, and visual function. A single dose of ETP69 also increased color X-maze spontaneous alternation in aged WT mice (p = 0.0027; Figure 15A), indicating that ETP69 can improve cognitive function in normal aging.

[0129] Synaptic loss and dendritic spine abnormalities are associated with cognitive decline. To analyze these features in ETP69-treated aged mice, Golgi-Cox neuron staining and synaptic marker staining were performed in the cerebral cortex and hippocampus. Dendritic spines were classified according to their size and shape as thin (filopodial and elongated), short and thick, or mushroom-shaped spines, and spine density was quantified from high-magnification photographs.

[0130] Both wild-type and neurodegenerative mice showed a 1.2-fold increase in the number of dendritic spines in both the hippocampus and cerebral cortex of ETP69-treated mice compared to mice treated with DMSO controls (Figure 15B).

[0131] There was also a functional correlation between increased dendritic spine density and cognitive improvement. Thin spines are newly formed and are associated with new learning and memory formation. Lower thin spine density in the cortex and hippocampus correlated with poorer performance in the Barnes maze and contextual fear conditioning tests (r = -0.54, p = 0.03 and r = 0.67, p = 0.0063, respectively; Figure 15C). Analysis of dendritic spine ratios showed that ETP69 treatment induced a higher thin spine-to-total spine ratio and a lower mushroom spine-to-total spine ratio (Figure 15D), counteracting the effects of AD on these dendritic spine subtypes. Furthermore, improved cognitive performance in the Barnes maze test correlated with higher thin spines and a lower mushroom spine-to-total spine ratio (Figure 15E).

[0132] Example 6: Reduction of inhibitory marks in the cerebral cortex by ETP69 administration This example demonstrates how ETP69 can reduce inhibitory marks, an effect that may be related to anti-degeneration. H3K9me3 immunoreactive regions were distributed throughout all layers of the cerebral cortex, but showed differences between layers due to variable neuronal population densities. Therefore, quantification was performed in the most densely populated cortical layers II / III and VI, as shown in Figure 16A. Cortical and hippocampal levels of H3K9me3 were significantly higher in DMSO control neurodegenerative (AD) mice compared to WT mice (p<0.05-0.0001; Figure 2h-l). + ) significantly increased 1.3-1.5-fold in the cortical H3K9me3 subpopulation. Elevated cortical H3K9me3 levels were significantly and negatively correlated with cognitive performance, as observed in the X-maze color mode (r = -0.77, p < 0.0001; Figure 16B).

[0133] The effect of ETP69 on brain H3K9me3 levels was examined in aged mice, both in the neurodegenerative model and in WT siblings. Brain H3K9me3 levels were measured on days 4 (short-term) and 15 (long-term) after intraperitoneal administration. ETP69 injections (S regimen cohort) were discontinued. Data showed that ETP69 dramatically reduced H3K9me3 IR regions in the cortex of both WT (27%, p = 0.0004) and neurodegenerative (40%, p < 0.0001) aged mice 4 days after injection. Notably, the magnitude of cortical H3K9me3 reduction by ETP69 remained stable even after 15 days in neurodegenerative mice (40%, p = 0.0069; Figure 16A). Quantitative IHC analysis showed that ETP69 treatment persistently reduced hippocampal H3K9me3 levels 15 days after injection in WT mice (CA, 36%, p<0.05; Figure 21) and neurodegenerative mice (CA, 54%, p<0.0001; DG, 42%, p<0.0001; Figure 16C). These findings indicate that a single administration of ETP69 is sufficient to persistently reduce H3K9me3 in the brains of aged WT and neurodegenerative mice. Consistent with observations in 18-month-old mice, ETP69 also downregulated ionized calcium-binding adaptor molecule 1 (Iba-1) in neurodegenerative mice. +It reduced neuroinflammation, including through a reduction in microgliosis (40%, p=0.0021; Figure 16D).

[0134] Example 7: Activation of pathways related to learning and cognition by ETP69 administration 14-month-old WT and neurodegenerative (AD) + ) Mass spectrometry (MS) analysis was performed on the soluble fraction of brain homogenates extracted from a cohort of mice (DMSO-treated WT mice: n = 8; ETP69-treated WT mice: n = 7; DMSO-treated AD mice: n = 1). + Mice: n=6; ETP69-treated AD + :n=6). AD + / WT and AD + Of the 162 overlapping DEPs between the ETP69 / DMSO comparisons, the disease state (AD + 159 DEPs that were up- or down-regulated due to the WT (vs. WT) were reversed by ETP69 treatment (R 2 =0.86, p<0.0001; Figure 17A).

[0135] The effects of ETP69 on molecular pathways related to neuroprotection and cognitive function were evaluated. Ingenuity Pathway Analysis (IPA) revealed that ETP69 administration significantly activated pathways related to learning, cognition, neuronal mass, and dendritic growth and branching, completely reversing the AD-related inhibitory effects of these pathways (Figure 17B). The STRING network shows overlapping DEPs between three functions: learning, neuronal mass, and dendritic growth / branching (Figure 17C). The data also show that leucine-rich repeat neuronal protein 4 (Lrrn4), which plays a key role in hippocampal-dependent learning and long-term memory, is significantly upregulated compared with DMSO controls. + The results showed that the most upregulated protein was 1.73-fold in ETP69-treated mice compared with AD mice (p = 0.015). Furthermore, glial cell line-derived neurotrophic factor (GDNF) receptor 2 (Gfra2), which promotes neuronal survival, was upregulated in AD mice. +In AD mice, the microtubule-associated protein tau (Mapt), a major component of the neuronal cytoskeleton, was also downregulated in the ETP69-treated mice compared to the WT mice. + It is a top-down-regulated protein in mice and is associated with AD. + The leading response in mice was ETP69, which was upregulated 2.4-fold (p=0.0188).

[0136] The five proteins that overlapped between the three pathways included the Bdnf / Nt-3 growth factor receptor (neurotrophic receptor tyrosine kinase 2; Ntrk2), involved in neuronal survival and neuroplasticity; SH3 and multiple ankyrin repeat domain protein 3 (Shank3); the major scaffolding postsynaptic density protein, spastin (Spast), involved in axonal growth; tuberous sclerosis complex 2 (Tsc2, also known as tuberin); and the neurosecretory protein nerve growth factor-inducible Vgf, involved in neurogenesis and neuroplasticity (Figure 6b).

[0137] The top IPA upstream regulators induced or inhibited by ETP69 treatment are shown in Figure 17C. Rictor, GABA, and BDNF were the top activated networks in response to ETP69 treatment (z scores: 3.59, 2.50, and 2.42, respectively), and these pathways were not associated with AD. + It was among the top inhibitory pathways in versus WT mice.

[0138] Example 8: Clinical Trials for the Treatment of Parkinson's Disease The purpose of this study is to study the effects of ETP69 on Parkinson's disease. Additionally, the study will generate data on the safety, tolerability, and pharmacokinetics of the treatment in subjects with Parkinson's disease. Individuals will receive weekly placebo or ETP69 and be monitored for at least 12 weeks of the study. Subjects will be evaluated for motor and cognitive measures before the study and at the end of treatment. The treatment may improve at least one symptom of Parkinson's disease. The treatment may delay the progression of at least one symptom of Parkinson's disease.

[0139] Example 9: Clinical Trials for the Treatment of Huntington's Disease The purpose of this study is to study the effects of ETP69 on Huntington's disease. Additionally, the study will generate data on the safety, tolerability, and pharmacokinetics of the treatment in subjects with Huntington's disease. Individuals will receive weekly placebo or ETP69 and be monitored for at least 12 weeks of the study. Subjects will be evaluated for motor and cognitive measures before and after treatment. The treatment may improve at least one symptom of Huntington's disease. The treatment may delay the progression of at least one symptom of Huntington's disease.

[0140] Example 10: Clinical Trial for the Treatment of Amyotrophic Lateral Sclerosis (ALS) The purpose of this study is to study the effects of ETP69 on ALS. Additionally, the study will generate data on the safety, tolerability, and pharmacokinetics of the treatment in subjects with ALS. Individuals will receive weekly doses of placebo or ETP69 and be monitored for at least 12 weeks of the study. Subjects will be assessed for motor and cognitive measures before the study and at the end of treatment. The treatment may improve at least one symptom of ALS. The treatment may delay the progression of at least one symptom of ALS.

[0141] Example 11: Clinical Trials for the Treatment of Learning Disabilities The purpose of this study is to investigate the effects of ETP69 on learning disabilities. Additionally, the study will generate data on the safety, tolerability, and pharmacokinetics of the treatment in subjects with learning disabilities. Individuals will receive weekly placebo or ETP69 and be monitored for at least 12 weeks of the study. Subjects will be assessed for motor and cognitive measures before the study and at the end of treatment. Treatment may improve at least one symptom of learning disabilities.

[0142] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. 1. A method of treating Parkinson's disease, Huntington's disease, ALS, or a learning disability in a subject in need of such treatment, comprising administering to the subject a compound comprising an inhibitor of histone 3, lysine 9 (H3K9) trimethylation.

2. The method of claim 1 , wherein the compound comprises an inhibitor of SUV39H1.

3. The method of claim 1 , wherein the compound comprises an inhibitor of SUV39H2.

4. The compound is represented by formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein p is 2, 3, or 4; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R １６ and R １８ are independently hydrogen, halogen, -N ３ , -CF ３ , -CCl ３ , -CBr ３ , -CI ３ , -CN, -CHO, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ２ , -SO ２ Cl, —SO ３ H, -SO ４ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

5. 2. The method of claim 1, wherein the compound comprises (Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile) (ETP69) or a pharmaceutically acceptable salt thereof.

6. 10. The method of claim 1, wherein said administration improves locomotor activity in said subject.

7. 10. The method of claim 1, wherein said administering reduces neuroinflammation in said subject.

8. The method of claim 1, wherein said administration increases or improves a neuroprotective phenotype.

9. 8. The method of claim 7, wherein said administering activates brain-derived neurotrophic factor (BDNF) or VGF nerve growth factor-induced (VGF) signaling in said subject.

10. 10. The method of claim 1, wherein administration reduces or ameliorates a phenotype associated with Parkinson's disease, Huntington's disease, ALS, or a learning disability in the subject.

11. 11. The method of claim 10, wherein the subject has or has been diagnosed with Parkinson's disease.

12. 11. The method of claim 10, wherein the subject has or has been diagnosed with Huntington's disease.

13. 11. The method of claim 10, wherein the subject has or has been diagnosed with ALS.

14. 11. The method of claim 10, wherein the subject has or has been diagnosed with a learning disability.

15. 1. A method of inhibiting an enzyme selected from the group consisting of ASH1L, MLL1 complex, MLL4 complex, NSD3, Setlb complex, SMYD2, SMYD3, SUV39H1, and SUV39H2, comprising: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein p is 2, 3, or 4; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R １６ and R １８ are independently hydrogen, halogen, -N ３ , -CF ３ , -CCl ３ , -CBr ３ , -CI ３ , -CN, -CHO, -OH, -NH ２ , -COOH, -CONH ２ , -NO ２ , -SH, -SO ２ , -SO ２ Cl, —SO ３ H, -SO ４ H, -SO ２ NH ２ , -NHNH ２ , -ONH ２ , -NHC(O)NHNH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

16. 16. The method of claim 15, wherein the compound comprises (Rac-(3S,6S,7S,8aS)-6-(benzo[d][1,3]dioxol-5-yl)-2,3,7-trimethyl-1,4-dioxohexahydro-6H-3,8a-epidithiopyrrolo[1,2-a]pyrazine-7-carbonitrile) (ETP69) or a pharmaceutically acceptable salt thereof.

17. 16. The method of claim 15, wherein the contacting is in vitro.

18. 16. The method of claim 15, wherein the contacting is in vivo.

19. 19. The method of claim 18, wherein the contact is in a neuron of the subject.

20. 20. The method of claim 18, wherein the contacting is in a human subject.

21. 16. The method of claim 15, further comprising assessing the activity of the enzyme during or after contacting the enzyme with the compound.

22. 22. The method of claim 21, wherein the activity of the enzyme is reduced by at least 75% after contacting the enzyme with the compound.

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