EP4705454A2 - Compounds and methods for treating human subjects - Google Patents

Abstract

Described herein are compounds and methods that can be used to treat a disease or condition by increasing functional MeCP2 protein.

Description

COMPOUNDS AND METHODS FOR TREATING HUMAN SUBJECTS CROSS REFERENCE [0001] This application claims benefit of United States Provisional Patent Application No. 63/498,404 filed April 26, 2023, which is incorporated herein by reference in its entirety. BACKGROUND [0002] Deficient MeCP2 protein or activity has been observed in subjects with Rett syndrome. Rett syndrome is a rare, severe neurodevelopmental disorder that mostly affects females. Rett syndrome is linked to MECP2 mutations in more than 95% of cases. The mutations are nearly all de novo, and T158M is the most common missense mutation identified in classic Rett syndrome. Characteristics include deceleration of head growth, loss of learned language skills, hand stereotypes and loss of purposeful hand skills, irregular breathing, motor and severe intellectual impairment, and seizures (60-80% of patients), and 40% lose ambulation or never walk. Subjects have an increased risk of premature death, with 70% surviving until age 50; and mortality rates are higher for classic versus atypical diagnosis. No neuronal cell loss or neurodegeneration has been noted post-mortem in Rett patients, indicating there are no major changes in brain structure; thus, treatment after onset of developmental regression could potentially mitigate the severity of symptoms. Rett syndrome typically presents with developmental regression at 6-18 months of age, and a stage of stabilization often follows regression. The median age of onset of epilepsy is 50 months. Diagnosis is based on clinical findings (using RTT Diagnostic Criteria Worksheet) and can be determined with genetic testing. Though genetic testing is common in current diagnostic pathways, many older women have not undergone testing. [0003] To date, there are no therapies approved specifically for the treatment of Rett syndrome. Management includes occupational, speech, and physical therapy, as well as drugs for seizures, muscle stiffness, anxiety, or sleep. Epilepsy affects 60-80% of patients with Rett syndrome and is drug-resistant in approximately one-third of cases. There is a need for therapeutic agents that can be used to treat such conditions or diseases by increasing MeCP2 protein or activity. SUMMARY [0004] Provided herein are therapeutic agents that can be used to increase MeCP2 protein or activity and treat conditions or diseases. [0005] Provided herein, in some aspects, is a compound of Formula (I): X_AX_N1X_N2X_N3X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇X₁₈X₁₉X₂₀X_C1X_C2X_C3X_B wherein X_A is and B_A is when X_N1, X_N2 and X_N3 and X₅ are absent, (ii) when X_N1, X_N2 and X_N3 are absent and X₅ is present, when X_N and X_N2 are absent and X_N3 and X₅ are present, when X_N1 is absent and X_N2 and X_N3 and X₅ are present, or when X_N1, X_N2 and X_N3 and X₅ are present; X_N1 is or absent, wherein if X_N1 is present X_N2 and X_N3 and X₅ are present; X_N2 is or absent, wherein if X_N2 is present X_N3 and X₅ are present; X_N3 is or absent, wherein if X_N3 is present X₅ is present; X₅ is or absent; X₆ is X₂₀ is or absent; X_C1 is or absent, wherein if X_C1 is present X₂₀ is present; X_C2 is or absent, wherein if X_C2 is present X_C1 and X₂₀ are present; X_C3 is or absent, wherein if X_C3 is present X_C1 and X_C2 and X₂₀ are present; and X_B is and B_B is when X₂₀ and X_C1, X_C2 and X_C3 are present, (ii) when X₂₀ and X_C1 and X_C2 are present and X_C3 is absent, when X₂₀ and X_C1 is present and X_C2 and X_C3 are absent, when X₂₀ is present and X_C1, X_C2 and X_C3 are absent, or when X₂₀ and X_C1, X_C2 and X_C3 are absent. [0006] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is ; X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is (v) [0007] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0008] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is ; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0009] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is

[0010] In some aspects, absent; X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0011] In some aspects, B_A is X_N1 is absent; X_N2 is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0012] In some aspects, B_A is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0013] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is

absent; and B_B is [0014] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X_C2 is absent; X_C3 is absent; and B_B is [0015] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0016] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is (v) [0017] In some aspects, B_A is X_N1 absent; X_N2 absent; X_N3 is absent; X₅ is absent; [0018] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is

absent; and B_B is [0019] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X_C2 is absent; X_C3 is absent; and B_B is [0020] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0021] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is (v) [0022] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0023] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₆ is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0024] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₆ is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is (v) [0025] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is (v) [0026] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is

absent; X_C3 is absent; and B_B is [0027] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is

X_C3 is absent; and B_B is [0028] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X_C3 is absent; and B_B is [0029] In some aspects, B_A is X_N1 absent; X_N2 absent; X_N3 is absent; X₅ is absent; [0030] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; and B_B is [0031] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X_C2 is absent; X_C3 is absent; and B_B is [0032] Provided herein, in some aspects, is a compound of Formula (I): X_AX_N1X_N2X_N3X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇X₁₈X₁₉X₂₀X_C1X_C2X_C3X_B wherein X_A is and B_A is when X_N1, X_N2 and X_N3 and X₅ are absent, (ii) when X_N1, X_N2 and X_N3 are absent and X₅ is present, when X_N1 and X_N2 are absent and X_N3 and X₅ are present, when X_N1 is absent and X_N2 and X_N3 and X₅ are present, or when X_N1, X_N2 and X_N3 and X₅ are present; X_N1 is or absent, wherein if X_N1 is present X_N2 and X_N3 and X₅ are present; X_N2 is or absent, wherein if X_N2 is present X_N3 and X₅ are present; X_N3 is absent, wherein if X_N3 is present X₅ is present; X₅ is or absent; X₆ is or absent; X_C1 is or absent, wherein if X_C1 is present X₂₀ is present; X_C2 is or absent, wherein if X_C2 is present X_C1 and X₂₀ are present; X_C3 is or absent, wherein if X_C3 is present X_C1 and X_C2 and X₂₀ are present; and XB is and B_B is when X_C1, X_C2 and X_C3 and X₂₀ are present, when X_C1 and X_C2 and X₂₀ are present and X_C3 is absent, when X_C1 and X₂₀ are present and X_C2 and X_C3 are absent, when X₂₀ is present and X_C1, X_C2 and X_C3 are absent, or when X₂₀ and X_C1, X_C2 and X_C3 are absent. [0033] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₁₀ is

X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and [0034] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0035] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X_C2 is absent; X_C3 is absent; and B_B is [0036] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is

X_C3 is absent; and B_B is [0037] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is

[0038] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B [0039] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X_C2 is absent; X_C3 is absent; and B_B is [0040] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is X_C2 is absent; X_C3 is absent; and B_B is [0041] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B [0042] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0043] In some aspects, B_A is X_N1 is absent; X_N2 is absent; X_N3 is

X_C2 is absent; X_C3 is absent; and B_B is . [0044] In some aspects, B_A is ; X_N1 is absent; X_N2 is X_N3 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B [0045] In some aspects, B_A is X_N1 is absent; X_N2 is X_N3 is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is [0046] In some aspects, BA is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B [0047] Provided herein, in some aspects, is a compound selected from the group consisting of: ,

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. [0048] Provided herein, in some aspects, is a compound that is an antisense oligonucleotide (ASO) having a sequence according to SEQ ID NO: 103 or 211, wherein the ASO comprises a backbone modification comprising a phosphoryl guanidine diester or derivative thereof. [0049] In some aspects, the ASO comprises CnTACAGAAGCAAGGTG, CTnACAGAAGCAAGGTG, CTnACAGAAGCAAGGTG, CTACnAGAAGCAAGGTG, CTACAnGAAGCAAGGTG, CTACAGnAAGCAAGGTG, CTACAGAnAGCAAGGTG, CTACAGAAnGCAAGGTG, CTACAGAAGnCAAGGTG, CTACAGAAGCnAAGGTG, CTACAGAAGCAnAGGTG, CTACAGAAGCAAnGGTG, CTACAGAAGCAAGnGTG, CTACAGAAGCAAGGnTG, CTACAGAAGCAAGGTnG, CnTnACAGAAGCAAGGTnG, CTnAnCAGAAGCAAGGTnG, CTAnCnAGAAGCAAGGTnG, CTACnAnGAAGCAAGGTnG, CTACAnGnAAGCAAGGTnG, CTACAGnAnAGCAAGGTnG, CTACAGAnAnGCAAGGTnG, CTACAGAAnGnCAAGGTnG, CTACAGAAGnCnAAGGTnG, CTACAGAAGCnAnAGGTnG, CTACAGAAGCAAnGnGTnG, CTACAGAAGCAnAnGGnTG, CTACAGAAGCnAnAGnGTG, CnTnACnAGAAGCAAGGTG, CTnACnAnGAAGCAAGGTG, CTAnCAnGnAAGCAAGGTG, CTACnAGnAnAGCAAGGTG, CTACAnGAnAnGCAAGGTG, CnTACAGAAGCAAGGTnG, CTnACAGAAGCAAGGnTG, CTACAGAAGCAAGGnTG or CTACAGAAGCAAGGTnG, wherein n is the phosphoryl guanidine diester or derivative thereof. [0050] In some aspects, the ASO further comprises a backbone modification comprising a phosphorothioate (PS) linkage or a phosphoroamidate linkage. [0051] In some aspects, the phosphoryl guanidine diester or derivative thereof comprises a (1,3- dimethylimididazolidin-2-ylidene) phosphoramidate; ((4-acetamidophenyl) sulfonyl) phosphoramidate; ((1,3-dimethyltetrahydropyrimidin-2(1H)-ylidene) phosphoramidate; (1,3- dimethyl-1,3-diazepan-2-ylidene) phosphoramidate; or (did(pyrrolidin-1-yl)methylene) phosphoramidate. [0052] In some aspects, the ASO comprises a 2'- O-methyl, 2'-Fluoro, and/or a 2'-O- methoxyethyl moiety. [0053] In some aspects, the ASO comprises at least one modified sugar moiety. [0054] In some aspects, the compound is conjugated to a lipid. [0055] Provided herein, in some aspects, is a compound that is an antisense oligonucleotide (ASO) having a sequence according to SEQ ID NO: 103 or 211, wherein the ASO is conjugated to a lipid. [0056] In some aspects, the lipid is conjugated to a 5' end or 3' end of the compound. [0057] In some aspects, the lipid is conjugated to the compound via a phosphate, a phosphoroamidate or a phosphorothioate. [0058] In some aspects, the lipid is conjugated to the compound via a linker. [0059] In some aspects, the linker is selected from the group consisting of a proline-based linker, an aminohexyl linker, and a glycerol-based linker. [0060] In some aspects, the linker is a linker selected from the group consisting of [0061] In some aspects, the lipid is selected from the group consisting of stearic acid, oleic acid, elaidic acid, linoleic acid, linoleaidic acid, linolenic acid, arachidic acid, myristic acid, capric acid, caprylic acid, lauric acid, palmitic acid, arachidonic acid, and eicosenoic acid. [0062] In some aspects, the lipid is stearic acid. [0063] In some aspects, the compound has a structure according to formula (I): lipid-linker- ASO. [0064] In some aspects, the compound has a structure selected from the group consisting of: . [0065] In some aspects, the compound has a structure according to formula (II): ASO-linker- lipid. [0066] In some aspects, the compound has a structure selected from the group consisting of: . INCORPORATION BY REFERENCE [0067] 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. BRIEF DESCRIPTION OF THE DRAWINGS [0068] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which: [0069] FIGs.1A-1B depict a schematic representation of MECP2 pre-mRNA splicing isoforms (FIG.1A) and protein domains (FIG.1B). [0070] FIG.2 is a schematic depicting the targeting strategy for modulating the alternative splicing of MECP2 pre-mRNA. [0071] FIG.3 an ASO walk for the depicted MECP2 region. [0072] FIG.4 depicts an ASO walk for the MECP2 exon 2 region. [0073] FIG.5 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were treated with 20 µM of the indicated ASOs and allowed to freely uptake the ASOs for 72 hours. [0074] FIG.6 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were treated with 20 µM of the indicated ASOs and allowed to freely uptake the ASOs for 72 hours. [0075] FIG.7 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were treated with 20 µM of the indicated ASOs and allowed to freely uptake the ASOs for 72 hours. [0076] FIG.8 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were treated with 20 µM of the indicated ASOs and allowed to freely uptake the ASOs for 72 hours. [0077] FIG.9 shows results demonstrating that the indicated compounds (#8 and #50) switch MECP2 isoforms and increase MECP2 protein expression in vitro. [0078] FIG.10A depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells treated with increasing concentrations of the indicated compounds (#8, #8-1, #8- 2, and #8-3). [0079] FIG.10B depicts a graph comparing the results from FIG.10A. [0080] FIG.11 shows results from adult WT and T158M/+ mice treated with compound #8. T158M/+ mice showed similar pharmacology to WT mice. Treatment with compound #8 upregulated protein expression in adult WT and MECP2 T158M/+ mice. [0081] FIG.12 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were either nucleofected for 24 hours with 3 µM of the indicated lipidated ASOs or treated with 30 µM of the indicated lipidated ASOs and allowed to freely uptake the ASOs for 72 hours. [0082] FIG.13 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were either nucleofected for 24 hours with 1 µM of the indicated stearic acid- conjugated ASOs or treated with 30 µM of the indicated stearic acid-conjugated ASOs and allowed to freely uptake the ASOs for 72 hours. [0083] FIG.14A depicts an exemplary structure of an ASO with a P3'→N5' phosphoramidate (PN) linkage. FIG.14B depicts an exemplary structure of a PN linkage. [0084] FIG.15 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were either nucleofected for 24 hours with 1 µM of the indicated PN linkage modified ASOs or treated with 20 µM of the indicated PN linkage modified ASOs and allowed to freely uptake the ASOs for 72 hours. [0085] FIG.16 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were either nucleofected for 24 hours with 1 µM of the indicated PN linkage modified ASOs or treated with 20 µM of the indicated PN linkage modified ASOs and allowed to freely uptake the ASOs for 72 hours. [0086] FIGs.17A-17D depict RT-PCR results for MECP2 exon 2 inclusion using RNA from neonate WT mice treated with compound #8 or compound #8-1 on Day 8 (FIG.17A), Day 15 (FIG.17B), Day 29 (FIG.17C), and Day 114 (FIG.17D). PBS was used as the control group. ICV injection was performed at postnatal day 2 (PND2). Mice were euthanized at PND9, PND16, PND30, and PND114 for collecting cortex tissue. Data Represented as mean with SD. Statistical analysis was performed with one way ANOVA with Sidak correction. [0087] FIGs.17E-17H depict protein expression results for MeCP2 from neonate MECP2 mutant mice treated with compound #8 or compound #8-1 on Day 8 (FIG.17E), Day 15 (FIG. 17F), Day 29 (FIG.17G), and Day 114 (FIG.17H). PBS was used as the control group. ICV injection was performed at PND2. Mice were euthanized at PND9, PND16, PND30, and PND114 for collecting cortex tissue. Data Represented as mean with SD. Statistical analysis was performed with one way ANOVA with Sidak correction. [0088] FIGs.18A-18B depict an exemplary process for synthesizing a 5’ conjugate of the ASOs. An aminohexyl-linked oligo is an intermediate of the first portion (FIG.18A), and a lipidated ASO is the product from the second portion (FIG.18B) [0089] FIGs.19A-19B depict an exemplary process for synthesizing a 3’ conjugate of the ASOs. An aminohexyl-linked oligo is an intermediate of the first portion (FIG.19A), and a lipidated ASO is the product from the second portion (FIG.19B) [0090] FIG.20 depicts an exemplary process for synthesizing a PN linkage. [0091] FIGs.21A-21D are histograms illustrating the relative MeCP2 exon 2 expression in wild-type MeCP2 protein-expressing neurons treated with a Mock substance (Wt x Mock), human MeCP2 T158M neurons treated with a Mock substance (Mut x Mock), and human MeCP2 T158M neurons treated with tested ASO compounds: compound #8 (FIG.21A), compound #8-1 (FIG.21B), compound #8-4 (FIG.21C), and compound #8-5 (FIG.21D) at various concentrations (0.001 µM, 1.0 µM, 10.0 µM, and 20.0 µM). All values are normalized to Mut x Mock controls. Numbers on top of each bar represent the mean fold change over Mut x Mock controls. Each data point is the average of 25 fields of view per well normalized to neuron count. The number at the bottom of each bar is the number of wells imaged. [0092] FIGs.22A-22D are histograms illustrating the relative protein expression in wild-type MeCP2 protein-expressing neurons treated with a Mock substance (Wt x Mock), human MeCP2 T158M neurons treated with a Mock substance (Mut x Mock), and human MeCP2 T158M neurons treated with tested ASO compounds: compound #8 (FIG.22A), compound #8-1 (FIG. 22B), compound #8-4 (FIG.22C), and compound #8-5 (FIG.22D) at various concentrations (0.001 µM, 1.0 µM, 10.0 µM, and 20.0 µM). All values are normalized to Mut x Mock controls. Numbers on top of each bar represent the mean fold change over Mut x Mock controls. Each data point is the average of 25 fields of view per well normalized to neuron count. The number at the bottom of each bar is the number of wells imaged. [0093] FIGs.23A-23D are histograms illustrating the relative dendrite outgrowth measurements in wild-type MeCP2 protein-expressing neurons treated with a Mock substance (Wt x Mock), human MeCP2 T158M neurons treated with a Mock substance (Mut x Mock), and human MeCP2 T158M neurons treated with tested ASO compounds: compound #8 (FIG.23A), compound #8-1 (FIG.23B), compound #8-4 (FIG.23C), and compound #8-5 (FIG.23D) at various concentrations (0.001 µM, 1.0 µM, 10.0 µM, and 20.0 µM). All values are normalized to Mut x Mock controls. Numbers on top of each bar represent the mean fold change over Mut x Mock controls. Each data point is the average of 25 fields of view per well normalized to neuron count. The number at the bottom of each bar is the number of wells imaged. [0094] FIGs.24A-24D are histograms illustrating the relative Synapsin puncta counts in wild- type MeCP2 protein-expressing neurons treated with a Mock substance (Wt x Mock), human MeCP2 T158M neurons treated with a Mock substance (Mut x Mock), and human MeCP2 T158M neurons treated with tested ASO compounds: compound #8 (FIG.24A), compound #8- 1 (FIG.24B), compound #8-4 (FIG.24C), and compound #8-5 (FIG.24D) at various concentrations (0.001 µM, 1.0 µM, 10.0 µM, and 20.0 µM). All values are normalized to Mut x Mock controls. Numbers on top of each bar represent the mean fold change over Mut x Mock controls. Each data point is the average of 25 fields of view per well normalized to neuron count. The number at the bottom of each bar is the number of wells imaged. DETAILED DESCRIPTION [0095] Certain specific details of this description are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the present disclosure may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure. [0096] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise. [0097] The coordinate as used herein refers to the coordinate of the genome reference assembly GRCh38 (Genome Research Consortium human build 38), also known as Hg38 (Human genome build 38). [0098] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. [0099] As used herein, an alternative 3’ splice site of an intron is equivalent to an alternative 5’ splice site of the exon immediately downstream of that intron. [0100] As used herein, an alternative 5’ splice site of an intron is equivalent to an alternative 3’ splice site of the exon immediately upstream of that intron. [0101] Unless specific definitions are provided, the nomenclature utilized in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. [0102] Unless otherwise indicated, the following terms have the following meanings: [0103] “Administering” can mean providing a pharmaceutical agent to an animal, and includes, but is not limited to administering by a medical professional and self-administering. “Amelioration” refers to a lessening, slowing, stopping, or reversing of at least one indicator of the severity of a syndrome or condition. The severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art. [0104] “Animal” can refer to a human or non-human animal, including, but not limited to, mice, rats, rabbits, dogs, cats, pigs, and non-human primates, including, but not limited to, monkeys and chimpanzees. [0105] “Antisense oligomer” can mean an oligomeric compound that is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. Examples of antisense oligomers include single- stranded and double -stranded compounds, such as, antisense oligonucleotides, siRNAs, shRNAs, and ssRNAs. [0106] “Antisense inhibition” or “inhibition” can mean reduction of target nucleic acid levels in the presence of an antisense oligomer complementary to a target nucleic acid compared to target nucleic acid levels or in the absence of the antisense oligomer. [0107] “Antisense mechanisms” can refer to all those mechanisms involving hybridization of a compound with a target nucleic acid, wherein the outcome or effect of the hybridization is either target degradation or target occupancy with concomitant stalling of the cellular machinery involving, for example, transcription or splicing. An antisense oligomer provided herein can be “antisense” to a target nucleic acid, meaning that the antisense oligomer is capable of undergoing hybridization to a target nucleic acid through hydrogen bonding. [0108] “Antisense oligonucleotide” can mean a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding segment of a target nucleic acid. [0109] “Base complementarity” can refer to the capacity for the precise base pairing of nucleobases of an antisense oligonucleotide with corresponding nucleobases in a target nucleic acid (i.e., hybridization), and is mediated by Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen binding between corresponding nucleobases. [0110] “Bicyclic sugar” can mean a furanose ring modified by the bridging of two atoms. A bicyclic sugar is a modified sugar. [0111] “Bicyclic nucleoside” (also “BNA”) can mean a nucleoside having a sugar moiety comprising a bridge connecting two carbon atoms of the sugar ring, thereby forming a bicyclic ring system. In certain embodiments, the bridge connects the 4’-carbon and the 2’-carbon of the sugar ring. [0112] “Cap structure” or “terminal cap moiety” can mean chemical modifications, which have been incorporated at either terminus of an antisense oligomer. “cEt” or “constrained ethyl” can mean a bicyclic nucleoside having a sugar moiety comprising a bridge connecting the 4’-carbon and the 2’-carbon, wherein the bridge has the formula: 4’-CH(CH3)-0-2. [0113] “Constrained ethyl nucleoside” (also cEt nucleoside) can mean a nucleoside comprising a bicyclic sugar moiety comprising a 4’-CH(CH3)-0-2’ bridge. [0114] “Chimeric antisense oligomer” can mean an antisense oligomer that has at least two chemically distinct regions, each position having a plurality of subunits. [0115] “Complementarity” can mean the capacity for pairing between nucleobases of a first nucleic acid and a second nucleic acid. [0116] “Contiguous nucleobases” can mean nucleobases immediately adjacent to each other. [0117] “Diluent” can mean an ingredient in a composition that lacks pharmacological activity but is pharmaceutically necessary or desirable. For example, in drugs that are injected, the diluent may be a liquid, e.g., saline solution. [0118] “Effective amount” in the context of modulating an activity or of treating or preventing a condition can mean the administration of that amount of pharmaceutical agent to an individual in need of such modulation, treatment, or prophylaxis, either in a single dose or as part of a series, that is effective for modulation of that effect, or for treatment or prophylaxis or improvement of that condition. The effective amount may vary among individuals depending on the health and physical condition of the individual to be treated, the taxonomic group of the individuals to be treated, the formulation of the composition, assessment of the individual’s medical condition, and other relevant factors. [0119] “Efficacy” or “potency,” which are used herein interchangeably, can mean the ability to produce a desired effect. [0120] “Expression” can include all the processes by which a gene’s coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to, the products of transcription and translation. [0121] “Gapmer” can mean a chimeric antisense oligomer in which an internal region having a plurality of nucleosides that support RNase H cleavage is positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region can be referred to as a “gap” and the external regions can be referred to as the “wings.” [0122] “Hybridization” can mean the annealing of complementary nucleic acid molecules. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense oligomer and a target nucleic acid. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an antisense oligonucleotide and a nucleic acid target. [0123] “Individual” can mean a human or non-human animal selected for treatment or therapy. [0124] “Inhibiting SYNGAP” or “inhibiting SYNGAP” can mean reducing the level or expression of a SYNGAP mRNA and/or SYNGAP protein. In certain embodiments, SYNGAP mRNA and/or SYNGAP protein levels are inhibited in the presence of an antisense oligomer targeting SYNGAP, including an antisense oligonucleotide targeting SYNGAP, as compared to expression of SYNGAP mRNA and/or SYNGAP protein levels in the absence of a SYNGAP antisense oligomer, such as an antisense oligonucleotide. [0125] “Inhibiting the expression or activity” can refer to a reduction or blockade of the expression or activity and does not necessarily indicate a total elimination of expression or activity. [0126] “Internucleoside linkage” can refer to the chemical bond between nucleosides. [0127] “Intra-cisterna magna” or “ICM” injection or delivery can refer to injection of an agent or pharmaceutical composition provided herein in the cerebrospinal fluid (CSF)-filled subarachnoid space between the cerebellum and the dorsal side of the medulla oblongata. [0128] “Linked nucleosides” can refer to adjacent nucleosides linked together by an internucleoside linkage. [0129] “SYNGAP antisense oligomer” can mean an antisense oligomer targeting SYNGAP mRNA. [0130] “Mismatch” or “non-complementary nucleobase” can refer to the case when a nucleobase of a first nucleic acid is not capable of pairing with the corresponding nucleobase of a second or target nucleic acid. [0131] “Modified internucleoside linkage” can refer to a substitution or any change from a naturally occurring internucleoside bond (i.e., a phosphodiester internucleoside bond). [0132] “Modified nucleobase” can refer to any nucleobase other than adenine, cytosine, guanine, thymidine, or uracil. An “unmodified nucleobase” means the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U). [0133] “Modified nucleoside” can refer to a nucleoside having, independently, a modified sugar moiety and/or modified nucleobase. [0134] “Modified nucleotide” can refer to a nucleotide having, independently, a modified sugar moiety, modified internucleoside linkage, and/or modified nucleobase. [0135] “Modified antisense oligonucleotide” can refer to an oligonucleotide comprising at least one modified internucleoside linkage, modified sugar, and/or modified nucleobase. [0136] “Modified sugar” can refer to substitution and/or any change from a natural sugar moiety. [0137] “Monomer” can refer to a single unit of an oligomer. Monomers include, but are not limited to, nucleosides and nucleotides, whether naturally occurring or modified. “Motif means the pattern of unmodified and modified nucleosides in an antisense oligomer. [0138] “Natural sugar moiety” can refer to a sugar moiety found in DNA (2’-H) or RNA (2’ - OH). [0139] “Naturally occurring internucleoside linkage” can refer to a 3’ to 5’ phosphodiester linkage. [0140] “Non-complementary nucleobase” can refer to a pair of nucleobases that do not form hydrogen bonds with one another or otherwise support hybridization. [0141] “Nucleic acid” can refer to molecules composed of monomeric nucleotides. A nucleic acid includes, but is not limited to, ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, double -stranded nucleic acids, small interfering ribonucleic acids (siRNA), and microRNAs (miRNA). [0142] “Nucleobase” can mean a heterocyclic moiety capable of pairing with a base of another nucleic acid. “Nucleobase complementarity” can refer to a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In certain embodiments, complementary nucleobase refers to a nucleobase of an antisense oligomer that is capable of base pairing with a nucleobase of its target nucleic acid. For example, if a nucleobase at a certain position of an antisense oligomer is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be complementary at that nucleobase pair. [0143] “Nucleobase sequence” can refer to the order of contiguous nucleobases independent of any sugar, linkage, and/or nucleobase modification. [0144] “Nucleoside” can refer to a nucleobase linked to a sugar. [0145] “Nucleoside mimetic” can include those structures used to replace the sugar or the sugar and the base and not necessarily the linkage at one or more positions of an oligomeric compound such as for example nucleoside mimetics having morpholino, cyclohexenyl, cyclohexyl, tetrahydropyranyl, bicyclo, or tricyclo sugar mimetics, e.g., non-furanose sugar units. Nucleotide mimetic includes those structures used to replace the nucleoside and the linkage at one or more positions of an oligomeric compound such as for example peptide nucleic acids or morpholinos (morpholinos linked by -N(H)-C(=0)-0- or other non-phosphodiester linkage). Sugar surrogate overlaps with the slightly broader term nucleoside mimetic but is intended to indicate replacement of the sugar unit (furanose ring) only. The tetrahydropyranyl rings provided herein are illustrative of an example of a sugar surrogate wherein the furanose sugar group has been replaced with a tetrahydropyranyl ring system. “Mimetic” can refer to groups that are substituted for a sugar, a nucleobase, and/or internucleoside linkage. Generally, a mimetic can be used in place of the sugar or sugar-internucleoside linkage combination, and the nucleobase is maintained for hybridization to a selected target. [0146] “Nucleotide” can refer to a nucleoside having a phosphate group covalently linked to the sugar portion of the nucleoside. [0147] “Oligomeric compound” or “oligomer,” which are used herein interchangeably, can refer to a polymer of linked monomeric subunits which is capable of hybridizing to at least a region of a nucleic acid molecule. [0148] “Oligonucleotide” can refer to a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another. [0149] “Parenteral administration” can refer to administration through injection (e.g., bolus injection) or infusion. Parenteral administration can include subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, or intracranial administration, e.g., intrathecal, intracerebroventricular, or intra cisterna magna administration. [0150] “Peptide” can refer to a molecule formed by linking at least two amino acids by amide bonds. Without limitation, as used herein, peptide refers to polypeptides and proteins. [0151] “Pharmaceutical agent” can refer to a substance that provides a therapeutic benefit when administered to an individual. For example, in certain embodiments, an antisense oligonucleotide targeted to SYNGAP is a pharmaceutical agent. [0152] “Pharmaceutical composition” can refer to a mixture of substances suitable for administering to an individual. For example, a pharmaceutical composition can comprise an antisense oligonucleotide and a sterile aqueous solution. [0153] “Pharmaceutically acceptable salts” can refer to physiologically and pharmaceutically acceptable salts of a pharmaceutically active ingredient (e.g., an antisense oligomer provided herein), such as salts that retain the desired biological activity of the active ingredient and do not impart undesired toxicological effects thereto. [0154] “Phosphorothioate linkage” can mean a linkage between nucleosides where the phosphodiester bond is modified by replacing one of the non-bridging oxygen atoms with a sulfur atom. A phosphorothioate linkage is a modified internucleoside linkage. [0155] “Portion” can mean a defined number of contiguous (i.e., linked) nucleobases of a nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of a target nucleic acid. In certain embodiments, a portion is a defined number of contiguous nucleobases of an antisense oligomer. [0156] “Prevent” or “preventing” can mean delaying or forestalling the onset or development of a disorder or syndrome for a period of time from minutes to days, weeks to months, or indefinitely. [0157] “Prophylactically effective amount” can mean an amount of a pharmaceutical agent that provides a prophylactic or preventative benefit to an animal. [0158] “Ribonucleotide” can mean a nucleotide having a hydroxy at the 2’ position of the sugar portion of the nucleotide. Ribonucleotides may be modified with any of a variety of substituents. [0159] “Segments” are defined as smaller or sub-portions of regions within a target nucleic acid. [0160] “Targeting” or “targeted” can mean the process of design and selection of an antisense oligomer that will specifically hybridize to a target nucleic acid and induce a desired effect. [0161] “Target nucleic acid,” “target RNA,” and “target RNA transcript” and “nucleic acid target” all can mean a nucleic acid capable of being targeted by antisense oligomers. In certain embodiments, the target nucleic acid is a UBE2A nucleic acid. [0162] “Target region” can mean a portion of a target nucleic acid to which one or more antisense oligomers is targeted. [0163] “Target segment” can mean the sequence of nucleotides of a target nucleic acid to which an antisense oligomer is targeted. “5’ target site” refers to the 5’-most nucleotide of a target segment. “3’ target site” refers to the 3’-most nucleotide of a target segment. [0164] “Therapeutically effective amount” can mean an amount of a pharmaceutical agent that provides a therapeutic benefit to an individual. “Treat” or “treating” or “treatment” can refer to administering a composition to effect an alteration or improvement of the disorder or syndrome. [0165] “Unmodified nucleobases” can mean the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). [0166] “Unmodified nucleotide” can mean a nucleotide composed of naturally occurring nucleobases, sugar moieties, and internucleoside linkages. In certain embodiments, an unmodified nucleotide is an RNA nucleotide (i.e., β-D-ribonucleosides) or a DNA nucleotide (i.e., β-D-deoxyribonucleoside). [0167] “Wing segment” can mean a plurality of nucleosides modified to impart to an oligonucleotide property such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases. [0168] In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 12 to 30 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 12 to 25 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 12 to 22 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 14 to 20 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 15 to 25 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 18 to 22 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 19 to 21 subunits in length. In certain embodiments, the antisense oligomer is 8 to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 30, 18 to 50, 19 to 30, 19 to 50, or 20 to 30 linked subunits in length. [0169] In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 12 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 13 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 14 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 15 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 16 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 17 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 18 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 19 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 20 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 21 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 22 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 23 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 24 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 25 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 26 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 27 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 28 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 29 subunits in length. In certain embodiments, an antisense oligomer targeted to a target nucleic acid is 30 subunits in length. In certain embodiments, the antisense oligomer targeted to a target nucleic acid is 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 linked subunits in length, or a range defined by any two of the above values. In certain embodiments the antisense oligomer is an antisense oligonucleotide, and the linked subunits are nucleosides. [0170] Antisense oligomers provided herein can have nucleotides that mismatch the target sequence. For instance, an antisense oligonucleotide of 25 nucleobases in length can have 8 or 11 mismatch bases near the ends of the antisense oligonucleotides, while still being able to direct specific cleavage of the target mRNA, albeit to a lesser extent than the antisense oligonucleotides that contained no mismatches. In some cases, the antisense oligonucleotide provided herein has 12 to 30 subunits in length (e.g., nucleobases), including those with 1 or 3 mismatches. [0171] Chemically Modified Antisense Oligomer [0172] In certain embodiments, antisense oligomers provided herein have chemically modified subunits arranged in patterns, or motifs, to confer to the antisense oligomer properties such as enhanced inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases. [0173] In some cases, provided herein are chimeric antisense oligomers. For instance, chimeric antisense oligomers can contain at least one region modified so as to confer increased resistance to nuclease degradation, increased cellular uptake, increased binding affinity for the target nucleic acid, and/or increased inhibitory activity. A second region of a chimeric antisense oligomer can optionally serve as a substrate for the cellular endonuclease RNase H, which cleaves the RNA strand of an RNA:DNA duplex. [0174] In some cases, the antisense oligomers provided herein have a gapmer motif. Antisense oligomers having a gapmer motif can be considered chimeric antisense oligomers. In a gapmer an internal region having a plurality of nucleotides that supports RNaseH cleavage can be positioned between external regions having a plurality of nucleotides that are chemically distinct from the nucleosides of the internal region. In the case of an antisense oligonucleotide having a gapmer motif, the gap segment can serve as the substrate for endonuclease cleavage, while the wing segments comprise modified nucleosides. In certain embodiments, the regions of a gapmer are differentiated by the types of sugar moieties comprising each distinct region. The types of sugar moieties that are used to differentiate the regions of a gapmer can include β-D- ribonucleosides, β-D-deoxyribonucleosides, 2’- modified nucleosides (such 2’-modified nucleosides may include 2’-MOE, and 2’-0-CH₃, among others), and bicyclic sugar modified nucleosides (such bicyclic sugar modified nucleosides may include those having a 4’- (CH₂)_n-0- 2’ bridge, where n=1 or n=2 and 4’-CH₂-0-CH₂-2’). In certain embodiments, wings include several modified sugar moieties, including, for example 2’-MOE. In certain embodiments, wings include several modified and unmodified sugar moieties. In certain embodiments, wings include various combinations of 2’-MOE nucleosides and 2’-deoxynucleosides. [0175] Each distinct region can comprise uniform sugar moieties, variant, or alternating sugar moieties. The wing-gap-wing motif is frequently described as “X-Y-Z”, where “X” represents the length of the 5’ wing, ‘Ύ” represents the length of the gap, and “Z” represents the length of the 3’ wing. “X” and “Z” can comprise uniform, variant, or alternating sugar moieties. In certain embodiments, “X” and “Y” include one or more 2’-deoxynucleosides. “Y” can comprise 2’- deoxynucleosides. As used herein, a gapmer described as “X-Y-Z” can have a configuration such that the gap is positioned immediately adjacent to each of the 5’ wing and the 3’ wing. Thus, no intervening nucleotides can exist between the 5’ wing and gap, or the gap and the 3’ wing. Any of the antisense oligomers described herein can have a gapmer motif. In certain embodiments, “X” and “Z” are the same; in other cases, they are different. [0176] In certain cases, gapmers provided herein include, for example 20-mers having a motif of 5-10-5 in the form of “X-Y-Z” as described herein. In certain embodiments, gapmers provided herein include, for example 19-mers having a motif of 5-9-5 in the form of “X-Y-Z” as described herein. In certain embodiments, gapmers provided herein include, for example 18- mers having a motif of 5-8-5 in the form of “X-Y-Z” as described herein. In certain embodiments, gapmers provided herein include, for example 18-mers having a motif of 4-8-6 in the form of “X-Y-Z” as described herein. In certain embodiments, gapmers provided herein include, for example 18-mers having a motif of 6-8-4 in the form of “X-Y-Z” as described herein. In certain embodiments, gapmers provided herein include, for example 18-mers having a motif of 5-7-6 in the form of “X-Y-Z” as described herein. [0177] In some cases, the antisense oligomer comprises: a 5’ region consisting of three, four, five, or six linked nucleosides (e.g., “X” part discussed above); a central region consisting of eight, nine, ten, eleven, or twelve linked nucleosides(e.g., “Y” part discussed above); and a 3’ region consisting of three, four, five, or six linked nucleosides (e.g., “Z” part discussed above). In some cases, each of the three, four, five, or six linked nucleosides in the 5’ region and each of three, four, five, or six linked nucleosides in the 3’ region comprise a modified sugar moiety, and each of the eight, nine, ten, eleven, or twelve linked nucleosides in the central region is a deoxyribonucleoside. In some cases, the modified sugar moiety includes a 2’-O-methyl moiety, a 2’-Fluoro moiety, a 2’-O-methoxyethyl moiety, a 2’-NMA moiety, or any combination thereof. In some cases, one or more the nucleosides in the 5’ region and in the 3’ region further comprise other modification as disclosed herein. In some cases, all the nucleosides in the 5’ region and in the 3’ region further comprise other modification as disclosed herein. [0178] Complementarity [0179] An agent provided herein can have a polynucleotide sequence complementary to a target nucleic acid when a sufficient number of nucleobases in the polynucleotide sequence (for instance antisense oligomer) can hydrogen bond with the corresponding nucleobases of the target nucleic acid, such that a desired effect can occur (e.g., antisense inhibition of a target nucleic acid, such as a SYNGAP nucleic acid). [0180] Non-complementary nucleobases between an agent (e.g., an antisense oligomer) and a target nucleic acid may be tolerated provided that the agent (e.g., antisense oligomer) remains able to specifically hybridize to a target nucleic acid. Moreover, an agent (e.g., antisense oligomer) can hybridize to one or more segments of a target nucleic acid such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure). [0181] In certain embodiments, the agents (e.g., antisense oligomers) provided herein, or a specified portion thereof, are, or are at least, 70%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementary to a SYNGAP nucleic acid, a target region, target segment, or specified portion thereof. Percent complementarity of an antisense oligomer with a target nucleic acid can be determined using routine methods, such as using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403410; Zhang and Madden, Genome Res., 1997, 7, 649656). Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482489). [0182] In certain embodiments, the agents (e.g., antisense oligomers) provided herein, or specified portions thereof, are fully complementary (i.e., 100% complementary) to a target nucleic acid, or specified portion thereof. For example, agents (e.g., antisense oligomers) provided herein can be fully complementary to a SYNGAP nucleic acid, or a target region, or a target segment or target sequence thereof. As used herein, “fully complementary” can mean that each nucleobase of an antisense oligomer is capable of precise base pairing with the corresponding nucleobases of a target nucleic acid. [0183] The location of a non-complementary nucleobase can be at the 5 ‘ end or 3 ‘ end of the antisense oligomer. Alternatively, the non-complementary nucleobase or nucleobases can be at an internal position of the antisense oligomer. When two or more non-complementary nucleobases are present, they can be contiguous (i.e., linked) or non-contiguous. In one embodiment, a non-complementary nucleobase is located in the wing segment of a gapmer antisense oligonucleotide. [0184] In certain embodiments, antisense oligomers provided herein that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in length comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, or specified portion thereof. [0185] In certain embodiments, antisense oligomers provided herein that are, or are up to 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, or specified portion thereof. [0186] The agents (e.g., antisense oligomers) provided herein can also include those which are complementary to a portion of a target nucleic acid. As used herein, “portion” can refer to a defined number of contiguous (i.e., linked) nucleobases within a region or segment of a target nucleic acid. A “portion” can also refer to a defined number of contiguous nucleobases of an antisense oligomer. In certain embodiments, the agents (e.g., antisense oligomers) are complementary to at least an 8-nucleobase portion of a target segment. In certain embodiments, the agents (e.g., antisense oligomers) are complementary to at least a 9-nucleobase portion of a target segment. In certain embodiments, the agents (e.g., antisense oligomers) are complementary to at least a 10-nucleobase portion of a target segment. In certain embodiments, the agents (e.g., antisense oligomers) are complementary to at least an 11-nucleobase portion of a target segment. In certain embodiments, the agents (e.g., antisense oligomers) are complementary to at least a 12-nucleobase portion of a target segment. In certain embodiments, the agents (e.g., antisense oligomers) are complementary to at least a 13-nucleobase portion of a target segment. In certain embodiments, the agents (e.g., antisense oligomers) are complementary to at least a 14-nucleobase portion of a target segment. In certain embodiments, the agents (e.g., antisense oligomers) are complementary to at least a 15-nucleobase portion of a target segment. Also contemplated are antisense oligomers that are complementary to at least a 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleobase portion of a target segment, or a range defined by any two of these values. [0187] The agents (e.g., antisense oligomers) provided herein can also have a defined percent identity to a particular nucleotide sequence, SEQ ID NO, or portion thereof. As used herein, an antisense oligomer is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, an RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine. Shortened and lengthened versions of the antisense oligomers described herein as well as oligomers having non-identical bases relative to the antisense oligomers provided herein also are contemplated. The non-identical bases can be adjacent to each other or dispersed throughout the antisense oligomer. Percent identity of an antisense oligomer is calculated according to the number of bases that have identical base pairing relative to the sequence to which it is being compared. [0188] In certain embodiments, the agents (e.g., antisense oligomers), or portions thereof, are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to one or more of the agents (e.g., antisense oligomers) or SEQ ID NOs, or a portion thereof, disclosed herein. [0189] In certain embodiments, a portion of the agent (e.g., antisense oligomer) is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid. [0190] In certain embodiments, a portion of the antisense oligonucleotide is compared to an equal length portion of the target nucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is compared to an equal length portion of the target nucleic acid. [0191] Modifications [0192] In some embodiments, an antisense oligomer provided herein can have one or more chemical modifications as compared to a naturally occurring nucleotide (or a native form of the antisense oligomer) that has the same or comparable polynucleotide sequence. Modifications to antisense oligomers encompass substitutions or changes to internucleoside linkages, sugar moieties, or nucleobases. Modified antisense oligomers can be preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, or increased inhibitory activity. [0193] Chemically modified nucleosides can be employed to increase the binding affinity of a shortened or truncated antisense oligonucleotide for its target nucleic acid. Consequently, comparable results can often be obtained with shorter antisense oligomers that have such chemically modified nucleosides. [0194] A nucleoside can be a base-sugar combination. The nucleobase (also known as base) portion of the nucleoside can be a heterocyclic base moiety in native form. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to the 2’, 3’, or 5’ hydroxyl moiety of the sugar. Oligonucleotides are formed through the covalent linkage of adjacent nucleosides to one another, to form a linear polymeric oligonucleotide. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside linkages of the oligonucleotide. [0195] Modified Internucleoside Linkages [0196] The naturally occurring internucleoside linkage of RNA and DNA is a 3’ to 5’ phosphodiester linkage. Antisense oligomers provided herein can have one or more modified, i.e., non-naturally occurring, internucleoside linkages. Antisense oligomers having one or more modified internucleotide linkages can have desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for target nucleic acids, and increased stability in the presence of nucleases. [0197] Oligonucleotides having modified internucleoside linkages can include internucleoside linkages that retain a phosphorus atom as well as internucleoside linkages that do not have a phosphorus atom. Representative phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates. [0198] In certain embodiments, antisense oligomers targeted to a SYNGAP nucleic acid comprise one or more modified internucleoside linkages. In certain embodiments, the modified internucleoside linkages are interspersed throughout the antisense oligomer. In certain embodiments, the modified internucleoside linkages are phosphorothioate linkages. In certain embodiments, each internucleoside linkage of an antisense oligomer is a phosphorothioate internucleoside linkage. [0199] Modified Sugar Moieties [0200] Antisense oligomers provided herein can contain one or more nucleosides wherein the sugar group has been modified. Such sugar modified nucleosides can impart enhanced nuclease stability, increased binding affinity, or some other beneficial biological property to the antisense oligomers. In certain embodiments, nucleosides comprise chemically modified ribofuranose ring moieties. [0201] Examples of chemically modified ribofuranose rings include without limitation, addition of substitute groups (including 5’ and 2’ substituent groups, bridging of non-geminal ring atoms to form bicyclic nucleic acids (BNA), replacement of the ribosyl ring oxygen atom with S, N(R), or C(R₁)(R₂) (R, R₁ and R₂ are each independently H, C₁-C₁₂ alkyl or a protecting group) and combinations thereof. Examples of chemically modified sugars include 2’-F-5’-methyl substituted nucleoside (see PCT International Application WO 2008/101157 for other disclosed 5’,2’-bis substituted nucleosides) or replacement of the ribosyl ring oxygen atom with S with further substitution at the 2’-position (see published U.S. Patent Application US2005-0130923, published on June 16, 2005) or alternatively 5’-substitution of a BNA (see PCT International Application WO 2007/134181 wherein LNA is substituted with for example a 5’-methyl or a 5’- vinyl group). [0202] Examples of nucleosides having modified sugar moieties include without limitation nucleosides comprising 5’-vinyl, 5’-methyl (R or S), 4’-S, 2’-F, 2’-OCH₃, 2’-OCH₂CH₃, 2’- OCH₂CH₂F, 2’-NMA, and 2’-O(CH₂)₂OCH₃ substituent groups. The substituent at the 2’ position can also be selected from allyl, amino, azido, thio, O-allyl, O-C₁-C₁₀ alkyl, OCF₃, OCH₂F, O(CH₂)₂SCH₃, O(CH₂)₂-O-N(R_m)(R_n), O-CH₂-C(=O)-N(R_m)(R_n), and O-CH₂-C(=O)- N(Rl)-(CH₂)₂-N(R_m)(R_n), where each Rl, R_m and R_n is, independently, H or substituted or unsubstituted C₁-C₁₀ alkyl. [0203] As used herein, “bicyclic nucleosides” can refer to modified nucleosides comprising a bicyclic sugar moiety. Examples of bicyclic nucleosides include without limitation nucleosides comprising a bridge between the 4’ and the 2’ ribosyl ring atoms. In certain embodiments, antisense oligomers provided herein include one or more bicyclic nucleosides comprising a 4’ to 2’ bridge. Examples of such 4’ to 2’ bridged bicyclic nucleosides, include but are not limited to one of those described in U.S. Patent Nos.7,399,845, 8,278,283, U.S. Patent Application 7,696,345, 7,427,672, 8,278,426, 6,268,490; 6,525, 191; 6,670,461; 6,770,748; 6,794,499; 7,034, 133; 7,053,207, 7,399,845, 7,547,684, 7,741,457, and 7,696,345; U.S. Patent Nos.; U.S. Patent Publication No. US2008-0039618; and Chattopadhyaya et al, J. Org. Chem., 2009, 74, 1 18-134); Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Wahlestedt et al, Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al, J. Org. Chem., 1998, 63, 10035- 10039; Srivastava et al, J. Am. Chem. Soc, 2007, 129(26) 8362-8379; Elayadi et al, Curr. Opinion Invest. Drugs, 2001, 2, 558-561; Braasch et al, Chem. Biol, 2001, 8, 1-7; and Orum et al, Curr. Opinion Mol. Ther., 2001, 3, 239-243. Each of the foregoing bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations including for example a-L- ribofuranose and β-D-ribofuranose (see PCT international application PCT/DK98/00393, published on March 25, 1999 as WO 99/14226). In certain embodiments, bicyclic sugar moieties of BNA nucleosides include, but are not limited to, described in US Patent No.11,129,844. [0204] The synthesis and preparation of the methyleneoxy (4’-CH₂-0-2’) BNA monomers adenine, cytosine, guanine, 5 -methyl -cytosine, thymine and uracil, along with their oligomerization, and nucleic acid recognition properties have been described (Koshkin et al., Tetrahedron, 1998, 54, 3607-3630). [0205] As used herein, “4’-2’ bicyclic nucleoside” or “4’ to 2’ bicyclic nucleoside” can refer to a bicyclic nucleoside comprising a furanose ring comprising a bridge connecting two carbon atoms of the furanose ring connects the 2’ carbon atom and the 4’ carbon atom of the sugar ring. [0206] As used herein, “monocylic nucleosides” can refer to nucleosides comprising modified sugar moieties that are not bicyclic sugar moieties. In certain embodiments, the sugar moiety, or sugar moiety analogue, of a nucleoside is modified or substituted at any position. [0207] As used herein, “2’-modified sugar” can mean a furanosyl sugar modified at the 2’ position. In certain embodiments, such modifications include substituents selected from: a halide, including, but not limited to substituted and unsubstituted alkoxy, substituted and unsubstituted thioalkyl, substituted and unsubstituted amino alkyl, substituted and unsubstituted alkyl, substituted and unsubstituted allyl, and substituted and unsubstituted alkynyl. In certain embodiments, 2’ modifications are selected from substituents including, but not limited to: O[(CH₂)_nO]_mCH₃, O(CH₂)_nNH₂, O(CH₂)_nCH₃, O(CH₂)_nF, O(CH₂)_nONH₂, OCH₂C(=O)N(H)CH₃ and O(CH₂)_nON[(CH₂)_nCH₃]₂, where n and m are from 1 to about 10. Other 2’- substituent groups can also be selected from: C₁-C₁₂ alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃, OCN, CI, Br, CN, F, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving pharmacokinetic properties, or a group for improving the pharmacodynamic properties of an antisense oligomer, and other substituents having similar properties. In certain embodiments, modified nucleosides comprise a 2’-MOE side chain (Baker et al, J. Biol. Chem., 1997, 272, 11944-12000). Such 2’-MOE substitution have been described as having improved binding affinity compared to unmodified nucleosides and to other modified nucleosides, such as 2’- O- methyl, O-propyl, and O-aminopropyl. Oligonucleotides having the 2’-MOE substituent also have been shown to be antisense inhibitors of gene expression with promising features for in vivo use (Martin, Helv. Chim. Acta, 1995, 78, 486-504; Altmann et al., Chimia, 1996, 50, 168-176; Altmann et al., Biochem. Soc. Trans., 1996, 24, 630-637; and Altmann et al, Nucleosides Nucleotides, 1997, 16, 917-926). [0208] As used herein, “2’-NMA” can mean a -O-CH₂-C(=O)-NH-CH₃ group in place of the 2’- OH group of a ribosyl sugar moiety. A “2’-NMA sugar moiety” or “2’-NMA moiety” is a sugar moiety with a 2’-O-CH₂-C(=O)-NH-CH₃ group in place of the 2’-OH group of a nbosyl sugar moiety. Unless otherwise indicated, a 2’-NMA sugar moiety is in the β-D configuration. “NMA” can mean O-N-methyl acetamide. [0209] As used herein, “2’-NMA nucleoside” can mean a nucleoside comprising a 2’-NMA sugar moiety. [0210] As used herein, “2’-F” can refer to a nucleoside comprising a sugar comprising a fluoro group at the 2’ position. [0211] As used herein, “2’-OMe” or “2’-OCH₃” or “2’-O-methyl” each can refer to a nucleoside comprising a sugar comprising an -OCH₃ group at the 2’ position of the sugar ring. [0212] As used herein, “MOE” or “2’-MOE” or “2’-OCH₂CH₂OCH₃” or “2’-O-methoxyethyl” each refers to a nucleoside comprising a sugar comprising a -OCH₂CH₂OCH₃ group at the 2’ position of the sugar ring. [0213] In certain embodiments, one or more of the plurality of nucleosides is modified. In certain embodiments, an oligonucleotide comprises one or more ribonucleosides (RNA) and/or deoxyribonucleosides (DNA). In certain embodiments, an oligonucleotide comprises a mix of one or more ribonucleosides (RNA) and deoxyribonucleosides (DNA). [0214] Many other bicyclo and tricyclo sugar surrogate ring systems are also known in the art that can be used to modify nucleosides for incorporation into antisense oligomers (see for example review article: Leumann, Bioorg. Med. Chem., 2002, 10, 841-854). Such ring systems can undergo various additional substitutions to enhance activity. [0215] Methods for the preparations of modified sugars are well known to those skilled in the art. [0216] In nucleotides having modified sugar moieties, the nucleobase moieties (natural, modified or a combination thereof) are maintained for hybridization with an appropriate nucleic acid target. [0217] In certain embodiments, antisense oligomers comprise one or more nucleosides having modified sugar moieties. In certain embodiments, the modified sugar moiety is 2’-MOE. In certain embodiments, the 2’ -MOE modified nucleosides are arranged in a gapmer motif. In certain embodiments, the modified sugar moiety is a bicyclic nucleoside having a (4’-CH(CH₃)- 0-2’) bridging group. In certain embodiments, the (4’- CH(CH₃)-0-2’) modified nucleosides are arranged throughout the wings of a gapmer motif. [0218] “5’-methylcytosine” can mean a cytosine modified with a methyl group attached to the 5’ position. A 5’-methylcytosine is a modified nucleobase. [0219] “5’-methyluracil” can mean a uracil modified with a methyl group attached to the 5’ position. A 5’-methyluracil is a modified nucleobase. [0220] “5’-methylthymine” can mean a thymine modified with a methyl group attached to the 5’ position. A 5’-methylthymine is a modified nucleobase. [0221] In some cases, antisense oligomers provided herein comprise 5’-methylcytosine, 5’- methyluracil, 5’-methylthymine, or a combination thereof. In some cases, each cytosine in the antisense oligomer is methylated, i.e., having a methyl group attached to the 5’ position. In some cases, each uracil in the antisense oligomer is methylated, i.e., having a methyl group attached to the 5’ position. In some cases, the antisense oligomer has 1, 2, 3, 4, 5, 6, 7, 8, or more 5’- methylcytosine. In some cases, the antisense oligomer has 1, 2, 3, 4, 5, 6, 7, 8, or more 5’- methyluracil. In some cases, the antisense oligomer has both methylcytosine and methyluracil. [0222] Pharmaceutical Compositions and Methods of Treatment [0223] In some aspects, provided herein are pharmaceutical compositions comprising an agent of the present disclosure, e.g., an antisense oligomer, or a vector encoding the agent. [0224] Pharmaceutical compositions or formulations comprising the agent, e.g., antisense oligomer, or a vector encoding the agent, of the described compositions and for use in any of the described methods can be prepared according to conventional techniques well known in the pharmaceutical industry and described in the published literature. In some embodiments, a pharmaceutical composition or formulation for treating a subject comprises an effective amount of any antisense oligomer as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or ester thereof. The pharmaceutical formulation comprising an antisense oligomer may further comprise a pharmaceutically acceptable excipient, diluent, or carrier. [0225] Agents (e.g., antisense oligomers) or vectors provided herein can be admixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. An agent (e.g., antisense oligomer) targeted to a SYNGAP nucleic acid can be utilized in pharmaceutical compositions by combining the agent with a suitable pharmaceutically acceptable diluent or carrier. A pharmaceutically acceptable diluent can include phosphate -buffered saline (PBS), artificial cerebrospinal fluid (aCSF), physiological saline, or any other suitable solutions. [0226] Pharmaceutically acceptable salts are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit/risk ratio. (See, e.g., S. M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference for this purpose. The salts can be prepared in situ during the final isolation and purification of the compounds, or separately by reacting the free base form with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other documented methodologies such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. [0227] In some embodiments, the compositions are formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. In embodiments, the compositions are formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. In embodiments, a pharmaceutical formulation or composition of the present disclosure includes, but is not limited to, a solution, emulsion, microemulsion, foam or liposome-containing formulation (e.g., cationic or noncationic liposomes). [0228] The pharmaceutical composition or formulation described herein may comprise one or more penetration enhancers, carriers, excipients or other active or inactive ingredients as appropriate and well known to those of skill in the art or described in the published literature. In embodiments, liposomes also include sterically stabilized liposomes, e.g., liposomes comprising one or more specialized lipids. These specialized lipids result in liposomes with enhanced circulation lifetimes. In embodiments, a sterically stabilized liposome comprises one or more glycolipids or is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. In some embodiments, a surfactant is included in the pharmaceutical formulation or compositions. The use of surfactants in drug products, formulations and emulsions is well known in the art. In embodiments, the present disclosure employs a penetration enhancer to effect the efficient delivery of the antisense oligonucleotide, e.g., to aid diffusion across cell membranes and /or enhance the permeability of a lipophilic drug. In some embodiments, the penetration enhancers are a surfactant, fatty acid, bile salt, chelating agent, or non-chelating nonsurfactant. [0229] In some embodiments, the pharmaceutical formulation comprises multiple agents (e.g., antisense oligomers). In embodiments, the agent (e.g., antisense oligomer) or a vector encoding the agent is administered in combination with another drug or therapeutic agent. [0230] Pharmaceutical compositions comprising antisense oligomers can encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense oligomers, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. [0231] A prodrug can include the incorporation of additional nucleosides at one or both ends of an antisense oligomer which are cleaved by endogenous nucleases within the body, to form the active antisense oligomer. [0232] Antisense oligomers disclosed herein can be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution, or cellular uptake of the resulting antisense oligomers. Conjugate groups can include cholesterol moieties and lipid moieties. Additional conjugate groups can include carbohydrates, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. [0233] Antisense oligomers of the present disclosure can also be modified to have one or more stabilizing groups that are generally attached to one or both termini of antisense oligomers to enhance properties such as, for example, nuclease stability. Included in stabilizing groups are cap structures. These terminal modifications can protect the antisense oligomer having terminal nucleic acid from exonuclease degradation and can help in delivery and/or localization within a cell. The cap can be present at the 5’-terminus (5’-cap), or at the 3’-terminus (3’-cap), or can be present on both termini. Cap structures can include, for example, inverted deoxy abasic caps. Further 3’ and 5’-stabilizing groups that can be used to cap one or both ends of an antisense oligomer to impart nuclease stability can include those disclosed in WO 03/004602 published on January 16, 2003. [0234] Alternative splicing in certain genes can lead to non-productive or less productive mRNA transcripts which in turn can downregulate protein expression. Therapeutic agents that can target the alternative splicing events in these genes can modulate the expression level of proteins. Such therapeutic agents can be used to treat a condition caused by protein deficiency. [0235] One of the alternative splicing events that can lead to non-productive or less productive mRNA transcripts can be the inclusion of an exon containing an inefficient translation region, which can result in inefficient translation of the mRNA transcript. In some cases, the mRNA transcript with the inefficient translation region has significantly lower translation efficiency as compared to a corresponding mRNA transcript that is otherwise identical but without the inefficient region. [0236] In one aspect, the present disclosure provides compositions and methods for modulating alternative splicing of genes that can have a pre-mRNA that has an exon having an inefficient translation region to increase the production of mRNAs that is efficiently translated and codes for a target peptide sequence, and thus the translated target peptide sequence. The compositions and methods include antisense oligomers (ASOs) that can cause exon skipping and promote the generation of mRNA that can be efficiently translated. In various examples, the target peptide sequence can be increased using the methods of the disclosure to treat a condition caused by deficiency of the target peptide sequence or a relevant protein. [0237] Described herein, in some embodiments, is a method of modulating expression of a target peptide sequence by cells having a pre-mRNA that encodes the target peptide sequence and comprises an inefficient translation region, the method comprising contacting the cells with a therapeutic agent that binds to a targeted region of the pre-mRNA encoding the target peptide sequence, whereby splicing of the inefficient translation region from the pre-mRNA encoding the target peptide sequence is modulated, thereby modulating a level of a first processed mRNA that is devoid of the inefficient translation region and encodes the target peptide sequence, and thereby modulating the expression of the target peptide sequence in the cells, wherein the processed mRNA has a higher translation efficiency for producing the target peptide sequence in the cells as compared to a second processed mRNA that comprises the inefficient translation region. In some cases, the second processed mRNA is otherwise identical to the first processed mRNA but comprises the inefficient translation region. In some cases, the first processed mRNA and the second processed mRNA are both splicing products of the same pre-mRNA. In some cases, the subject therapeutic agent modulates the splicing of the pre-mRNA, thereby modulating the balance between the first processed mRNA and the second processed mRNA in the cell. [0238] In some embodiments, one of the alternative splicing events that can lead to non- productive or less productive mRNA transcript is the inclusion of an exon that contains a premature termination codon (PTC) followed by an alternative start codon. In these cases, the pre-mRNA has a first start codon, a second start codon (alternative start codon), and a PTC located downstream of the first start codon and upstream of the second start codon. Without wishing to be bound by a certain theory, the motif or the exon containing the PTC and the alternative start codon can contribute to the low productivity of the mRNA transcript. In some embodiments, the motif or the exon containing the PTC and the alternative start codon leads to inefficient translation of the downstream exon sequences. In some embodiments, the motif or the exon containing the PTC and the alternative start codon leads to less stable protein product expressed by the downstream exon sequences or deficient post-translational modification, or some other processes at the molecular or cellular level, which can result in deficient protein expression or function. Without wishing to be bound by a certain theory, the presence of the alternative start codon can contribute to the lack of nonsense-mediated decay (NMD) of the mRNA transcript, as the translating ribosome can reinitiate translation at the alternative start codon right after encountering the PTC rather than triggering the recruitment of the NMD machinery, which ultimately can lead to the degradation of the mRNA transcript. [0239] In one aspect, the present disclosure provides compositions and methods for modulating alternative splicing of genes that can have a pre-mRNA that has an exon containing a PTC followed by an alternative start codon to increase the production of mature mRNAs that codes for a target peptide sequence, and thus the translated target peptide sequence. In some cases, the compositions include ASOs that can cause exon skipping and promote the generation of an mRNA that can be efficiently translated. In various examples, the target peptide sequence can be increased using the methods of the disclosure to treat a condition caused by deficiency of the target peptide sequence or a relevant protein. [0240] Described herein, in some embodiments, is a method of modulating expression of a target peptide sequence by cells having a pre-mRNA that encodes the target peptide sequence and comprises a first start codon, a second start codon, and a premature termination codon (PTC) located downstream of the first start codon and upstream of the second start codon, the method comprising contacting the cells with a therapeutic agent that binds to a targeted portion of the pre-mRNA encoding the target peptide sequence, whereby splicing of the PTC and the second start codon from the pre-mRNA is modulated, thereby modulating a level of a first processed mRNA that that is devoid of the PTC and the second start codon and encodes the target peptide sequence, and thereby modulating the expression of the target peptide sequence in the cells. [0241] RNA Splicing [0242] Intervening sequences or introns are removed by a large and highly dynamic RNA- protein complex termed the spliceosome, which orchestrates complex interactions between primary transcripts, small nuclear RNAs (snRNAs) and a large number of proteins. Spliceosomes assemble ad hoc on each intron in an ordered manner, starting with recognition of the 5’ splice site (5’ss) by U1 snRNA or the 3’splice site (3’ss) by the U2 pathway, which involves binding of the U2 auxiliary factor (U2AF) to the 3’ss region to facilitate U2 binding to the branch point sequence (BPS). U2AF is a stable heterodimer composed of a U2AF2-encoded 65-kD subunit (U2AF65), which binds the polypyrimidine tract (PPT), and a U2AF1-encoded 35-kD subunit (U2AF35), which interacts with highly conserved AG dinucleotides at 3‘ss and stabilizes U2AF65 binding. In addition to the BPS/PPT unit and 3’ss/5’ss, accurate splicing requires auxiliary sequences or structures that activate or repress splice site recognition, known as intronic or exonic splicing enhancers or silencers. These elements allow genuine splice sites to be recognized among a vast excess of cryptic or pseudo-sites in the genome of higher eukaryotes, which have the same sequences but outnumber authentic sites by an order of magnitude. Although they often have a regulatory function, the exact mechanisms of their activation or repression are poorly understood. [0243] The decision of whether to splice or not can be typically modeled as a stochastic rather than deterministic process, such that even the most defined splicing signals can sometimes splice incorrectly. However, under normal conditions, pre-mRNA splicing can proceed at surprisingly high fidelity. This can be attributed in part to the activity of adjacent cis-acting auxiliary exonic and intronic splicing regulatory elements (ESRs or ISRs). Typically, these functional elements are classified as either exonic or intronic splicing enhancers (ESEs or ISEs) or silencers (ESSs or ISSs) based on their ability to stimulate or inhibit splicing, respectively. Although there is now evidence that some auxiliary cis-acting elements may act by influencing the kinetics of spliceosome assembly, such as the arrangement of the complex between U1 snRNP and the 5’ss, it seems very likely that many elements function in concert with trans-acting RNA-binding proteins (RBPs). For example, the serine- and arginine-rich family of RBPs (SR proteins) is a conserved family of proteins that have a key role in defining exons. SR proteins promote exon recognition by recruiting components of the pre-spliceosome to adjacent splice sites or by antagonizing the effects of ESSs in the vicinity. The repressive effects of ESSs can be mediated by members of the heterogeneous nuclear ribonucleoprotein (hnRNP) family and can alter recruitment of core splicing factors to adjacent splice sites. In addition to their roles in splicing regulation, silencer elements are suggested to have a role in repression of pseudo-exons, sets of decoy intronic splice sites with the typical spacing of an exon but without a functional open reading frame. ESEs and ESSs, in cooperation with their cognate trans-acting RBPs, represent important components in a set of splicing controls that specify how, where and when mRNAs are assembled from their precursors. [0244] The sequences marking the exon-intron boundaries are degenerate signals of varying strengths that can occur at high frequency within human genes. In multi-exon genes, different pairs of splice sites can be linked together in many different combinations, creating a diverse array of transcripts from a single gene. This is commonly referred to as alternative pre-mRNA splicing. Although most mRNA isoforms produced by alternative splicing can be exported from the nucleus and translated into functional polypeptides, different mRNA isoforms from a single gene can vary greatly in their translation efficiency. Those mRNA isoforms with premature termination codons (PTCs) at least 50 bp upstream of an exon junction complex are likely to be targeted for degradation by the nonsense-mediated mRNA decay (NMD) pathway. In some embodiments, however, an alternative start codon that follows the PTC can prevent the induction of NMD event, as exemplified in the case of MECP2 e2 mRNA isoform (discussed below). Mutations in traditional (BPS/PPT/3’ss/5’ss) and auxiliary splicing motifs can cause aberrant splicing, such as exon skipping or cryptic (or pseudo-) exon inclusion or splice-site activation, and contribute significantly to human morbidity and mortality. Both aberrant and alternative splicing patterns can be influenced by natural DNA variants in exons and introns. [0245] In some embodiments, the compositions and methods make use of cryptic splice sites to modulate alternative splicing in order to produce desirable splicing isoform, in order to modulate the expression level of target peptide sequence. Cryptic (or pseudo-) splice sites can have the same splicing recognition sequences as genuine splice sites but are not used in splicing reactions. They outnumber genuine splice sites in the human genome by an order of a magnitude and are normally repressed by thus far poorly understood molecular mechanisms. Cryptic 5’ splice sites have the consensus NNN/GUNNNN or NNN/GCNNNN where N is any nucleotide and / is the exon-intron boundary. Cryptic 3’ splice sites have the consensus NAG/N. Their activation is positively influenced by surrounding nucleotides that make them more similar to the optimal consensus of authentic splice sites, namely MAG/GURAGU and YAG/G, respectively, where M is C or A, R is G or A, and Y is C or U. [0246] Splice sites and their regulatory sequences can be readily identified by a skilled person using suitable algorithms publicly available, listed for example in Kralovicova, J. and Vorechovsky, I. (2007) Global control of aberrant splice site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition. Nucleic Acids Res., 35, 6399- 6413, (available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2095810/pdf/gkm680.pdf) [0247] The cryptic splice sites or splicing regulatory sequences may compete for RNA-binding proteins, such as U2AF. In some embodiments, an agent may bind to a cryptic splice site or splicing regulatory sequence to prevent binding of RNA-binding proteins and thereby favor binding of RNA-binding proteins to the desirable splice sites. [0248] MECP2 mRNA Splicing [0249] In some embodiments, the methods of the present disclosure exploit the alternative splicing of the pre-mRNA transcribed from MECP2 gene. MECP2 pre-mRNA can have 4 exons and be alternatively spliced (FIG.1). Exemplary MECP2 pre-mRNA sequences include the transcripts of Table 1. In some embodiments, MECP2 pre-mRNA can be spliced into two isoforms, which can result in production of MeCP2α or e1 protein isoform, and MeCP2β or e2 isoform, respectively. Skipping of exon 2 can result in the production of the major MeCP2α or e1 isoform, whereas inclusion of exon 2 can give rise to MeCP2β or e2-isoform. The MeCP2-e1 and e2 isoforms can have a unique N-terminal sequence of 21aa and 9aa respectively. The relative expression level of these isoforms can vary among tissues, with MeCP2-e1 being more dominant in adult brain. MeCP2-e2 is expressed more abundantly in placenta, liver, and skeletal muscle. Furthermore, in some cases, deletion of MeCP2-e2 by disrupting exon 2 does not result in RTT-associated phenotypes in mice. Exon 2 is an out-of-frame exon. It has both a PTC as well as an alternative start codon. Translation from a downstream start codon can be very inefficient. Mutagenesis studies have shown that the presence of two start codons in the full- length (e2) transcript dramatically reduces translation efficiency of the downstream open- reading-frame. When the upstream ATG in exon 1 is eliminated, translation of MeCP2-e2 can increase significantly. In some embodiments, skipping (splicing out) of exon 2 from full length (e2) MECP2 transcripts can reduce the nonproductive transcript pool, leading to increased translation of MeCP2-e1 protein. In adult human brain, approximately 50% of the transcripts can contain exon 2 as determined by RNA-seq (Lister PMID 23828890). In some cases, the isoform containing exon 2 can be dispensable in adult brain, as a result, exon 2 skipping induced by a therapeutic agent (e.g., ASO) can be a viable therapeutic strategy to increase MeCP2 expression in patients suffering from MeCP2 protein deficiency, e.g., Rett syndrome patients. [0250] In some embodiments, the therapeutic agent targets a sequence about 4 to about 300 nucleotides upstream (or 5’) from the 5’ end of the inefficient translation region, e.g., exon 2 region of MECP2 pre-mRNA. In some embodiments, the therapeutic agent targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides upstream (or 5’) from the 5’ end of the inefficient translation region. In some embodiments, the therapeutic agent may target a sequence more than 300 nucleotides upstream from the 5’ end of the inefficient translation region. In some embodiments, the therapeutic agent targets a sequence about 4 to about 300 nucleotides downstream (or 3’) from the 3’ end of the inefficient translation region. In some embodiments, the therapeutic agent targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides downstream from the 3’ end of the inefficient translation region. In some embodiments, the therapeutic agent targets a sequence more than 300 nucleotides downstream from the 3’ end of the inefficient translation region. [0251] In some embodiments, the therapeutic agent targets a sequence about 4 to about 300 nucleotides upstream (or 5’) from the 5’ end of the exon containing the PTC and the second start codon (alternative start codon), e.g., exon 2 region of MECP2 pre-mRNA. In some embodiments, the therapeutic agent targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides upstream (or 5’) from the 5’ end of the exon containing the PTC and the alternative start codon. In some embodiments, the therapeutic agent may target a sequence more than 300 nucleotides upstream from the 5’ end of the exon containing the PTC and the alternative start codon. In some embodiments, the therapeutic agent targets a sequence about 4 to about 300 nucleotides downstream (or 3’) from the 3’ end of the exon containing the PTC and the alternative start codon. In some embodiments, the therapeutic agent targets a sequence about 1 to about 20 nucleotides, about 20 to about 50 nucleotides, about 50 to about 100 nucleotides, about 100 to about 150 nucleotides, about 150 to about 200 nucleotides, about 200 to about 250 nucleotides, or about 250 to about 300 nucleotides downstream from the 3’ end of the exon containing the PTC and the alternative start codon. In some embodiments, the therapeutic agent targets a sequence more than 300 nucleotides downstream from the 3’ end of the exon containing the PTC and the alternative start codon. [0252] In some embodiments, the pre-mRNA transcript that can be targeted by a method or composition provided herein is encoded by a genetic sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an MeCP2 genetic sequence, such as ENSG00000169057. In some embodiments, the pre-mRNA transcript that can be targeted by a method or composition provided herein comprises a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of the sequences of Table 1 or the transcripts ENST00000453960.7, ENST00000303391.11, ENST00000628176.2, ENST00000407218.5, ENST00000415944.3, ENST00000630151.2, ENST00000637917.1, ENST00000369957.5, ENST00000675526.1, ENST00000674996.1, ENST00000460227.4, ENST00000488293.4, ENST00000463644.5, ENST00000626422.2, ENST00000627864.1, ENST00000631210.1, ENST00000611468.2, ENST00000625300.1, ENST00000496908.5, ENST00000676382.1, ENST00000637533.1, ENST00000637791.1, ENST00000637467.1, ENST00000638041.1, ENST00000486506.5, ENST00000629277.1, ENST00000675841.1, ENST00000481807.3. [0253] In some embodiments, the therapeutic agent targets intron 1, exon 2, or intron 2 of MECP2 pre-mRNA. [0254] In some embodiments, the therapeutic agent targets a sequence about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream (or 5’) from the 5’ end of exon 2 of MECP2 pre-mRNA. In some embodiments, the therapeutic agent targets a sequence at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream (or 5’) from the 5’ end of exon 2 of MECP2 pre-mRNA. [0255] In some embodiments, the therapeutic agent targets a sequence about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream (or 3’) from the 3’ end of exon 2 of MECP2 pre-mRNA. In some embodiments, the therapeutic agent targets a sequence at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream (or 3’) from the 3’ end of exon 2 of MECP2 pre-mRNA. [0256] In some embodiments, the therapeutic agent is an ASO and the ASO has a sequence complementary to the targeted portion of the pre-mRNA according to any one of the sequences of Table 1 or the transcripts ENST00000453960.7, ENST00000303391.11, ENST00000628176.2, ENST00000407218.5, ENST00000415944.3, ENST00000630151.2, ENST00000637917.1, ENST00000369957.5, ENST00000675526.1, ENST00000674996.1, ENST00000460227.4, ENST00000488293.4, ENST00000463644.5, ENST00000626422.2, ENST00000627864.1, ENST00000631210.1, ENST00000611468.2, ENST00000625300.1, ENST00000496908.5, ENST00000676382.1, ENST00000637533.1, ENST00000637791.1, ENST00000637467.1, ENST00000638041.1, ENST00000486506.5, ENST00000629277.1, ENST00000675841.1, ENST00000481807.3. In some embodiments, the ASO has a sequence complementary to a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one selected from the group consisting of any one of the sequences of Table 1 or the transcripts ENST00000453960.7, ENST00000303391.11, ENST00000628176.2, ENST00000407218.5, ENST00000415944.3, ENST00000630151.2, ENST00000637917.1, ENST00000369957.5, ENST00000675526.1, ENST00000674996.1, ENST00000460227.4, ENST00000488293.4, ENST00000463644.5, ENST00000626422.2, ENST00000627864.1, ENST00000631210.1, ENST00000611468.2, ENST00000625300.1, ENST00000496908.5, ENST00000676382.1, ENST00000637533.1, ENST00000637791.1, ENST00000637467.1, ENST00000638041.1, ENST00000486506.5, ENST00000629277.1, ENST00000675841.1, ENST00000481807.3. [0257] In some embodiments, the ASOs target a sequence containing an exon-intron boundary (or junction). [0258] In some embodiments, the methods and compositions of the present disclosure are used to increase the expression of MeCP2 by inducing exon skipping of exon 2 of a MECP2 pre- mRNA. [0259] In some cases, the target peptide sequence is a portion of MECP2 protein. In some cases, the therapeutic agent increases a level of a first processed mRNA encoding a protein and decreases a level of a second processed mRNA encoding a protein having a sequence MVAGMLGLREEKSEDQDLQGLKDKPLKFKKVKKDKKEEKEGKHEPVQPSAHHSAEPA EAGKAETSEGSGSAPAVPEASASPKQRRSIIRDRGPMYDDPTLPEGWTRKLKQRKSGRS AGKYDVYLINPQGKAFRSKVELIAYFEKLQELAEAGDAPKGAAPRDPRRPRQRVCR. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of genomic site GRCh38/ hg38: chrX 154092307. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of genomic site GRCh38/ hg38: chrX 154092307. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream of the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream of the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream of genomic site GRCh38/ hg38: chrX 154092184. In some cases. the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream of genomic site GRCh38/ hg38: chrX 154092184. In some cases, the targeted region of the pre-mRNA is within the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is within a sequence between a pair of genomic sites GRCh38/ hg38: chrX 154092307, and GRCh38/ hg38: chrX 154092184. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence with 100% sequence identity to the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the therapeutic agent increases level of a first processed mRNA encoding a protein, and decreases level of a second processed mRNA encoding a protein having a sequence MVAGMLGLREEKSEDQDLQGLKDKPLKFKKVKKDKKEEKEGKHEPVQPSAHHSAEPA EAGKAETSEGSGSAPAVPEASASPKQRRSIIRDRGPMYDDPTLPEGWTRKLKQRKSGRS AGKYDVYLINPQGKAFRSKVELIAYFEKVGDTSLDPNDFDFTVTGRGSPSRREQKPPKK PKSPKAPGTGRGRGRPKGSGTTRPKAATSEGVQVKRVLEKSPGKLLVKMPFQTSPGGK AEGGGATTSTQVMVIKRPGRKRKAEADPQAIPKKRGRKPGSVVAAAAAEAKKKAVKE SSIRSVQETVLPIKKRKTRETVSIEVKEVVKPLLVSTLGEKSGKGLKTCKSPGRKSKESSP KGRSSSASSPPKKEHHHHHHHSESPKAPVPLLPPLPPPPPEPESSEDPTSPPEPQDLSSSVC KEEKMPRGGSLESDGCPKEPAKTQPAVATAATAAEKYKHRGEGERKDIVSSSMPRPNR EEPVDSRTPVTERVS. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of genomic site GRCh38/ hg38: chrX 154092307. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides upstream of genomic site GRCh38/ hg38: chrX 154092307. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream of the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream of the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is at most about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream of genomic site GRCh38/ hg38: chrX 154092184. In some cases. the targeted region of the pre-mRNA is at least about 1500 nucleotides, about 1000 nucleotides, about 800 nucleotides, about 700 nucleotides, about 600 nucleotides, about 500 nucleotides, about 400 nucleotides, about 300 nucleotides, about 200 nucleotides, about 100 nucleotides, about 80 nucleotides, about 70 nucleotides, about 60 nucleotides, about 50 nucleotides downstream of genomic site GRCh38/ hg38: chrX 154092184. In some cases, the targeted region of the pre-mRNA is within a sequence the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the targeted region of the pre-mRNA is within a sequence between a pair of genomic sites GRCh38/ hg38: chrX 154092307, and GRCh38/ hg38: chrX 154092184. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the therapeutic agent is an antisense oligomer complementary to a sequence with 100% sequence identity to the sequence GCTCCATAAAAATACAGACTCACCAGTTCCTGCTTTGATGTGACATGTGACTCCCCA GAATACACCTTGCTTCTGTAGACCAGCTCCAACAGGATTCCATGGTAGCTGGGATGT TAGGGCTCAG. In some cases, the therapeutic agent is an antisense oligomer that has a sequence with at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1-245. In some cases, the therapeutic agent is an antisense oligomer that has a sequence selected from the group consisting of SEQ ID NOs: 1-245. In some cases, the target peptide sequence is a portion of MECP2 protein, and the method treats a disease or the condition that comprises Intellectual Disability; Rett Syndrome, Preserved Speech Variant; Lubs X-linked mental retardation syndrome; Encephalopathy, Neonatal Severe, due to MeCP2 Mutations; Mental Retardation with Psychosis, Pyramidal Signs, and Macroorchidism; Mental Retardation, X-Linked, With Spasticity; Trisomy Xq28; Mental Retardation, X-Linked 16; Epileptic encephalopathy; Mental Retardation, X-Linked, Syndromic 13; Mental Retardation, X-Linked 1; Rett Syndrome, Atypical; Mental Retardation, X-Linked 79; Microcephaly; Ppm-X Syndrome; Rett Syndrome, Zappella Variant; Rett Syndrome; or Autism susceptibility, X-linked 3. [0260] In some cases, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA (i.e., exon 2 included) in a cell for a period of time. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. In some embodiments, the therapeutic agent provided herein stably decreases the full- length MeCP2 mRNA in the cell to about 0.9 fold or less as compared to the level of the full- length MeCP2 mRNA in a control cell (i.e., the expression level in the cell is 0.9 times or less of that in the control cell) for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell to about 0.8- fold or less as compared to the level of the full-length MeCP2 mRNA in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell to about 0.7-fold or less as compared to the level of the full-length MeCP2 mRNA in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell to about 0.6-fold or less as compared to the level of the full-length MeCP2 mRNA in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell to about 0.5- fold or less as compared to the level of the full-length MeCP2 mRNA in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell to about 0.4-fold or less as compared to the level of the full-length MeCP2 mRNA in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell to about 0.3-fold or less as compared to the level of the full-length MeCP2 mRNA in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell to about 0.2- fold or less as compared to the level of the full-length MeCP2 mRNA in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably decreases the full-length MeCP2 mRNA in the cell to about 0.1-fold or less as compared to the level of the full-length MeCP2 mRNA in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some cases, the cell is a brain cell. In some cases, the brain cell is from cortex. [0261] Protein Expression [0262] In some embodiments, the methods described herein are used to increase the production of a functional protein, e.g., having a target peptide sequence, e.g., a MeCP2 protein. As used herein, the term “functional” refers to the amount of activity or function of a protein that is necessary to eliminate any one or more symptoms of a treated condition or disease, e.g., Rett syndrome. In some embodiments, the methods are used to increase the production of a partially functional MeCP2 protein. As used herein, the term “partially functional” refers to any amount of activity or function of the protein that is less than the amount of activity or function that is necessary to eliminate or prevent any one or more symptoms of a disease or condition, e.g., Rett syndrome. In some embodiments, a partially functional protein will have at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% less activity relative to the fully functional protein. [0263] In some embodiments, the method is a method of increasing the expression of a target peptide sequence by cells of a subject having a pre-mRNA encoding the target peptide sequence, wherein the subject has a disease or condition caused by a deficient amount of activity of a functional target protein that the target peptide sequence is at least functionally equivalent to. In such an embodiment, the subject has a first allele encoding a functional target protein is not produced. In another such embodiment, the subject has a first allele encoding a functional target protein, and a second allele encoding a nonfunctional target protein. In another such embodiment, the subject has a first allele encoding a functional target protein, and a second allele encoding a partially functional target protein. In some of these embodiments, the antisense oligomer binds to a targeted portion of the pre-mRNA transcribed from the second allele that codes for a target peptide sequence and comprises an exon containing an inefficient translation region, thereby inducing skipping of the inefficient translation region from the pre-mRNA, and causing an increase in the level of mature mRNA encoding the target peptide sequence, and an increase in the expression of the target peptide sequence in the cells of the subject. In some of these embodiments, the antisense oligomer binds to a targeted portion of the pre-mRNA transcribed from the second allele that codes for a target peptide sequence and comprises an exon containing a PTC followed by an alternative start codon, thereby inducing skipping of the PTC and the start codon from the pre-mRNA, and causing an increase in the level of mature mRNA encoding the target peptide sequence, and an increase in the expression of the target peptide sequence in the cells of the subject. [0264] In some embodiments, the target peptide sequence as described herein can be a fully functional protein. In some embodiments, the target peptide sequence is a portion of a full- length protein, for instance, an N-terminal portion of a full-length protein, or a C-terminal portion of a full-length protein. In the case of MeCP2, the target peptide sequence can be a C- terminal portion of MeCP2. In some embodiments, the target peptide sequence is encoded by a portion of the pre-mRNA downstream of the inefficient translation region or the alternative start codon. In some embodiments, the target peptide sequence is encoded by a portion of the pre- mRNA upstream of the inefficient translation region or the alternative start codon. The target peptide sequence can comprise at least about 10 amino acids (aa), 20 aa, 30 aa, 40 aa, 50 aa, 60 aa, 70 aa, 80 aa, 90 aa, 100 aa, 120 aa, 150 aa, 200 aa, 300 aa, 400 aa, 500 aa, 600 aa, 700 aa, 800 aa, 100 aa, 1500 aa, or 2000 aa. The target peptide sequence can comprise about 10 amino acids (aa), 20 aa, 30 aa, 40 aa, 50 aa, 60 aa, 70 aa, 80 aa, 90 aa, 100 aa, 120 aa, 150 aa, 200 aa, 300 aa, 400 aa, 500 aa, 600 aa, 700 aa, 800 aa, 100 aa, 1500 aa, or 2000 aa. [0265] In some embodiments, the method is a method of increasing the expression of a functional target protein having a target peptide sequence, e.g., MeCP2-e1 isoform encoded by exon 1, 3 and 4 of MECP2 gene, by cells of a subject having a pre-mRNA encoding the target peptide sequence, wherein the subject has a disease or condition caused by a deficient amount of activity of MeCP2 protein. In such an embodiment, the subject has an allele encoding a partially functional MeCP2, e.g., a hypomorphic allele. In such embodiment, the subject has a first allele encoding a functional MeCP2 protein, and a second allele encoding a partially functional MeCP2 protein. In some of these embodiments, the antisense oligomer binds to a targeted portion of the pre-mRNA transcribed from the second allele that codes for MeCP2 and comprises exon 2 of MECP2, thereby inducing skipping of at least part of MECP2 exon 2 from the pre-mRNA, and causing an increase in the level of mature mRNA encoding MeCP2-e1 isoform, and an increase in the expression of MeCP2-e1 isoform in the cells of the subject. Without wishing to be bound by a certain theory, due to X inactivation, in a subject having cells having a WT allele and a mutant allele encoding a partially functional MeCP2, e.g., a hypomorphic allele, there can be about 50% cells having the mutant allele that express the WT allele but not the mutant allele, and another about 50% cells having the mutant allele that express the mutant allele but not the WT allele. In some cases, the methods and compositions provided herein can increase expression of a functional target protein having a target peptide sequence, e.g., MeCP2-e1 isoform encoded by exon 1, 3, and 4 of MECP2 gene, from the mutant hypomorphic allele in cells having pre-mRNA transcripts from the hypomorphic allele. In some cases, the methods and compositions provided herein can increase expression of MeCP2-e1 isoform in about 50% of cells having a hypomorphic mutant allele in a subject. In some cases, the methods and compositions restore the functional of MeCP2, e.g., equivalent to the functional level as having a normal amount of WT MeCP2 protein, in about 50% of cells having a hypomorphic mutant allele in a subject. [0266] In some embodiments, the method is a method of increasing the expression of the target protein by cells of a subject having a pre-mRNA encoding the target protein and comprising an exon that contains an inefficient translation region or a PTC followed by an alternative start codon, wherein the subject has a disease or condition caused by a deficient amount or activity of target protein is caused by autosomal recessive inheritance. In some embodiments, the method is a method of increasing the expression of the target protein by cells of a subject having a pre- mRNA encoding the target protein and comprising an exon that contains an inefficient translation region or a PTC followed by an alternative start codon, wherein the subject has a disease or condition caused by a deficient amount or activity of target protein that is caused by autosomal dominant inheritance. In some embodiments, the disease or condition is caused by or associated with haploinsufficiency of the target gene encoding the target protein. In some embodiments, the method is a method of increasing the expression of the target protein by cells of a subject having a pre-mRNA encoding the target protein and comprising an exon that contains an inefficient translation region or a PTC followed by an alternative start codon, wherein the subject has a disease or condition caused by a deficient amount or activity of target protein is caused by X-linked dominant mutation. For instance, the method can be a method of increasing the expression of MeCP2-e1 isoform by cells (e.g., brain cells, e.g., neurons or glial cells) of a subject having a pre-mRNA encoding MeCP2 and comprising exon2, wherein the subject has Rett syndrome caused by a deficient amount or activity of MeCP2 that is caused by X-linked dominant mutation. [0267] In some embodiments, the pre-mRNA transcript that encodes the protein that is causative of the disease or condition is targeted by the ASOs described herein. In some embodiments, a pre-mRNA transcript that encodes a protein that is not causative of the disease is targeted by the ASOs. For example, a disease that is the result of a mutation or deficiency of a first protein in a particular pathway may be ameliorated by targeting a pre-mRNA that encodes a second protein (e.g., containing a target peptide sequence), thereby increasing production of the second protein. In some embodiments, the function of the second protein is able to compensate for the mutation or deficiency of the first protein (which is causative of the disease or condition). [0268] In some embodiments, the methods and compositions are applicable to treat a subject that has: (a) a first mutant allele from which the target protein is produced at a reduced level compared to production from a wild-type allele, the target protein is produced in a form having reduced function compared to an equivalent wild-type protein, or the target protein is not produced; and a second mutant allele from which the target protein is produced at a reduced level compared to production from a wild-type allele, the target protein is produced in a form having reduced function compared to an equivalent wild-type protein, or the target protein is not produced. [0269] In some embodiments, the level of the first processed mRNA encoding the first protein that comprises the target peptide sequence in the cell contacted with the therapeutic agent provided herein is increased as compared to the level of the first processed mRNA in a control cell that is otherwise identical but not contacted with the therapeutic agent. In some embodiments, the level of the first processed mRNA encoding the first protein that comprises the target peptide sequence in the cell contacted with the therapeutic agent provided herein is increased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5- fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9- fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9- fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1- fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to the level of first processed mRNA in a control cell. In some embodiments, the level of the second processed mRNA that comprises the inefficient translation region and encodes the second protein comprising the target peptide sequence in the cell contacted with the therapeutic agent provided herein is decreased as compared to the level of the second processed mRNA in a control cell that is otherwise identical but not contacted with the therapeutic agent. In some embodiments, the level of the second processed mRNA that comprises the inefficient translation region and encodes the second protein comprising the target peptide sequence in the cell contacted with the therapeutic agent provided herein is decreased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7-fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7-fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8-fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4- fold, at least about 5-fold, or at least about 10-fold, compared to the level of second processed mRNA in a control cell. [0270] In some embodiments, the therapeutic agent provided herein increases the expression of the target peptide sequence in the cell. In some embodiments, the level of the target peptide sequence in the cell contacted with the therapeutic agent is increased compared to the level of the target peptide sequence in a control cell that is otherwise identical but not contacted with the therapeutic agent. In some embodiments, the level of the target peptide sequence in the cell contacted with the therapeutic agent is increased about 1.1 to about 10-fold, about 1.5 to about 10-fold, about 2 to about 10-fold, about 3 to about 10-fold, about 4 to about 10-fold, about 1.1 to about 5-fold, about 1.1 to about 6-fold, about 1.1 to about 7-fold, about 1.1 to about 8-fold, about 1.1 to about 9-fold, about 2 to about 5-fold, about 2 to about 6-fold, about 2 to about 7- fold, about 2 to about 8-fold, about 2 to about 9-fold, about 3 to about 6-fold, about 3 to about 7- fold, about 3 to about 8-fold, about 3 to about 9-fold, about 4 to about 7-fold, about 4 to about 8- fold, about 4 to about 9-fold, at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 3.5-fold, at least about 4-fold, at least about 5-fold, or at least about 10-fold, compared to the level of the target peptide sequence in a control cell. [0271] In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in a cell for a period of time. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.1-fold as compared to the level of the target peptide in a control cell (i.e., the expression level in the cell is 1.1 times or more of that in the control cell) for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.2- fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.3-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.4-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.5-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.6-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.7-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.8-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 1.9-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 2.0-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 2.1-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 2.2-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 2.3-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 2.4-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 2.5-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some embodiments, the therapeutic agent provided herein stably increases the expression of the target peptide in the cell to at least 3.0-fold as compared to the level of the target peptide in a control cell for at least 1 week, at least 2 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 4 months. In some cases, the cell is a brain cell. In some cases, the brain cell is from cortex. In some embodiments, the target peptide is MeCP2 protein. [0272] Inefficient Translation Region [0273] As described herein, an inefficient translation region can refer to any region in an mRNA transcript that contributes to inefficient translation of a target peptide sequence encoded by the mRNA transcript, in a manner that a corresponding mRNA transcript without the inefficient translation region would have a higher translation efficiency for producing the target peptide sequence as compared to the mRNA transcript with the inefficient translation region. The inefficient translation region can decrease the translation efficiency of the mRNA transcript for the target peptide sequence at the stage of translation initiation, elongation, termination, or any combination thereof. In some embodiments, an mRNA transcript having the inefficient translation region has a translation efficiency about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower than a corresponding mRNA transcript without the inefficient translation region. In some embodiments, an mRNA transcript having the inefficient translation region has a translation efficiency about 1.2, 1.5, 1.8, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 15, 18, 20, 22, 25, 28, 30, 35, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 5000, 10⁴, 10⁵, or even greater times lower than a corresponding mRNA transcript without the inefficient translation region. In some embodiments, an mRNA transcript having the inefficient translation region has a translation efficiency at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% lower than a corresponding mRNA transcript without the inefficient translation region. In some embodiments, an mRNA transcript having the inefficient translation region has a translation efficiency at least about 1.2, 1.5, 1.8, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 15, 18, 20, 22, 25, 28, 30, 35, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 5000, 10⁴, or 10⁵ times lower than a corresponding mRNA transcript without the inefficient translation region. [0274] In some embodiments, the inefficient translation region comprises a PTC followed by an alternative start codon. Without wishing to be bound by a certain theory, the motif or the exon containing the PTC and the alternative start codon can contribute to the inefficient translation of the downstream sequences because while the PTC induces premature termination of translation of the upstream open reading frame in the mRNA, the close proximity of the alternative start codon to the PTC can prevent the induction of nonsense-mediated decay, rather re-initiation of translation of the downstream open reading frame. In this regard, the efficiency of the translation initiation of the downstream open reading frame can be relatively much lower than the canonical open reading frame starting from the canonical start codon (e.g., upstream of the downstream open reading frame). As exemplified in the case of MECP2 mRNA processing, the removal of exon 2 that contains a PTC and an alternative start codon can lead to increased production of MeCP2-e1 isoform, however, the relative mature mRNA level can remain stable, suggesting the MECP2 e1 mRNA isoform, which is devoid of exon 2 containing the PTC and alternative start codon, has a higher translation efficiency as compared to MECP2 e2 mRNA isoform with exon 2. In some embodiments, the distance between PTC and the downstream start codon in the inefficient translation region is short, for instance, at most 75 nucleotides (nt), 70 nt, 60 nt, 55 nt, 50 nt, 45 nt, 40 nt, 35 nt, 30 nt, 27 nt, 24 nt, 21 nt, 18 nt, 15 nt, 12 nt, 10 nt, 9 nt, 6 nt, 3 nt, or 2 nt. In some embodiments, the distance between PTC and the downstream start codon in the inefficient translation region is about 3 nt, 6 nt, 9 nt, 10 nt, 12 nt, 15 nt, 18 nt, 21 nt, 24 nt, 27 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt, 60 nt, 70 nt, or 75 nt. In some cases, the distance between PTC and the downstream start codon in the inefficient translation region is at least 2 nt, 3 nt, 6 nt, 9 nt, 10 nt, 12 nt, 15 nt, 18 nt, 21 nt, 24 nt, 27 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, or 55 nt. In some cases, distance between PTC and the downstream start codon in the inefficient translation region is 2 nt to 75 nt, 5 nt to 70 nt, 10 nt to 65 nt, 15 nt to 60 nt, 20 nt to 55 nt, 25 nt to 50 nt, 30 nt to 45 nt, 40 nt to 50 nt, 45 nt to 55 nt, 50 nt to 60 nt, 55 nt to 70 nt, or 60 nt to 75 nt. [0275] In some embodiments, the inefficient translation region comprises a region that codes for proline-rich peptide sequence. Without wishing to be bound by a certain theory, mRNA sequence coding for proline-rich peptide sequence can contribute to inefficient translation, for instance, inefficient translation elongation, of the mRNA transcript that contains it. In some embodiments, the inefficient translation region encodes peptide sequence having at least about 5, 8, 10, 12, 15, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95, or 100 prolines. In some embodiments, the inefficient translation region encodes peptide sequence having contiguous peptide sequences consisting of at least about 5, 8, 10, 12, 15, 16, 18, 20, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 95, or 100 prolines. In some embodiments, the inefficient translation region encodes peptide sequence having at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% proline. [0276] The inefficient translation region can be in any length. In some embodiments, the inefficient translation region can be from 5 nucleotides to 10 nucleotides in length, from 10 nucleotides to 15 nucleotides in length, from 15 nucleotides to 20 nucleotides in length, from 20 nucleotides to 25 nucleotides in length, from 25 nucleotides to 30 nucleotides in length, from 30 nucleotides to 35 nucleotides in length, from 35 nucleotides to 40 nucleotides in length, from 40 nucleotides to 45 nucleotides in length, from 45 nucleotides to 50 nucleotides in length, from 50 nucleotides to 55 nucleotides in length, from 55 nucleotides to 60 nucleotides in length, from 60 nucleotides to 65 nucleotides in length, from 65 nucleotides to 70 nucleotides in length, from 70 nucleotides to 75 nucleotides in length, from 75 nucleotides to 80 nucleotides in length, from 80 nucleotides to 85 nucleotides in length, from 85 nucleotides to 90 nucleotides in length, from 90 nucleotides to 95 nucleotides in length, or from 95 nucleotides to 100 nucleotides in length. In some embodiments, the inefficient translation region can be at least 10 nucleotides, at least 20 nucleotides, at least 30 nucleotides, at least 40 nucleotides, at least 50 nucleotides, at least 60 nucleoids, at least 70 nucleotides, at least 80 nucleotides in length, at least 90 nucleotides, or at least 100 nucleotides in length. In some embodiments, the inefficient translation region can be from 100 to 200 nucleotides in length, from 200 to 300 nucleotides in length, from 300 to 400 nucleotides in length, from 400 to 500 nucleotides in length, from 500 to 600 nucleotides in length, from 600 to 700 nucleotides in length, from 700 to 800 nucleotides in length, from 800 to 900 nucleotides in length, from 900 to 1,000 nucleotides in length. In some embodiments, the inefficient translation region may be longer than 1,000 nucleotides in length. [0277] Modulation of Translation of Various Targets [0278] In aspects, the methods, compositions, and kits are applicable to modulation of translation of various targets, for instance, for target peptide sequences whose translation is modulated by an inefficient translation region present in a processed mRNA transcript encoding the target peptide sequence. In some cases, the inefficient translation region comprises at least a portion of an exon that comprises a PTC followed by an alternative start codon. Table 1 below lists exemplary target genes and their corresponding pre-mRNA transcript that can be processed into mRNA transcript having an exon that comprises a PTC followed by an alternative start codon. The sequences of the exons (and SEQ ID NOs) and their corresponding genomic coordinates are listed in the table. In some cases, the subject methods, compositions, and kits are applicable to modulation of translation of the target peptide sequences encoded by the target genes that are listed Table 1. Table 1. Exemplary Genes and Exons Containing PTC and Alternative Start Codons. Therapeutic Agents [0279] In various embodiments of the present disclosure, compositions and methods comprising a therapeutic agent are provided to modulate protein expression level. In some embodiments, provided herein are compositions and methods to modulate alternative splicing of a pre-mRNA that encodes a target peptide sequence. In some embodiments, provided herein are compositions and methods to induce exon skipping in the splicing of the pre-mRNA that encodes the target peptide sequence. In other embodiments, therapeutic agents may be used to induce the inclusion of an exon in order to decrease the protein expression level. [0280] In some cases, a therapeutic agent comprises a polynucleic acid polymer. In some cases, a therapeutic agent comprises a viral vector expressing a polynucleic acid polymer that binds to the targeted region of a pre-mRNA the encodes the target peptide sequence. In some cases, the viral vector comprises an adenoviral vector, adeno-associated viral (AAV) vector, lentiviral vector, Herpes Simplex Virus (HSV) viral vector, retroviral vector, or any applicable viral vector. In some cases, a therapeutic agent comprises a gene editing tool that is configured to modify a gene encoding the target peptide sequence such that a gene region that encodes the inefficient translation region is deleted. In some cases, a gene editing tool comprises vector, e.g., viral vector, for gene editing based on CRISPR-Cas9, TALEN, Zinc Finger, or other applicable technologies. [0281] According to one aspect of the present disclosure, provided herein is a method of treating a disease or a condition in a subject in need thereof by modulating expression of a target peptide sequence in a cell of the subject, the cell having a pre-mRNA that encodes the target peptide sequence and comprises an inefficient translation region, the method comprising: contacting the cell of the subject with a therapeutic agent that modulates splicing of the inefficient translation region from the pre-mRNA encoding the target peptide sequence, wherein the therapeutic agent binds to a targeted region of the pre-mRNA, whereby splicing of the inefficient translation region from the pre-mRNA is modulated, thereby modulating a level of a first processed mRNA that is devoid of the inefficient translation region and encodes the target peptide sequence, and thereby modulating the expression of the target peptide sequence in the cell of the subject, wherein the first processed mRNA has a higher translation efficiency for producing the target peptide sequence in the cells as compared to a second processed mRNA that comprises the inefficient translation region. In some cases, the second processed mRNA is otherwise identical to the first processed mRNA but comprises the inefficient translation region. [0282] In some other aspect, provided herein is a method of treating a disease or a condition in a subject in need thereof by modulating expression of a target peptide sequence in a cell of the subject, the cell having a pre-mRNA that encodes the target peptide sequence and comprises a first start codon, a second start codon, and a premature termination codon (PTC) located downstream of the first start codon and upstream of the second start codon, the method comprising: contacting the cell of the subject with a therapeutic agent that modulates splicing of the PTC and the second start codon from the pre-mRNA encoding the target peptide sequence, wherein the therapeutic agent binds to a targeted region of the pre-mRNA, whereby splicing of the PTC and the second start codon from the pre-mRNA is modulated, thereby modulating a level of first processed mRNA that is devoid of the PTC and the second start codon and encodes the target peptide sequence, and thereby modulating the expression of the target peptide sequence in the cell of the subject. [0283] Where reference is made to reducing inclusion of the inefficient translation region or the PTC followed by the alternative region in the mature mRNA, the reduction may be complete, e.g., 100%, or may be partial. The reduction may be clinically significant. The reduction/correction may be relative to the level of inclusion of the inefficient translation region or the PTC followed by the alternative region in the subject without treatment, or relative to the amount of inclusion of the inefficient translation region or the PTC followed by the alternative region in a population of similar subjects. The reduction/correction may be at least 10% less inclusion relative to the average subject, or the subject prior to treatment. The reduction may be at least 20% less inclusion relative to an average subject, or the subject prior to treatment. The reduction may be at least 40% less inclusion relative to an average subject, or the subject prior to treatment. The reduction may be at least 50% less inclusion relative to an average subject, or the subject prior to treatment. The reduction may be at least 60% less inclusion relative to an average subject, or the subject prior to treatment. The reduction may be at least 80% less inclusion relative to an average subject, or the subject prior to treatment. The reduction may be at least 90% less inclusion relative to an average subject, or the subject prior to treatment. [0284] Where reference is made to increasing MeCP2-e1 protein levels, the increase may be clinically significant. The increase may be relative to the level of MeCP2-e1 protein in the subject without treatment, or relative to the amount of active MeCP2-e1 protein in a population of similar subjects. The increase may be at least 10% more active MeCP2-e1 protein relative to the average subject, or the subject prior to treatment. The increase may be at least 20% more active MeCP2-e1 protein relative to the average subject, or the subject prior to treatment. The increase may be at least 40% more active MeCP2-e1 protein relative to the average subject, or the subject prior to treatment. The increase may be at least 50% more active MeCP2-e1 protein relative to the average subject, or the subject prior to treatment. The increase may be at least 80% more active MeCP2-e1 protein relative to the average subject, or the subject prior to treatment. The increase may be at least 100% more active MeCP2-e1 protein relative to the average subject, or the subject prior to treatment. The increase may be at least 200% more active MeCP2-e1 protein relative to the average subject, or the subject prior to treatment. The increase may be at least 500% more active MeCP2-e1 protein relative to the average subject, or the subject prior to treatment. [0285] In embodiments wherein the agent comprises a polynucleic acid polymer, the polynucleic acid polymer may be about 50 nucleotides in length. The polynucleic acid polymer may be about 45 nucleotides in length. The polynucleic acid polymer may be about 40 nucleotides in length. The polynucleic acid polymer may be about 35 nucleotides in length. The polynucleic acid polymer may be about 30 nucleotides in length. The polynucleic acid polymer may be about 24 nucleotides in length. The polynucleic acid polymer may be about 25 nucleotides in length. The polynucleic acid polymer may be about 20 nucleotides in length. The polynucleic acid polymer may be about 19 nucleotides in length. The polynucleic acid polymer may be about 18 nucleotides in length. The polynucleic acid polymer may be about 17 nucleotides in length. The polynucleic acid polymer may be about 16 nucleotides in length. The polynucleic acid polymer may be about 15 nucleotides in length. The polynucleic acid polymer may be about 14 nucleotides in length. The polynucleic acid polymer may be about 13 nucleotides in length. The polynucleic acid polymer may be about 12 nucleotides in length. The polynucleic acid polymer may be about 11 nucleotides in length. The polynucleic acid polymer may be about 10 nucleotides in length. The polynucleic acid polymer may be between about 10 and about 50 nucleotides in length. The polynucleic acid polymer may be between about 10 and about 45 nucleotides in length. The polynucleic acid polymer may be between about 10 and about 40 nucleotides in length. The polynucleic acid polymer may be between about 10 and about 35 nucleotides in length. The polynucleic acid polymer may be between about 10 and about 30 nucleotides in length. The polynucleic acid polymer may be between about 10 and about 25 nucleotides in length. The polynucleic acid polymer may be between about 10 and about 20 nucleotides in length. The polynucleic acid polymer may be between about 15 and about 25 nucleotides in length. The polynucleic acid polymer may be between about 15 and about 30 nucleotides in length. The polynucleic acid polymer may be between about 12 and about 30 nucleotides in length. [0286] The sequence of the polynucleic acid polymer may be at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% complementary to a target sequence of an mRNA transcript, e.g., a partially processed mRNA transcript. The sequence of the polynucleic acid polymer may be 100% complementary to a target sequence of a pre-mRNA transcript. [0287] The sequence of the polynucleic acid polymer may have 4 or fewer mismatches to a target sequence of the pre-mRNA transcript. The sequence of the polynucleic acid polymer may have 3 or fewer mismatches to a target sequence of the pre-mRNA transcript. The sequence of the polynucleic acid polymer may have 2 or fewer mismatches to a target sequence of the pre- mRNA transcript. The sequence of the polynucleic acid polymer may have 1 or fewer mismatches to a target sequence of the pre-mRNA transcript. The sequence of the polynucleic acid polymer may have no mismatches to a target sequence of the pre-mRNA transcript. [0288] The polynucleic acid polymer may specifically hybridize to a target sequence of the pre- mRNA transcript. For example, the polynucleic acid polymer may have 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100% sequence complementarity to a target sequence of the pre-mRNA transcript. The hybridization may be under high stringent hybridization conditions. [0289] The polynucleic acid polymer comprising a sequence with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1-245. The polynucleic acid polymer may comprise a sequence with 100% sequence identity to a sequence selected from the group consisting of SEQ ID NOs: 1-245. Table 2 below lists exemplary sequences that the polynucleic acid polymer can comprise. Table 2. Exemplary sequences of polynucleic acid polymers for translation modulation. [0290] Where reference is made to a polynucleic acid polymer sequence, the skilled person will understand that one or more substitutions may be tolerated, optionally two substitutions may be tolerated in the sequence, such that it maintains the ability to hybridize to the target sequence; or where the substitution is in a target sequence, the ability to be recognized as the target sequence. References to sequence identity may be determined by BLAST sequence alignment using standard/default parameters. For example, the sequence may have 99% identity and still function according to the present disclosure. In other embodiments, the sequence may have 98% identity and still function according to the present disclosure. In another embodiment, the sequence may have 95% identity and still function according to the present disclosure. In another embodiment, the sequence may have 90% identity and still function according to the present disclosure. [0291] Antisense Oligomers [0292] Provided herein is a composition comprising an antisense oligomer that induces exon skipping by binding to a targeted portion of a pre-mRNA that comprises an exon containing an inefficient translation region, or a PTC followed by an alternative start codon. As used herein, the terms “ASO” and “antisense oligomer” are used interchangeably and refer to an oligomer such as a polynucleotide, comprising nucleobases that hybridizes to a target nucleic acid (e.g., MECP2 pre-mRNA) sequence by Watson-Crick base pairing or wobble base pairing (G-U). The ASO may have exact sequence complementary to the target sequence or near complementarity (e.g., sufficient complementarity to bind the target sequence and enhancing splicing at a splice site). ASOs are designed so that they bind (hybridize) to a target nucleic acid (e.g., a targeted portion of a pre-mRNA transcript) and remain hybridized under physiological conditions. Typically, if they hybridize to a site other than the intended (targeted) nucleic acid sequence, they hybridize to a limited number of sequences that are not a target nucleic acid (to a few sites other than a target nucleic acid). Design of an ASO can take into consideration the occurrence of the nucleic acid sequence of the targeted portion of the pre-mRNA transcript or a sufficiently similar nucleic acid sequence in other locations in the genome or cellular pre-mRNA or transcriptome, such that the likelihood the ASO will bind other sites and cause “off-target” effects is limited. Any antisense oligomers known in the art, for example in PCT Application No. PCT/US2014/054151, published as WO 2015/035091, titled “Reducing Nonsense-Mediated mRNA Decay,” incorporated by reference herein, can be used to practice the methods described herein. [0293] In some embodiments, ASOs “specifically hybridize” to or are “specific” to a target nucleic acid or a targeted portion of a pre-mRNA. Typically, such hybridization occurs with a Tm substantially greater than 37 °C, preferably at least 50 °C, and typically between 60 °C to approximately 90 °C. Such hybridization preferably corresponds to stringent hybridization conditions. At a given ionic strength and pH, the Tm is the temperature at which 50% of a target sequence hybridizes to a complementary oligonucleotide. [0294] Oligomers, such as oligonucleotides, are “complementary” to one another when hybridization occurs in an antiparallel configuration between two single-stranded polynucleotides. A double-stranded polynucleotide can be “complementary” to another polynucleotide, if hybridization can occur between one of the strands of the first polynucleotide and the second. Complementarity (the degree to which one polynucleotide is complementary with another) is quantifiable in terms of the proportion (e.g., the percentage) of bases in opposing strands that are expected to form hydrogen bonds with each other, according to generally accepted base-pairing rules. The sequence of an antisense oligomer (ASO) need not be 100% complementary to that of its target nucleic acid to hybridize. In certain embodiments, ASOs can comprise at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence complementarity to a target region within the target nucleic acid sequence to which they are targeted. For example, an ASO in which 18 of 20 nucleobases of the oligomeric compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining non-complementary nucleobases may be clustered together or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. Percent complementarity of an ASO with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul, et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656). [0295] An ASO need not hybridize to all nucleobases in a target sequence and the nucleobases to which it does hybridize may be contiguous or noncontiguous. ASOs may hybridize over one or more segments of a pre-mRNA transcript, such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure or hairpin structure may be formed). In certain embodiments, an ASO hybridizes to noncontiguous nucleobases in a target pre-mRNA transcript. For example, an ASO can hybridize to nucleobases in a pre-mRNA transcript that are separated by one or more nucleobase(s) to which the ASO does not hybridize. [0296] The ASOs described herein comprise nucleobases that are complementary to nucleobases present in a target portion of a pre-mRNA. The term ASO embodies oligonucleotides and any other oligomeric molecule that comprises nucleobases capable of hybridizing to a complementary nucleobase on a target mRNA but does not comprise a sugar moiety, such as a peptide nucleic acid (PNA). The ASOs may comprise naturally occurring nucleotides, nucleotide analogs, modified nucleotides, or any combination of two or three of the preceding. The term “naturally occurring nucleotides” includes deoxyribonucleotides and ribonucleotides. The term “modified nucleotides” includes nucleotides with modified or substituted sugar groups and/or having a modified backbone. In some embodiments, all of the nucleotides of the ASO are modified nucleotides. Chemical modifications of ASOs or components of ASOs that are compatible with the methods and compositions described herein will be evident to one of skill in the art and can be found, for example, in U.S. Patent No. 8,258,109 B2, U.S. Patent No.5,656,612, U.S. Patent Publication No.2012/0190728, and Dias and Stein, Mol. Cancer Ther.2002, 347-355, herein incorporated by reference in their entirety. [0297] One or more nucleobases of an ASO may be any naturally occurring, unmodified nucleobase such as adenine, guanine, cytosine, thymine, and uracil, or any synthetic or modified nucleobase that is sufficiently similar to an unmodified nucleobase such that it is capable of hydrogen bonding with a nucleobase present on a target pre-mRNA. Examples of modified nucleobases include, without limitation, hypoxanthine, xanthine, 7-methylguanine, 5, 6- dihydrouracil, 5-methylcytosine, and 5-hydroxymethoylcytosine. [0298] The ASOs described herein also comprise a backbone structure that connects the components of an oligomer. The term “backbone structure” and “oligomer linkages” may be used interchangeably and refer to the connection between monomers of the ASO. In naturally occurring oligonucleotides, the backbone comprises a 3’-5’ phosphodiester linkage connecting sugar moieties of the oligomer. The backbone structure or oligomer linkages of the ASOs described herein may include (but are not limited to) phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoraniladate, phosphoramidate, and the like. See, e.g., LaPlanche, et al., Nucleic Acids Res.14:9081 (1986); Stec, et al., J. Am. Chem. Soc.106:6077 (1984), Stein, et al., Nucleic Acids Res.16:3209 (1988), Zon, et al., Anti-Cancer Drug Design 6:539 (1991); Zon, et al., Oligonucleotides and Analogues: A Practical Approach, pp.87-108 (F. Eckstein, Ed., Oxford University Press, Oxford England (1991)); Stec, et al., U.S. Pat. No.5,151,510; Uhlmann and Peyman, Chemical Reviews 90:543 (1990). In some embodiments, the backbone structure of the ASO does not contain phosphorous but rather contains peptide bonds, for example in a peptide nucleic acid (PNA), or linking groups including carbamate, amides, and linear and cyclic hydrocarbon groups. In some embodiments, the backbone modification is a phosphothioate linkage. In some embodiments, the backbone modification is a phosphoramidate linkage. [0299] In some embodiments, the stereochemistry at each of the phosphorus internucleotide linkages of the ASO backbone is random. In some embodiments, the stereochemistry at each of the phosphorus internucleotide linkages of the ASO backbone is controlled and is not random. For example, U.S. Pat. App. Pub. No.2014/0194610, “Methods for the Synthesis of Functionalized Nucleic Acids,” incorporated herein by reference, describes methods for independently selecting the handedness of chirality at each phosphorous atom in a nucleic acid oligomer. In some embodiments, an ASO used in the methods of the disclosure, including, but not limited to, any of the ASOs set forth herein in Tables 5 and 6, comprises an ASO having phosphorus internucleotide linkages that are not random. In some embodiments, a composition used in the methods of the disclosure comprises a pure diastereomeric ASO. In some embodiments, a composition used in the methods of the disclosure comprises an ASO that has diastereomeric purity of at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, about 100%, about 90% to about 100%, about 91% to about 100%, about 92% to about 100%, about 93% to about 100%, about 94% to about 100%, about 95% to about 100%, about 96% to about 100%, about 97% to about 100%, about 98% to about 100%, or about 99% to about 100%. [0300] In some embodiments, the ASO has a nonrandom mixture of Rp and Sp configurations at its phosphorus internucleotide linkages. For example, it has been suggested that a mix of Rp and Sp is required in antisense oligonucleotides to achieve a balance between good activity and nuclease stability (Wan, et al., 2014, “Synthesis, biophysical properties and biological activity of second-generation antisense oligonucleotides containing chiral phosphorothioate linkages,” Nucleic Acids Research 42(22): 13456-13468, incorporated herein by reference). In some embodiments, an ASO used in the methods of the disclosure, including, but not limited to, any of the ASOs set forth herein in SEQ ID NOs: 1-245, comprises about 5-100% Rp, at least about 5% Rp, at least about 10% Rp, at least about 15% Rp, at least about 20% Rp, at least about 25% Rp, at least about 30% Rp, at least about 35% Rp, at least about 40% Rp, at least about 45% Rp, at least about 50% Rp, at least about 55% Rp, at least about 60% Rp, at least about 65% Rp, at least about 70% Rp, at least about 75% Rp, at least about 80% Rp, at least about 85% Rp, at least about 90% Rp, or at least about 95% Rp, with the remainder Sp, or about 100% Rp. In some embodiments, an ASO used in the methods of the disclosure, including, but not limited to, any of the ASOs set forth herein comprise a sequence with at least about 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of any one of SEQ ID NOs: 1-245, comprises about 10% to about 100% Rp, about 15% to about 100% Rp, about 20% to about 100% Rp, about 25% to about 100% Rp, about 30% to about 100% Rp, about 35% to about 100% Rp, about 40% to about 100% Rp, about 45% to about 100% Rp, about 50% to about 100% Rp, about 55% to about 100% Rp, about 60% to about 100% Rp, about 65% to about 100% Rp, about 70% to about 100% Rp, about 75% to about 100% Rp, about 80% to about 100% Rp, about 85% to about 100% Rp, about 90% to about 100% Rp, or about 95% to about 100% Rp, about 20% to about 80% Rp, about 25% to about 75% Rp, about 30% to about 70% Rp, about 40% to about 60% Rp, or about 45% to about 55% Rp, with the remainder Sp. [0301] In some embodiments, an ASO used in the methods of the disclosure, including, but not limited to, any of the ASOs set forth herein comprise a sequence with at least about 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of any one of SEQ ID NOs: 1-245, comprises about 5-100% Sp, at least about 5% Sp, at least about 10% Sp, at least about 15% Sp, at least about 20% Sp, at least about 25% Sp, at least about 30% Sp, at least about 35% Sp, at least about 40% Sp, at least about 45% Sp, at least about 50% Sp, at least about 55% Sp, at least about 60% Sp, at least about 65% Sp, at least about 70% Sp, at least about 75% Sp, at least about 80% Sp, at least about 85% Sp, at least about 90% Sp, or at least about 95% Sp, with the remainder Rp, or about 100% Sp. In embodiments, an ASO used in the methods of the disclosure, including, but not limited to, any of the ASOs set forth herein comprise a sequence with at least about 80%, 85%, 90%, 95%, 97%, or 100% sequence identity to a region comprising at least 8 contiguous nucleic acids of any one of SEQ ID NOs: 1-245, comprises about 10% to about 100% Sp, about 15% to about 100% Sp, about 20% to about 100% Sp, about 25% to about 100% Sp, about 30% to about 100% Sp, about 35% to about 100% Sp, about 40% to about 100% Sp, about 45% to about 100% Sp, about 50% to about 100% Sp, about 55% to about 100% Sp, about 60% to about 100% Sp, about 65% to about 100% Sp, about 70% to about 100% Sp, about 75% to about 100% Sp, about 80% to about 100% Sp, about 85% to about 100% Sp, about 90% to about 100% Sp, or about 95% to about 100% Sp, about 20% to about 80% Sp, about 25% to about 75% Sp, about 30% to about 70% Sp, about 40% to about 60% Sp, or about 45% to about 55% Sp, with the remainder Rp. [0302] Any of the ASOs described herein may contain a sugar moiety that comprises ribose or deoxyribose, as present in naturally occurring nucleotides, or a modified sugar moiety or sugar analog, including a morpholine ring. Non-limiting examples of modified sugar moieties include 2’ substitutions such as 2’-O-methyl (2’-O-Me), 2’-O-methoxyethyl (2’MOE), 2’-O-aminoethyl, 2’F; N3’->P5’ phosphoramidate, 2’dimethylaminooxyethoxy, 2’dimethylaminoethoxyethoxy, 2’-guanidinidium, 2’-O-guanidinium ethyl, carbamate modified sugars, and bicyclic modified sugars. In some embodiments, the sugar moiety modification is selected from 2’-O-Me, 2’F, and 2’MOE. In some embodiments, the sugar moiety modification is an extra bridge bond, such as in a locked nucleic acid (LNA). In some embodiments the sugar analog contains a morpholine ring, such as phosphorodiamidate morpholino (PMO). In some embodiments, the sugar moiety comprises a ribofuransyl or 2’deoxyribofuransyl modification. In some embodiments, the sugar moiety comprises 2’4’-constrained 2’O-methyloxyethyl (cMOE) modifications. In some embodiments, the sugar moiety comprises cEt 2’, 4’ constrained 2’-O ethyl BNA modifications. In some embodiments, the sugar moiety comprises tricycloDNA (tcDNA) modifications. In some embodiments, the sugar moiety comprises ethylene nucleic acid (ENA) modifications. In some embodiments, the sugar moiety comprises MCE modifications. Modifications are known in the art and described in the literature, e.g., by Jarver, et al., 2014, “A Chemical View of Oligonucleotides for Exon Skipping and Related Drug Applications,” Nucleic Acid Therapeutics 24(1): 37-47, incorporated by reference for this purpose herein. [0303] In some embodiments, each monomer of the ASO is modified in the same way, for example each linkage of the backbone of the ASO comprises a phosphorothioate linkage or each ribose sugar moiety comprises a 2’O-methyl modification. Such modifications that are present on each of the monomer components of an ASO are referred to as “uniform modifications.” In some examples, a combination of different modifications may be desired, for example, an ASO may comprise a combination of phosphorodiamidate linkages and sugar moieties comprising morpholine rings (morpholinos). Combinations of different modifications to an ASO are referred to as “mixed modifications” or “mixed chemistries.” [0304] In some embodiments, the ASO comprises one or more backbone modifications. In some embodiments, the ASO comprises one or more sugar moiety modification. In some embodiments, the ASO comprises one or more backbone modifications and one or more sugar moiety modifications. In some embodiments, the ASO comprises a 2’MOE modification and a phosphorothioate backbone. In some embodiments, the ASO comprises a phosphorodiamidate morpholino (PMO). In some embodiments, the ASO comprises a peptide nucleic acid (PNA). Any of the ASOs or any component of an ASO (e.g., a nucleobase, sugar moiety, backbone) described herein may be modified in order to achieve desired properties or activities of the ASO or reduce undesired properties or activities of the ASO. For example, an ASO or one or more components of any ASO may be modified to enhance binding affinity to a target sequence on a pre-mRNA transcript; reduce binding to any non-target sequence; reduce degradation by cellular nucleases (i.e., RNase H); improve uptake of the ASO into a cell and/or into the nucleus of a cell; alter the pharmacokinetics or pharmacodynamics of the ASO; and/or modulate the half-life of the ASO. [0305] In some embodiments, the ASOs are comprised of 2'-O-(2-methoxyethyl) (MOE) phosphorothioate-modified nucleotides. ASOs comprised of such nucleotides are especially well-suited to the methods disclosed herein; oligomers having such modifications have been shown to have significantly enhanced resistance to nuclease degradation and increased bioavailability, making them suitable, for example, for oral delivery in some embodiments described herein. See e.g., Geary, et al., J Pharmacol Exp Ther.2001; 296(3):890-7; Geary, et al., J Pharmacol Exp Ther.2001; 296(3):898-904. [0306] Methods of synthesizing ASOs will be known to one of skill in the art. Alternatively or in addition, ASOs may be obtained from a commercial source. [0307] Unless specified otherwise, the left-hand end of single-stranded nucleic acid (e.g., pre- mRNA transcript, oligonucleotide, ASO, etc.) sequences is the 5’ end and the left-hand direction of single or double-stranded nucleic acid sequences is referred to as the 5’ direction. Similarly, the right-hand end or direction of a nucleic acid sequence (single or double stranded) is the 3’ end or direction. Generally, a region or sequence that is 5’ to a reference point in a nucleic acid is referred to as “upstream,” and a region or sequence that is 3’ to a reference point in a nucleic acid is referred to as “downstream.” Generally, the 5’ direction or end of an mRNA is where the initiation or start codon is located, while the 3’ end or direction is where the termination codon is located. In some aspects, nucleotides that are upstream of a reference point in a nucleic acid may be designated by a negative number, while nucleotides that are downstream of a reference point may be designated by a positive number. For example, a reference point (e.g., an exon- exon junction in mRNA) may be designated as the “zero” site, and a nucleotide that is directly adjacent and upstream of the reference point is designated “minus one,” e.g., “-1,” while a nucleotide that is directly adjacent and downstream of the reference point is designated “plus one,” e.g., “+1.” [0308] In some embodiments, the ASOs are complementary to (and bind to) a targeted portion of a pre-mRNA that that comprises an exon containing an inefficient translation region or a PTC followed by an alternative start codon, and the targeted portion is downstream (in the 3’ direction) of the 5’ splice site of the exon. In some embodiments, the target portion is within the region about +1 to about +500 relative to the 5’ splice site (or 3’ end) of the exon. In some embodiments, the targeted portion is within the region between nucleotides +6 and +40,000 relative to the 5’ splice site (or 3’ end) of the exon. In some aspects, the ASOs are complementary to a targeted portion that is within the region about +1 to about +40,000, about +1 to about +30,000, about +1 to about +20,000, about +1 to about +15,000, about +1 to about +10,000, about +1 to about +5,000, about +1 to about +4,000, about +1 to about +3,000, about +1 to about +2,000, about +1 to about +1,000, about +1 to about +500, about +1 to about +490, about +1 to about +480, about +1 to about +470, about +1 to about +460, about +1 to about +450, about +1 to about +440, about +1 to about +430, about +1 to about +420, about +1 to about +410, about +1 to about +400, about +1 to about +390, about +1 to about +380, about +1 to about +370, about +1 to about +360, about +1 to about +350, about +1 to about +340, about +1 to about +330, about +1 to about +320, about +1 to about +310, about +1 to about +300, about +1 to about +290, about +1 to about +280, about +1 to about +270, about +1 to about +260, about +1 to about +250, about +1 to about +240, about +1 to about +230, about +1 to about +220, about +1 to about +210, about +1 to about +200, about +1 to about +190, about +1 to about +180, about +1 to about +170, about +1 to about +160, about +1 to about +150, about +1 to about +140, about +1 to about +130, about +1 to about +120, about +1 to about +110, about +1 to about +100, about +1 to about +90, about +1 to about +80, about +1 to about +70, about +1 to about +60, about +1 to about +50, about +1 to about +40, about +1 to about +30, or about +1 to about +20 relative to 5’ splice site (or 3’ end) of the exon. In some aspects, the ASOs are complementary to a targeted portion that is within the region from about +1 to about +100, from about +100 to about +200, from about +200 to about +300, from about +300 to about +400, or from about +400 to about +500 relative to 5’ splice site (or 3’ end) of the exon. [0309] In some embodiments, the ASOs are complementary to (and bind to) a targeted portion of a pre-mRNA that that comprises an exon containing an inefficient translation region or a PTC followed by an alternative start codon, and the targeted portion is upstream (in the 5’ direction) of the 5’ splice site (or 3’ end) of the exon. In some embodiments, the targeted portion is within the region about -4 to about -270 relative to the 5’ splice site (or 3’end) of the exon. In some embodiments, the targeted portion is within the region between nucleotides -1 and -40,000 relative to the 5’ splice site (or 3’ end) of the exon. In some aspects, the ASOs are complementary to a targeted portion that is within the region about -1 to about -40,000, about -1 to about -30,000, about -1 to about -20,000, about -1 to about -15,000, about -1 to about -10,000, about -1 to about -5,000, about -1 to about -4,000, about -1 to about -3,000, about -1 to about - 2,000, about -1 to about -1,000, about -1 to about -500, about -1 to about -490, about -1 to about -480, about -1 to about -470, about -1 to about -460, about -1 to about -450, about -1 to about - 440, about -1 to about -430, about -1 to about -420, about -1 to about -410, about -1 to about - 400, about -1 to about -390, about -1 to about -380, about -1 to about -370, about -1 to about - 360, about -1 to about -350, about -1 to about -340, about -1 to about -330, about -1 to about - 320, about -1 to about -310, about -1 to about -300, about -1 to about -290, about -1 to about - 280, about -1 to about -270, about -1 to about -260, about -1 to about -250, about -1 to about - 240, about -1 to about -230, about -1 to about -220, about -1 to about -210, about -1 to about - 200, about -1 to about -190, about -1 to about -180, about -1 to about -170, about -1 to about - 160, about -1 to about -150, about -1 to about -140, about -1 to about -130, about -1 to about - 120, about -1 to about -110, about -1 to about -100, about -1 to about -90, about -1 to about -80, about -1 to about -70, about -1 to about -60, about -1 to about -50, about -1 to about -40, about - 1 to about -30, or about -1 to about -20 relative to 5’ splice site (or 3’ end) of the exon. [0310] In some embodiments, the ASOs are complementary to (and bind to) a targeted portion of a pre-mRNA that that comprises an exon containing an inefficient translation region or a PTC followed by an alternative start codon, and the targeted portion is that is upstream (in the 5’ direction) of the 3’ splice site (or 5’ end) of the exon. In some embodiments, the targeted portion is within the region about -1 to about -500 relative to the 3’ splice site (or 5’ end) of the exon. In some embodiments, the ASOs are complementary to a targeted portion that is within the region - 1 to -40,000 relative to the 3’ splice site of the included exon. In some aspects, the ASOs are complementary to a targeted portion that is within the region about -1 to about -40,000, about -1 to about -30,000, -1 to about -20,000, about -1 to about -15,000, about -1 to about -10,000, about -1 to about -5,000, about -1 to about -4,000, about -1 to about -3,000, about -1 to about -2,000, about -1 to about -1,000, about -1 to about -500, about -1 to about -490, about -1 to about -480, about -1 to about -470, about -1 to about -460, about -1 to about -450, about -1 to about -440, about -1 to about -430, about -1 to about -420, about -1 to about -410, about -1 to about -400, about -1 to about -390, about -1 to about -380, about -1 to about -370, about -1 to about -360, about -1 to about -350, about -1 to about -340, about -1 to about -330, about -1 to about -320, about -1 to about -310, about -1 to about -300, about -1 to about -290, about -1 to about -280, about -1 to about -270, about -1 to about -260, about -1 to about -250, about -1 to about -240, about -1 to about -230, about -1 to about -220, about -1 to about -210, about -1 to about -200, about -1 to about -190, about -1 to about -180, about -1 to about -170, about -1 to about -160, about -1 to about -150, about -1 to about -140, about -1 to about -130, about -1 to about -120, about -1 to about -110, about -1 to about -100, about -1 to about -90, about -1 to about -80, about -1 to about -70, about -1 to about -60, about -1 to about -50, about -1 to about -40, about -1 to about -30, or about -1 to about -20 relative to 3’ splice site of the included exon. In some aspects, the ASOs are complementary to a targeted portion that is within the region from about - 1 to about -100, from about -100 to about -200, from about -200 to about -300, from about -300 to about -400, or from about -400 to about -500 relative to 3’ splice site of the included exon. [0311] In some embodiments, the ASOs are complementary to (and bind to) a targeted portion of a pre-mRNA that that comprises an exon containing an inefficient translation region or a PTC followed by an alternative start codon, and the targeted portion is downstream (in the 3’ direction) of the 3’ splice site (5’ end) of the exon. In some embodiments, the ASOs are complementary to a targeted portion that is within the region of about +1 to about +40,000 relative to the 3’ splice site of the exon. In some aspects, the ASOs are complementary to a targeted portion that is within the region about +1 to about +40,000, about +1 to about +30,000, about +1 to about +20,000, about +1 to about +15,000, about +1 to about +10,000, about +1 to about +5,000, about +1 to about +4,000, about +1 to about +3,000, about +1 to about +2,000, about +1 to about +1,000, about +1 to about +500, about +1 to about +490, about +1 to about +480, about +1 to about +470, about +1 to about +460, about +1 to about +450, about +1 to about +440, about +1 to about +430, about +1 to about +420, about +1 to about +410, about +1 to about +400, about +1 to about +390, about +1 to about +380, about +1 to about +370, about +1 to about +360, about +1 to about +350, about +1 to about +340, about +1 to about +330, about +1 to about +320, about +1 to about +310, about +1 to about +300, about +1 to about +290, about +1 to about +280, about +1 to about +270, about +1 to about +260, about +1 to about +250, about +1 to about +240, about +1 to about +230, about +1 to about +220, about +1 to about +210, about +1 to about +200, about +1 to about +190, about +1 to about +180, about +1 to about +170, about +1 to about +160, about +1 to about +150, about +1 to about +140, about +1 to about +130, about +1 to about +120, about +1 to about +110, about +1 to about +100, about +1 to about +90, about +1 to about +80, about +1 to about +70, about +1 to about +60, about +1 to about +50, about +1 to about +40, about +1 to about +30, or about +1 to about +20, or about +1 to about +10 relative to 3’ splice site of the exon. [0312] In some embodiments, the targeted portion is within the region +100 relative to the 5’ splice site (3’ end) of the exon to -100 relative to the 3’ splice site (5’ end) of the exon. In some embodiments, the targeted portion is within the exon that contains an inefficient translation region or a PTC followed by an alternative start codon. In some embodiments, the targeted portion comprises an exon and intron boundary. [0313] The ASOs may be of any length suitable for specific binding and effective enhancement of splicing. In some embodiments, the ASOs consist of 8 to 50 nucleobases. For example, the ASO may be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, or 50 nucleobases in length. In some embodiments, the ASOs consist of more than 50 nucleobases. In some embodiments, the ASO is from 8 to 50 nucleobases, 8 to 40 nucleobases, 8 to 35 nucleobases, 8 to 30 nucleobases, 8 to 25 nucleobases, 8 to 20 nucleobases, 8 to 15 nucleobases, 9 to 50 nucleobases, 9 to 40 nucleobases, 9 to 35 nucleobases, 9 to 30 nucleobases, 9 to 25 nucleobases, 9 to 20 nucleobases, 9 to 15 nucleobases, 10 to 50 nucleobases, 10 to 40 nucleobases, 10 to 35 nucleobases, 10 to 30 nucleobases, 10 to 25 nucleobases, 10 to 20 nucleobases, 10 to 15 nucleobases, 11 to 50 nucleobases, 11 to 40 nucleobases, 11 to 35 nucleobases, 11 to 30 nucleobases, 11 to 25 nucleobases, 11 to 20 nucleobases, 11 to 15 nucleobases, 12 to 50 nucleobases, 12 to 40 nucleobases, 12 to 35 nucleobases, 12 to 30 nucleobases, 12 to 25 nucleobases, 12 to 20 nucleobases, 12 to 15 nucleobases, 13 to 50 nucleobases, 13 to 40 nucleobases, 13 to 35 nucleobases, 13 to 30 nucleobases, 13 to 25 nucleobases, 13 to 20 nucleobases, 14 to 50 nucleobases, 14 to 40 nucleobases, 14 to 35 nucleobases, 14 to 30 nucleobases, 14 to 25 nucleobases, 14 to 20 nucleobases, 15 to 50 nucleobases, 15 to 40 nucleobases, 15 to 35 nucleobases, 15 to 30 nucleobases, 15 to 25 nucleobases, 15 to 20 nucleobases, 20 to 50 nucleobases, 20 to 40 nucleobases, 20 to 35 nucleobases, 20 to 30 nucleobases, 20 to 25 nucleobases, 25 to 50 nucleobases, 25 to 40 nucleobases, 25 to 35 nucleobases, or 25 to 30 nucleobases in length. In some embodiments, the ASOs are 18 nucleotides in length. In some embodiments, the ASOs are 15 nucleotides in length. In some embodiments, the ASOs are 25 nucleotides in length.

[0314] In some embodiments, the ASO comprises the following formula:

[0315] In some embodiments, the ASO comprises the following formula:

. [0316] In some embodiments, two or more ASOs with different chemistries but complementary to the same targeted portion of the pre-mRNA are used. In some embodiments, two or more ASOs that are complementary to different targeted portions of the pre-mRNA are used. [0317] In some embodiments, the antisense oligonucleotides of the disclosure are chemically linked to one or more moieties or conjugates, e.g., a targeting moiety or other conjugate that enhances the activity or cellular uptake of the oligonucleotide. Such moieties include, but are not limited to, a lipid moiety, e.g., as a cholesterol moiety, a cholesteryl moiety, an aliphatic chain, e.g., dodecandiol or undecyl residues, a polyamine or a polyethylene glycol chain, or adamantane acetic acid. Oligonucleotides comprising lipophilic moieties and preparation methods have been described in the published literature. In embodiments, the antisense oligonucleotide is conjugated with a moiety including, but not limited to, an abasic nucleotide, a polyether, a polyamine, a polyamide, a peptide, a carbohydrate, e.g., N-acetylgalactosamine (GalNAc), N-Ac-Glucosamine (GluNAc), or mannose (e.g., mannose-6-phosphate), a lipid, or a polyhydrocarbon compound. Conjugates can be linked to one or more of any nucleotides comprising the antisense oligonucleotide at any of several positions on the sugar, base, or phosphate group, as understood in the art and described in the literature, e.g., using a linker. Linkers can include a bivalent or trivalent branched linker. In embodiments, the conjugate is attached to the 3’ end of the antisense oligonucleotide. In embodiments, the conjugate is attached to the 5’ end of the antisense oligonucleotide. Methods of preparing oligonucleotide conjugates are described, e.g., in U.S. Pat. No.8,450,467, “Carbohydrate conjugates as delivery agents for oligonucleotides,” incorporated by reference herein. [0318] In some embodiments, the antisense oligonucleotides of the disclosure are chemically linked to a lipophilic group. Representative conjugate moieties can include lipophilic molecules (aromatic and non- aromatic) including sterol and steroid molecules. Lipophilic conjugate moieties can be used, for example, to counter the hydrophilic nature of an oligomeric compound and enhance cellular penetration. Lipophilic moieties include, for example, steroids and related compounds such as cholesterol (U.S. Pat. No.4,958,013 and Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553), thiocholesterol (Oberhauser et al, Nucl Acids Res., 1992, 20, 533), lanosterol, coprostanol, stigmasterol, ergosterol, calciferol, cholic acid, deoxycholic acid, estrone, estradiol, estratriol, progesterone, stilbestrol, testosterone, androsterone, deoxycorticosterone, cortisone, 17-hydroxycorticosterone, their derivatives, and the like. Other lipophilic conjugate moieties include aliphatic groups, such as, for example, straight chain, branched, and cyclic alkyls, alkenyls, and alkynyls. The aliphatic groups can have, for example, 5 to about 50, 6 to about 50, 8 to about 50, or 10 to about 50 carbon atoms. Example aliphatic groups include undecyl, dodecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, terpenes, bornyl, adamantyl, derivatives thereof and the like. In some embodiments, one or more carbon atoms in the aliphatic group can be replaced by a heteroatom such as O, S, or N (e.g., geranyloxyhexyl). Further suitable lipophilic conjugate moieties include aliphatic derivatives of glycerols such as alkylglycerols, bis(alkyl)glycerols, tris(alkyl)glycerols, monoglycerides, diglycerides, and triglycerides. In some embodiments, the lipophilic conjugate is di-hexyldecyl-rac-glycerol or 1 ,2-di-O- hexyldecyl-rac-glycerol (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651 ; Shea, et al., Nuc. Acids Res., 1990, 18, 3777) or phosphonates thereof. Saturated and unsaturated fatty functionalities, such as, for example, fatty acids, fatty alcohols, fatty esters, and fatty amines, can also serve as lipophilic conjugate moieties. In some embodiments, the fatty functionalities can contain from about 6 carbons to about 30 or about 8 to about 22 carbons. Example fatty acids include, capric, caprylic, lauric, palmitic, myristic, stearic, oleic, linoleic, linolenic, arachidic, arachidonic, eicosenoic acids and the like. In further embodiments, lipophilic conjugate groups can be polycyclic aromatic groups having from 6 to about 50, 10 to about 50, or 14 to about 40 carbon atoms. Example polycyclic aromatic groups include pyrenes, purines, acridines, xanthenes, fluorenes, phenanthrenes, anthracenes, quinolines, isoquinolines, naphthalenes, derivatives thereof and the like. [0037] Other suitable lipophilic conjugate moieties include menthols, trityls (e.g., dimethoxytrityl (DMT)), phenoxazines, lipoic acid, phospholipids, ethers, thioethers (e.g., hexyl-S-tritylthiol), derivatives thereof and the like. Preparation of lipophilic conjugates of oligomeric compounds are well-described in the art, such as in, for example, Saison- Behmoaras et al, EMBO J., 1991; Kabanov et al., FEBSLett., 1990, 259, 327; Svinarchuk et al, Biochimie, 1993, 75, 49; (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229, and Manoharan et al., Tetrahedron Lett., 1995, 36, 3651. [0319] Oligomeric compounds containing conjugate moieties with affinity for low density lipoprotein (LDL) can help provide an effective targeted delivery system. High expression levels of receptors for LDL on tumor cells makes LDL an attractive carrier for selective delivery of drugs to these cells (Rump, et al., Bioconjugate Chem., 1998, 9, 341; Firestone, Bioconjugate Chem., 1994, 5, 105; Mishra, et al., Biochim. Biophys. Acta, 1995, 1264, 229). Moieties having affinity for LDL include many lipophilic groups such as steroids (e.g., cholesterol), fatty acids, derivatives thereof and combinations thereof. In some embodiments, conjugate moieties having LDL affinity can be dioleyl esters of cholic acids such as chenodeoxycholic acid and lithocholic acid. [0320] In some embodiments, the conjugate group is or may comprise a lipophilic moiety, such as a sterol (for example, cholesterol, cholesteryl, cholestanol, stigmasterol, cholanic acid, and ergosterol). In some embodiments, the conjugate is or may comprise cholesterol. See for example, Soutschek et al., Nature (2004) 432, 173; KrQtzfeldt Nature 2005, NAR 2007. [0321] In some embodiments, the conjugate is, or may comprise a lipid, a phospholipid or a lipophilic alcohol, such as a cationic lipids, a neutral lipids, sphingolipids, and fatty acids such as stearic, oleic, elaidic, linoleic, linoleaidic, linolenic, arachidic, and myristic acids. In some embodiments the fatty acid comprises a C4 - C30 saturated or unsaturated alkyl chain. The alkyl chain may be linear or branched. [0322] In some embodiments, the fatty acid is a long-chain fatty acid. The long-chain fatty acid can be a palmitic acid. In some embodiments, the palmitic acid is attached to the 5’ of the antisense oligonucleotide. In some embodiments, the palmitic acid is attached to the 5’ of the antisense oligonucleotide by a linker. In some embodiments, the palmitic acid is attached to the 3’ of the antisense oligonucleotide. In some embodiments, the palmitic acid is attached to the 3’ of the antisense oligonucleotide by a linker. The long-chain fatty acid can be a stearic acid. In some embodiments, the stearic acid is attached to the 5’ of the antisense oligonucleotide. In some embodiments, the stearic acid is attached to the 5’ of the antisense oligonucleotide by a linker. In some embodiments, the stearic acid is attached to the 3’ of the antisense oligonucleotide. In some embodiments, the stearic acid is attached to the 3’ of the antisense oligonucleotide by a linker. [0323] In some embodiments, the linker to link the one or more moieties or conjugates (such as lipid moieties) to the antisense oligonucleotide is a glycerol-based linker. In some embodiments, the linker comprises a glycerol-based linker. In some embodiments, the glycerol-based linker is a glycerol-based linker attached to the 3’ end of the antisense oligonucleotide. In some embodiments, the glycerol-based linker is a glycerol-based linker attached to the 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the glycerol-based linker attached to the 3’ end of the antisense oligonucleotide comprises a structure below: [0324] In some embodiments, a palmitic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises a glycerol-based linker linking the palmitic acid and the antisense oligonucleotide. In some embodiments, the glycerol-based linker is a glycerol-based linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the palmitic acid. In some embodiments, the glycerol-based linker is a glycerol-based linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the palmitic acid. In some embodiments, the conjugate comprising a palmitic acid attached to the antisense oligonucleotide by a glycerol-based linker comprises a structure below: [0325] In some embodiments, a stearic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises a glycerol-based linker linking the stearic acid and the antisense oligonucleotide. In some embodiments, the glycerol-based linker is a glycerol-based linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the stearic acid. In some embodiments, the glycerol-based linker is a glycerol-based linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the stearic acid. In some embodiments, the conjugate comprising a stearic acid attached to the antisense oligonucleotide by a glycerol-based linker comprises a structure below: [0326] In some embodiments, an eicosanoic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises a glycerol-based linker linking the eicosanoic acid and the antisense oligonucleotide. In some embodiments, the glycerol-based linker is a glycerol-based linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the eicosanoic acid. In some embodiments, the glycerol-based linker is a glycerol-based linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the eicosanoic acid. In some embodiments, the conjugate comprising an eicosanoic acid attached to the antisense oligonucleotide by a glycerol-based linker comprises a structure below: [0327] In some embodiments, the linker to link the one or more moieties or conjugates (such as lipid moieties) to the antisense oligonucleotide is an aminohexyl linker. In some embodiments, the linker comprises an aminohexyl linker. In some embodiments, the aminohexyl linker is an aminohexyl linker attached to the 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the aminohexyl linker attached to the 3’ end of the antisense oligonucleotide comprises a structure below: [0328] In some embodiments, the aminohexyl linker is an aminohexyl linker attached to the 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the aminohexyl linker attached to the 5’ end of the antisense oligonucleotide comprises a structure below: [0329] In some embodiments, a palmitic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises an aminohexyl linker linking the palmitic acid and the antisense oligonucleotide. In some embodiments, the aminohexyl linker is an aminohexyl linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the palmitic acid. In some embodiments, the conjugate comprising a palmitic acid attached to the antisense oligonucleotide by an aminohexyl linker comprises a structure below: [0330] In some embodiments, a stearic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises an aminohexyl linker linking the stearic acid and the antisense oligonucleotide. In some embodiments, the aminohexyl linker is an aminohexyl linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the stearic acid. In some embodiments, the conjugate comprising a stearic acid attached to the antisense oligonucleotide by an aminohexyl linker comprises a structure below: [0331] In some embodiments, an eicosanoic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises an aminohexyl linker linking the eicosanoic acid and the antisense oligonucleotide. In some embodiments, the aminohexyl linker is an aminohexyl linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the eicosanoic acid. In some embodiments, the conjugate comprising an eicosanoic acid attached to the antisense oligonucleotide by an aminohexyl linker comprises a structure below: [0332] In some embodiments, a palmitic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises an aminohexyl linker linking the palmitic acid and the antisense oligonucleotide. In some embodiments, the aminohexyl linker is an aminohexyl linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the palmitic acid. In some embodiments, the conjugate comprising a palmitic acid attached to the antisense oligonucleotide by an aminohexyl linker comprises a structure below: [0333] In some embodiments, a stearic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises an aminohexyl linker linking the stearic acid and the antisense oligonucleotide. In some embodiments, the aminohexyl linker is an aminohexyl linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the stearic acid. In some embodiments, the conjugate comprising a stearic acid attached to the antisense oligonucleotide by an aminohexyl linker comprises a structure below: [0334] In some embodiments, an eicosanoic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises an aminohexyl linker linking the eicosanoic acid and the antisense oligonucleotide. In some embodiments, the aminohexyl linker is an aminohexyl linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the eicosanoic acid. In some embodiments, the conjugate comprising an eicosanoic acid attached to the antisense oligonucleotide by an aminohexyl linker comprises a structure below: [0335] In some embodiments, the linker to link the one or more moieties or conjugates (such as lipid moieties) to the antisense oligonucleotide is a proline-based linker. In some embodiments, the linker comprises a proline-based linker. In some embodiments, the proline-based linker is a proline-based linker attached to the 3’ end of the antisense oligonucleotide. In some embodiments, the proline-based linker is a proline-based linker attached to the 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the proline-based linker attached to the 3’ end of the antisense oligonucleotide comprises a structure below: [0336] In some embodiments, a palmitic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises a proline-based linker linking the palmitic acid and the antisense oligonucleotide. In some embodiments, the proline-based linker is a proline-based linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the palmitic acid. In some embodiments, the proline-based linker is a proline-based linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the palmitic acid. In some embodiments, the conjugate comprising a palmitic acid attached to the antisense oligonucleotide by a proline-based linker comprises a structure below: [0337] In some embodiments, a stearic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises a proline-based linker linking the stearic acid and the antisense oligonucleotide. In some embodiments, the proline-based linker is a proline- based linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the stearic acid. In some embodiments, the proline-based linker is a proline-based linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the stearic acid. In some embodiments, the conjugate comprising a stearic acid attached to the antisense oligonucleotide by a proline-based linker comprises a structure below: [0338] In some embodiments, an eicosanoic acid is attached to the antisense oligonucleotide by a linker. In some embodiments, the linker comprises a proline-based linker linking the eicosanoic acid and the antisense oligonucleotide. In some embodiments, the proline-based linker is a proline-based linker attached to the 3’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the eicosanoic acid. In some embodiments, the proline-based linker is a proline-based linker attached to the 5’ end of the antisense oligonucleotide and links the antisense oligonucleotide with the eicosanoic acid. In some embodiments, the conjugate comprising an eicosanoic acid attached to the antisense oligonucleotide by a proline-based linker comprises a structure below: [0339] In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8 (SEQ ID NO: 103) and a palmitic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8 (SEQ ID NO: 103) and a palmitic acid at or near 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8 (SEQ ID NO: 103) and a stearic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8 (SEQ ID NO: 103) and a stearic acid at or near 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8 (SEQ ID NO: 103) and an arachidic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8 (SEQ ID NO: 103) and an arachidic acid at or near 3’ end of the antisense oligonucleotide. [0340] In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-1 (SEQ ID NO: 211) and a palmitic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-1 (SEQ ID NO: 211) and a palmitic acid at or near 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-1 (SEQ ID NO: 211) and a stearic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-1 (SEQ ID NO: 211) and a stearic acid at or near 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-1 (SEQ ID NO: 211) and an arachidic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-1 (SEQ ID NO: 211) and an arachidic acid at or near 3’ end of the antisense oligonucleotide. [0341] In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-4 (SEQ ID NO: 246) and a palmitic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-4 (SEQ ID NO: 246) and a palmitic acid at or near 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-4 (SEQ ID NO: 246) and a stearic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-4 (SEQ ID NO: 246) and a stearic acid at or near 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-4 (SEQ ID NO: 246) and an arachidic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-4 (SEQ ID NO: 246) and an arachidic acid at or near 3’ end of the antisense oligonucleotide. [0342] In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-5 (SEQ ID NO: 247) and a palmitic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-5 (SEQ ID NO: 247) and a palmitic acid at or near 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-5 (SEQ ID NO: 247) and a stearic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-5 (SEQ ID NO: 247) and a stearic acid at or near 3’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-5 (SEQ ID NO: 247) and an arachidic acid at or near 5’ end of the antisense oligonucleotide. In some embodiments, the conjugate comprising the antisense oligonucleotide of Compound number 8-5 (SEQ ID NO: 247) and an arachidic acid at or near 3’ end of the antisense oligonucleotide. [0343] In some embodiments, the conjugate comprises the following formula: [0344] In some embodiments, the conjugate comprises the following formula:

. [0345] In some embodiments, the conjugate comprises the following formula: [0346] In some embodiments, the conjugate comprises the following formula:

[0347] In some embodiments, the conjugate comprises the following formula: [0348] In some embodiments, the conjugate comprises the following formula:

. [0349] In some embodiments, the conjugate comprises the following formula: . [0350] In some embodiments, the conjugate comprises the following formula:

[0351] In some embodiments, the conjugate comprises the following formula: [0352] In some embodiments, the conjugate comprises the following formula:

[0353] In some embodiments, the conjugate comprises the following formula: [0354] In some embodiments, the conjugate comprises the following formula:

. [0355] In some embodiments, the conjugate comprises the following formula: . [0356] The conjugate disclosed herein can be synthesized by oligonucleotide synthesis on a solid support (UnyLinker™). The oligonucleotide can be synthesized on the solid support with a free 5’ end that can be used to form a conjugate. An exemplary synthesis process is shown in FIG.18. For example, the precursor for the conjugation can be an aminohexyl linker, synthesized by solid phase oligo synthesis (FIG.18A). Synthesis of conjugates (lipidation) can be done by a peptide coupling reaction (FIG.18B) of the aminohexyl linker with fatty acids (lipids). HATU can be used as a coupling agent. The scheme shown in FIG.18B can be applicable to the synthesis of any of the 5’ conjugations disclosed herein. [0357] The conjugate disclosed herein can be synthesized by oligonucleotide synthesis on a glycerol support. The oligonucleotide can be synthesized on the glycerol support with a free 3’ end that can be used to form a conjugate. An exemplary synthesis process is shown in FIG.19. For example, the precursor (FIG.19A) for the 3’ conjugation can be an aminohexyl linker, synthesized by solid phase oligo synthesis. Synthesis of 3’conjugates (lipidation) can be done by a peptide coupling reaction (FIG.19B) of the aminohexyl linker with fatty acids (lipids). HATU can be used as a coupling agent. The scheme shown in FIG.19B can be applicable to the synthesis of any of the 3’ conjugations disclosed herein. [0358] In some embodiments, the nucleic acid to be targeted by an ASO is a pre-mRNA expressed in a cell, such as a eukaryotic cell. In some embodiments, the term “cell” may refer to a population of cells. In some embodiments, the cell is in a subject. In some embodiments, the cell is isolated from a subject. In some embodiments, the cell is ex vivo. In some embodiments, the cell is a condition or disease-relevant cell or a cell line. In some embodiments, the cell is in vitro (e.g., in cell culture). [0359] Pharmaceutical Compositions [0360] Pharmaceutical compositions or formulations comprising the agent, e.g., antisense oligonucleotide, of the described compositions and for use in any of the described methods can be prepared according to conventional techniques well known in the pharmaceutical industry and described in the published literature. In embodiments, a pharmaceutical composition or formulation for treating a subject comprises an effective amount of any antisense oligomer as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or ester thereof. The pharmaceutical formulation comprising an antisense oligomer may further comprise a pharmaceutically acceptable excipient, diluent, or carrier. [0361] Pharmaceutically acceptable salts are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit/risk ratio. (See, e.g., S. M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference for this purpose. The salts can be prepared in situ during the final isolation and purification of the compounds, or separately by reacting the free base form with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other documented methodologies such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate. [0362] In some embodiments, the compositions are formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. In embodiments, the compositions are formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. In embodiments, a pharmaceutical formulation or composition of the present disclosure includes, but is not limited to, a solution, emulsion, microemulsion, foam or liposome-containing formulation (e.g., cationic or noncationic liposomes). [0363] The pharmaceutical composition or formulation described herein may comprise one or more penetration enhancers, carriers, excipients or other active or inactive ingredients as appropriate and well known to those of skill in the art or described in the published literature. In embodiments, liposomes also include sterically stabilized liposomes, e.g., liposomes comprising one or more specialized lipids. These specialized lipids result in liposomes with enhanced circulation lifetimes. In embodiments, a sterically stabilized liposome comprises one or more glycolipids or is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. In some embodiments, a surfactant is included in the pharmaceutical formulation or compositions. The use of surfactants in drug products, formulations and emulsions is well known in the art. In embodiments, the present disclosure employs a penetration enhancer to effect the efficient delivery of the antisense oligonucleotide, e.g., to aid diffusion across cell membranes and /or enhance the permeability of a lipophilic drug. In some embodiments, the penetration enhancers are a surfactant, fatty acid, bile salt, chelating agent, or non-chelating nonsurfactant. [0364] In some embodiments, the pharmaceutical formulation comprises multiple antisense oligonucleotides. In embodiments, the antisense oligonucleotide is administered in combination with another drug or therapeutic agent. [0365] Combination Therapies [0366] In some embodiments, the ASOs disclosed in the present disclosure can be used in combination with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents can comprise a small molecule. For example, the one or more additional therapeutic agents can comprise a small molecule described in WO2016128343A1, WO2017053982A1, WO2016196386A1, WO201428459A1, WO201524876A2, WO2013119916A2, and WO2014209841A2, which are incorporated by reference herein in their entirety. In some embodiments, the one or more additional therapeutic agents comprise an ASO that can be used to correct intron retention. [0367] Treatment of Subjects [0368] Any of the compositions provided herein may be administered to an individual. “Individual” may be used interchangeably with “subject” or “patient.” An individual may be a mammal, for example a human or animal such as a non-human primate, a rodent, a rabbit, a rat, a mouse, a horse, a donkey, a goat, a cat, a dog, a cow, a pig, or a sheep. In embodiments, the individual is a human. In embodiments, the individual is a fetus, an embryo, or a child. In other embodiments, the individual may be another eukaryotic organism, such as a plant. In some embodiments, the compositions provided herein are administered to a cell ex vivo. [0369] In some embodiments, the compositions provided herein are administered to an individual as a method of treating a disease or disorder. In some embodiments, the individual has a genetic disease, such as any of the diseases described herein. In some embodiments, the individual is at risk of having a disease, such as any of the diseases described herein. In some embodiments, the individual is at increased risk of having a disease or disorder caused by insufficient amount of a protein or insufficient activity of a protein. If an individual is “at an increased risk” of having a disease or disorder caused insufficient amount of a protein or insufficient activity of a protein, the method involves preventative or prophylactic treatment. For example, an individual may be at an increased risk of having such a disease or disorder because of family history of the disease. Typically, individuals at an increased risk of having such a disease or disorder benefit from prophylactic treatment (e.g., by preventing or delaying the onset or progression of the disease or disorder). In embodiments, a fetus is treated in utero, e.g., by administering the ASO composition to the fetus directly or indirectly (e.g., via the mother). [0370] Suitable routes for administration of ASOs of the present disclosure may vary depending on cell type to which delivery of the ASOs is desired. The ASOs of the present disclosure may be administered to patients parenterally, for example, by intrathecal injection, intracerebroventricular injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, or intravenous injection. [0371] In embodiments, the antisense oligonucleotide is administered with one or more agents capable of promoting penetration of the subject antisense oligonucleotide across the blood-brain barrier by any method known in the art. For example, delivery of agents by administration of an adenovirus vector to motor neurons in muscle tissue is described in U.S. Pat. No.6,632,427, “Adenoviral-vector-mediated gene transfer into medullary motor neurons,” incorporated herein by reference. Delivery of vectors directly to the brain, e.g., the striatum, the thalamus, the hippocampus, or the substantia nigra, is described, e.g., in U.S. Pat. No.6,756,523, “Adenovirus vectors for the transfer of foreign genes into cells of the central nervous system particularly in brain,” incorporated herein by reference. [0372] In some embodiments, the antisense oligonucleotides are linked or conjugated with agents that provide desirable pharmaceutical or pharmacodynamic properties. In embodiments, the antisense oligonucleotide is coupled to a substance, known in the art to promote penetration or transport across the blood-brain barrier, e.g., an antibody to the transferrin receptor. In embodiments, the antisense oligonucleotide is linked with a viral vector, e.g., to render the antisense compound more effective or increase transport across the blood-brain barrier. In embodiments, osmotic blood brain barrier disruption is assisted by infusion of sugars, e.g., meso erythritol, xylitol, D(+) galactose, D(+) lactose, D(+) xylose, dulcitol, myo-inositol, L(-) fructose, D(-) mannitol, D(+) glucose, D(+) arabinose, D(-) arabinose, cellobiose, D(+) maltose, D(+) raffinose, L(+) rhamnose, D(+) melibiose, D(-) ribose, adonitol, D(+) arabitol, L(-) arabitol, D(+) fucose, L(-) fucose, D(-) lyxose, L(+) lyxose, and L(-) lyxose, or amino acids, e.g., glutamine, lysine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glycine, histidine, leucine, methionine, phenylalanine, proline, serine, threonine, tyrosine, valine, and taurine. Methods and materials for enhancing blood brain barrier penetration are described, e.g., in U.S. Pat. No.9,193,969, “Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types,” U.S. Pat. No.4,866,042, “Method for the delivery of genetic material across the blood brain barrier,” U.S. Pat. No.6,294,520, “Material for passage through the blood-brain barrier,” and U.S. Pat. No.6,936,589, “Parenteral delivery systems,” each incorporated herein by reference. [0373] In some embodiments, an ASO of the disclosure is coupled to a dopamine reuptake inhibitor (DRI), a selective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptake inhibitor (NRI), a norepinephrine-dopamine reuptake inhibitor (NDRI), and a serotonin- norepinephrine-dopamine reuptake inhibitor (SNDRI), using methods described in, e.g., U.S. Pat. No.9,193,969, incorporated herein by reference. [0374] In some embodiments, subjects treated using the methods and compositions are evaluated for improvement in condition using any methods known and described in the art. EXAMPLES [0375] The present disclosure will be more specifically illustrated by the following Examples. However, it should be understood that the present disclosure is not limited by these examples in any manner. Example 1: Confirmation of Exon 2 Inclusion Event in MECP2 mRNA Processing. [0376] RT-PCR analysis using cytoplasmic RNA from DMSO-treated or puromycin (Puro) or cycloheximide (CHX)-treated RenCellsVM (Neural progenitor cells) in exons can confirm the presence of a band corresponding to an exon that experiences alternative splicing during mRNA processing. Primers were designed to target exon 1 and exon 3 of MECP2 gene. Densitometry analysis of the bands was performed to calculate percent exon inclusion of total transcript. Treatment of cells with cycloheximide or puromycin did not lead to a significant change in e2 mRNA isoform. Example 2: ASO Walk for Exon 2 region of MECP2. [0377] An ASO walk was performed for the exon 2 region of MECP2 pre-mRNA with various ASOs targeting sequences immediately upstream of the 3’ splice site, across the 3’splice site, exon 2, across the 5’ splice site, and downstream of the 5’ splice site using 18-mer 2ʹ-MOE ASOs with PS backbones (FIG.4). ASOs were designed to cover these regions by shifting 5 nucleotides at a time. Example 3: ASO Walk Evaluated by RT-PCR. [0378] ASO walk sequences were evaluated by, for example, RT-PCR. RT-PCR was performed using RNA from HEK293 cells transfected for 24 hours with 80 nM ASOs. Primers for the RT- PCR analysis were positioned in exons 1 and 3. Quantification of the RT-PCR products was plotted as percentage of e2 isoform (e2/(e2+e1)*100) (N = 2). Example 4: Exemplary ASO Induces MECP2 Exon 2 Skipping and Increases MeCP2 Protein Expression. [0379] RT-PCR was performed using RNA from HEK293 cells transfected for 24 hours with 80 nM ASOs or not transfected (mock). HEK293 cells treated with ASOs against MECP2 induced either exon 2 inclusion or exon 2 skipping. ASO1 targets MECP2 but had no effect on exon 2 splicing. Bar chart represents mean ± SE. n = 3. Cells treated with exon skipping ASOs exhibited an isoform switch and increased total MeCP2 protein by western blot, which examined whole cell lysates of cells treated with ASOs as compared to mock at 72 hours post-transfection. Anti-MeCP2 antibody detects isoforms e1 & e2. Quantification of bands corresponding to MeCP2 were normalized to TBP (TATA-binding protein) loading control and plotted as fold change over control (Mock). Example 5: Quantification of total MECP2 mRNA (e1+e2). [0380] RT-PCR products from Example 4 were quantified and plotted as the sum of e1+e2. ASO treatment does not increase total mRNA levels. Example 6. Test of Exemplary ASOs in Murine Cells. [0381] In parallel with screening ASOs in human cell lines, ASOs were screened in murine cells. The exonic as well as flanking intronic sequence of MECP2 exon 2 is almost fully conserved between humans and mice. Lead candidates targeting a conserved region of the human transcript can retain their potency in murine cells (mouse embryonic fibroblasts, MEFs). RT-PCR was performed using RNA from MEF cells transfected for 24 hours with 10, 30, or 80 nM ASOs or not transfected (mock). MEF cells treated with ASOs against MECP2 induced either exon 2 inclusion or exon 2 skipping. The effect is dose-responsive. [0382] ASO microwalk sequences were evaluated by for example RT-PCR. RT-PCR using RNA from ReNcell VM nucleofected for 24 hours with 80 nM ASOs. Primers for the RT-PCR analysis were positioned in exon 1 and 3. Quantification of the RT-PCR products was plotted as percentage of e2 isoform (e2/(e2+e1)*100) (N = 2). Example 7. Test of Exemplary ASOs in Animal Model of Rett Syndrome. [0383] Select MECP2-targeting ASOs are tested in several mouse models to test the effect of (a) increased MeCP2 expression in wild-type mice; (b) increased MeCP2 expression in heterozygous null mice; and (c) increased of MeCP2 expression in mice carrying the partially functional MECP2 p.A140V variant. [0384] ASOs are delivered to neonate wild-type mice by bolus intracerebroventricular (ICV) injection. The effect of ASOs on Mecp2 exon 2 skipping and protein expression is assessed 2-14 days later. Once the duration and magnitude of the effect is established, the lead ASOs are tested in functional studies using mouse models of Rett syndrome. There can be concerns of inducing MECP2 duplication syndrome using TANGO-ASOs; thus, the effect of therapeutic ASOs is compared in wild-type and heterozygous null animals (JAX B6.129P2(C)-Mecp2^tm1.1Bird/J) using a battery of neurological and behavioral assessments. Studies using heterozygous null animals can also establish whether increase of MeCP2 in a subset of neurons is beneficial and can alleviate the phenotype. Mice lacking Mecp2 expression can recapitulate several disease phenotypes of Rett patients including muscle weakness and neurological phenotypes (PsychoGenics Inc.). Grip strength of 8- to 12-week-old heterozygous Mecp2-null female mice, as well as their latency to fall from a rotarod, can be significantly lower compared to those of wild-type littermates.16-week-old heterozygous female mice can have breathing abnormalities (breath variance and apnea duration) and show decreased expression of brain-derived neurotrophic factor (BNDF) compared to mice harboring two copies of Mecp2. [0385] The effect of ASO-mediated increase of MeCP2 expression is also tested in a mouse model expressing MECP2 p.A140V (JAX B6N.129-Mecp2^tm1.1Vnar/J). Hippocampal neurons in female Mecp2^A140/y animals can be significantly smaller compared to wild-type control. Furthermore, mTOR signaling can be deregulated as shown by reduced expression of the mTORC2 subunit RICTOR, as well as reduced phosphorylation of mTOR and 4E-BP1. The effect of the ASOs that increase MeCP2 expression is tested on the morphology of hippocampal neurons as well as mTOR signaling in the brain of these mice. Example 8. In vivo data - Adult Mouse Cortex. [0386] FIG.11 shows results from adult WT and T158M/+ mice treated with compound #8. Treatment of T158M/+ mice showed similar pharmacological effects relative to WT mice. A two-week treatment with compound #8 resulted in a decrease of exon 2 inclusion in Mecp2 mRNA in both adult WT and T158M/+ cortex samples (FIG.11, left panel). MeCP2 protein expression increased in adult WT and MECP2 T158M/+ mice treated with compound #8 relative to the PBS control (FIG.11, right panel). [0387] FIGs.17A-17H show results from neonate wild-type mice treated with compound #8 or compound #8-1. PBS was used as the control. FIGs.17A-17D show the percentage of full- length MECP2 mRNA (exon 2 included) in the cortex of the mice treated with the selected compounds at PND 8, PND 15, PND 29, and PND 114. Both compounds resulted in a stable decrease of the full-length MECP2 mRNA in the cells of the cortex of the mice as compared to the control group for a period time (from PND 8 to PND 114). FIGs.17E-17H show the MeCP2 protein expression level in the cortex of the mice treated with the selected compounds at PND 8, PND 15, PND 29, and PND 114. Both compounds resulted in a stable increase of the MeCP2 protein in the cortex of the mice as compared to the control group for a period time (from PND 8 to PND 114). Example 9. Effects of ASOs on MECP2 mRNA levels. [0388] ASOs of different lengths, nucleobase chemistries, linkages, and lipidation conjugates were tested via RT-PCR analysis from transfected HEK293 cells to identify the effects of the ASO lengths, nucleobase chemistries, linkages, and lipidation conjugates on the decrease in nonproductive MECP2 mRNA and the increase in productive MECP2 mRNA. FIG.5, FIG.6, FIG.7, and FIG.8 depict changes in full-length MECP2 mRNA in response to ASO treatment in compound-screening experiments in vitro. Cells were treated with 20 µM of the indicated ASOs and allowed to freely uptake the ASOs for 72 hours. Bar charts indicate % full-length MECP2 mRNA measured by RT-PCR in ASO-treated samples. NTC: No treatment control. FIG.9 shows results demonstrating that the indicated compounds (#8 and #50) switch MECP2 isoforms and increase MECP2 protein expression in vitro. HEK293 cells were treated with ASOs by nucleofection or by free uptake at the indicated concentrations. After a 3-day treatment, RNA and protein were collected to measure target engagement by RT-PCR (% full- length MECP2 mRNA), isoform expression by qPCR (fold-change relative to mock control), and protein expression by Western blot (fold change relative to mock treatment) FIG.10A depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells treated with increasing concentrations of the indicated compounds (#8, #8-1, #8-2 and #8-3) by free- uptake. Calculated EC50 concentrations (in µM) are indicated. FIG.10B depicts a graph comparing the results from FIG.10A. FIG.12 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were either nucleofected for 24 hours with 3 µM of the indicated lipidated ASOs or treated with 30 µM of the indicated lipidated ASOs and allowed to freely uptake the ASOs for 72 hours. Bar charts represent % full-length MECP2 mRNA isoform. The lipid conjugates do not have an impact on ASO activity (target engagement comparable to unconjugated parent compounds #8 and #8.1 in nucleofected samples) and increase free-uptake activity in HEK293 cells when compared to the unconjugated parent compound #8 or #8.1. FIG.13 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were either nucleofected for 24 hours with 1 µM of the indicated stearic acid-conjugated ASOs or treated with 30 µM of the indicated stearic acid-conjugated ASOs and allowed to freely uptake the ASOs for 72 hours. Bar charts represent % MECP2 exon 2 inclusion. The lipid conjugates do not have an impact on ASO activity (target engagement comparable to unconjugated parent compounds #8 and #8.1 in nucleofected samples) and increase free-uptake activity in HEK293 cells when compared to the unconjugated parent compounds #8 and #8.1. FIG.14 depicts the structure of a PN linkage. PN linkages can be synthesized by the procedure shown in FIG.20. In particular, the precursor for the PN-linked ASO 3 can be the phosphite triester 1 formed during solid-phase oligosynthesis. Treatment of the phosphite triester 1 with 2-Azido-1,3-dimethylimidazolinium hexafluorophosphate 2 (typically a 0.3 M solution, 20 equivalents) at room temperature can result in a Staudinger-type reaction leading to the oxidation of trivalent phosphorous. Subsequent treatment with diethyl amine (DEA) can result in the formation of a PN-linked ASO. [0389] FIG.15 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were either nucleofected for 24 hours with 1 µM of the indicated PN linkage- modified ASOs or treated with 20 µM of the indicated PN linkage-modified ASOs and allowed to freely uptake the ASOs for 72 hours. Bar charts represent five full-length MECP2 mRNA isoform. FIG.16 depicts RT-PCR results for MECP2 exon 2 inclusion using RNA from HEK293 cells. Cells were either nucleofected for 24 hours with 1 µM of the indicated PN linkage modified ASOs or treated with 20 µM of the indicated PN linkage modified ASOs and allowed to freely uptake the ASOs for 72 hours. Bar charts represent % full-length MECP2 mRNA isoform. Example 10. Lipidation of ASOs. [0390] FIG.18 provides a general procedure applicable to the syntheses of the 5’ conjugates disclosed herein. The precursor (FIG.18A) for the conjugation was an aminohexyl linker 1, synthesized by solid phase oligo synthesis. Synthesis of conjugates (lipidation) was done by a peptide coupling reaction (FIG.18B) of the aminohexyl linker 1 with fatty acids 2 (lipids). HATU was used as a coupling agent. The scheme shown in FIG.18B is generally applicable to the synthesis of any of the 5’ conjugations disclosed herein. [0391] In particular, DIPEA (10 equivalents) was added to a mixture of fatty acid 2 (2 equivalents) and HATU (2.2 equivalents) in 1.5 mL DMF or NMP. The reaction mixture was vortexed vigorously for 5 minutes at room temperature to form a “fatty acid-HATU” complex. A solution of aminohexyl linker 1 (35 mg in 1.5 mL water, 1 equivalent) was added to the “fatty acid-HATU” complex. The reaction mixture was vortexed vigorously for 10 minutes and kept at room temperature for 60 minutes with occasional vortex. The reaction mixture was diluted to 15 ml using water and purified by RP HPLC using 0.1 M NaOAc in water/Acetonitrile as eluents. Pure fractions were combined and desalted using a C-18 cartridge (10 g) to obtain the pure product. [0392] FIG.19 provides a general procedure applicable to the synthesis of the syntheses of 3’ conjugates disclosed herein. The precursor (FIG.19A) for the 3’ conjugation was an aminohexyl linker 4, synthesized by solid-phase oligo synthesis. Synthesis of 3’conjugates (lipidation) was done by a peptide coupling reaction (FIG.19B) of aminohexyl linker 4 with fatty acids 2 (lipids). HATU was used as a coupling agent. The scheme shown in FIG.19B is generally applicable to all 3’ conjugations reported herein. [0393] Particularly, DIPEA (10 equivalents) was added to a mixture of fatty acid 2 (2 equivalents) and HATU (2.2 equivalents) in 1.5 mL DMF or NMP. The reaction mixture was vortexed vigorously for 5 minutes at room temperature to form a “fatty acid-HATU” complex. A solution of aminohexyl linker 4 (35 mg in 1.5 mL water, 1 equivalent) was added to the “fatty acid-HATU” complex. The reaction mixture was vortexed vigorously for 10 minutes and kept at room temperature for 60 minutes with occasional vortex. The reaction mixture was diluted to 15 mL using water and purified by RP HPLC using 0.1 M NaOAc in water/Acetonitrile as eluents. Pure fractions were combined and desalted using a C-18 cartridge (10 g) to obtain the pure product. Example 11. Exemplary ASOs and ASO sequences. Table 3. Sequences of exemplary ASOs.

Table 4. Sequences of exemplary ASOs.

Table 5. Sequences of exemplary ASOs in microwalk.

Table 6. Sequences of exemplary PN linkage modified ASOs.

Table 7. Sequences of exemplary lipid-conjugated ASOs.

Example 12. Evaluation of ASO Compounds in Mouse Cortical Neurons (MCNs). [0394] Mouse cortical neurons (MCNs) were derived from the mouse cortex and allowed to freely uptake ASOs from their culture medium. Each tested ASO had a single nucleotide’s sugar moiety modified with 2’-F, a 2’-fluoro moiety, at the sugar’s second carbon (such nucleotides are designated with bold and italicized typeface in the sequence column of Table 8). These 2’- fluoro modifications of the nucleotide’s sugar moieties were placed at various positions along the ASO sequence. Dose-response curves of the ASO compounds were evaluated for their half- maximal effective concentrations (EC50) in nM and Hill coefficients. EC50 Ratios are calculated from the EC50 measured in the presence of the reference ASO compound (8-1) divided by the EC50 measured in the presence of the test ASO compound (8-X). EC50 ratios greater than 1.0 indicated that the activity of the test ASO compound (8-X) is greater than the reference ASO compound (8-1). EC50 ratios equal to or less than 1.0 indicated that the activity of the test ASO compound (8-X) is the same or worse than the reference compound (8-1). With the exception of the placement of the 2’-fluoro modifications in their sugar moieties, all the compounds’ nucleotide sequences (5’-CTACAGAAGCAAGGTG-3’) and their other modifications are identical (Bold = 2' MOE, Italicized = 2' O-Me, Underlined C = 5- methylcytosine). Compound 8-10, comprising a 2’-fluoro modification at the fifth nucleotide’s sugar moiety, had EC50 of 368 nM and an EC50 ratio of 0.27. Compound 8-4, comprising a 2’- fluoro modification at the sixth nucleotide’s sugar moiety, had an EC50 of 70 nM and an EC50 ratio of 1.49. Compound 8-12, comprising a 2’-fluoro modification at the seventh nucleotide’s sugar moiety, had an EC50 of 142 nM and an EC50 ratio of 1.10. Compound 8-13, comprising a 2’-fluoro modification at the eighth nucleotide’s sugar moiety, had an EC50 of 232 nM and an EC50 ratio of 0.67. Compound 8-1, comprising a 2’-fluoro modification at the ninth nucleotide’s sugar moiety, had an EC50 of 102 nM and an EC50 ratio of 1.00. Compound 8-14, comprising a 2’-fluoro modification at the tenth nucleotide’s sugar moiety, had an EC50 of 149 nM and an EC50 ratio of 1.05. Compound 8-15, comprising a 2’-fluoro modification at the eleventh nucleotide’s sugar moiety, had an EC50 of 99 nM and an EC50 ratio of 1.01. Compound 8-17, comprising a 2’-fluoro modification at the twelfth nucleotide’s sugar moiety, had an EC50 of 81 nM and an EC50 ratio of 0.63. EC50 and Hill coefficients for compound 8-1 and compound 8-4 in Table 8 are averages across assay sets. The EC50 Ratio for compound 8-4 is an average across assay sets. A summary of average EC50 values and Hill coefficients is presented in Table 9. Low-dose curves and other multi-dose experiments that did not yield EC50 values were excluded from the summary table. [0395] Table 8. EC50 measurements of various compounds from 2’-fluoro walk. Table 9. Summary of average EC50 values and Hill coefficients Example 13. Extended Dose Ranges Were Evaluated for Four ASO Compounds in Human MeCP2 T158M Neurons [0396] Four different ASO compounds (compound #8, #8-1, #8-4, and #8-5) were examined at low to high concentrations in human MeCP2 T158M neurons. Human T158M neurons comprise a T159M mutation in which amino acid residue 158 in MECP2 is mutated from threonine to methionine, resulting in the downregulation of MeCP2 protein expression. These human MeCP2 T158M neurons were differentiated from induced pluripotent stem cells (iPSCs) derived from patients and exposed to ASO compounds or controls (Mock) at day 3 post-differentiation for three days, followed by media change, and harvested on day 22 post-differentiation. Endpoints that were assessed include: (1) ASO-mediated target engagement and resultant MECP2 protein levels; (2) phenotypic response evaluated as dendrite outgrowth length; and (3) phenotypic response evaluated as Synapsin I puncta count. Experiments were conducted on three independently differentiated sets of human neurons. [0397] ASO-mediated Target Engagement and Resultant MeCP2 Protein Levels in Patient- Derived MeCP2 T158M Neurons [0398] After treatment with various ASO compounds, exon 2 levels were measured by quantitative RT-PCR of exons 1-2. Protein levels were measured from three independently differentiated sets of neurons, with 3-4 biological replicates of each differentiated set. MeCP2 protein was measured by capillary immuno-electrophoresis on a ProteinSimple JESS with COMPASS analysis using HDAC1 (histone deacetylase 1) as a loading control (3-4 replicates of each differentiation). Effective ASO-mediated target engagement was measured as a decrease in exon 2 inclusion and increase in MeCP2 protein levels. [0399] Exon 2 evaluation by qRT-PCR [0400] Controls comprised neurons expressing wild-type MeCP2 protein treated with water (Wt x Mock) and human MeCP2 T158M neurons treated with a Mock substance (Mut x Mock). Test conditions entailed various human MeCP2 T158M neurons treated with four different ASO compounds (compound #8, #8-1, #8-4, and #8-5) at various concentrations (0.001 µM, 1.0 µM, 10.0 µM, and 20.0 µM). MeCP2 exon 2 expression in each condition was normalized to Mut x Mock. [0401] Exon 2 expression decreased to about 0.65-fold of exon 2 expression in Mut x Mock controls when MeCP2 T158M neurons were treated with 10.0 µM of each tested ASO compound. Exon 2 expression was almost halved across all tested compounds relative to exon 2 expression in Mut x Mock controls when MeCP2 T158M neurons were treated with 20.0 µM of each of the ASO compounds. [0402] Exon 2 expression in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8 was 1.00-fold of exon 2 expression in Mut x Mock (i.e., no change). Exon 2 expression in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8 decreased to 0.89-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8 decreased to 0.65-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8 decreased to 0.56-fold of exon 2 expression in Mut x Mock (FIG.21A). [0403] Exon 2 expression in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-1 was 1.20-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-1 decreased to 0.95-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-1 decreased to 0.68-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-1 decreased to 0.51-fold of exon 2 expression in Mut x Mock (FIG.21B). [0404] Exon 2 expression in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-4 was 1.07-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-4 decreased to 0.87-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-4 decreased to 0.61-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-4 decreased to 0.51-fold of exon 2 expression in Mut x Mock (FIG.21C). [0405] Exon 2 expression in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-4 was 1.03-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-4 decreased to 0.97-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-4 decreased to 0.63-fold of exon 2 expression in Mut x Mock. Exon 2 expression in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-4 decreased to 0.52-fold of exon 2 expression in Mut x Mock (FIG.21D). [0406] MeCP2 protein expression levels [0407] MeCP2 protein expression in each tested condition was normalized to Mut x Mock. Protein expression increased to about 1.13-fold of protein expression in Mut x Mock controls when MeCP2 T158M neurons were treated with 10.0 µM of ASO compounds 8, 8-1, and 8-5. Protein expression increased to about 1.14-fold of protein expression in Mut x Mock controls when MeCP2 T158M neurons were treated with 1.0 µM of ASO compound 8-4. Protein expression was increased 1.32-fold relative to protein expression in Mut x Mock controls when MeCP2 T158M neurons were treated with 10.0 µM of ASO compound 8-4. [0408] Protein expression in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8 was 0.98-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8 was 1.08-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8 increased to 1.12-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8 increased to 1.16-fold of protein expression in Mut x Mock (FIG.22A). [0409] Protein expression in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-1 was 0.95-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-1 was 1.00-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-1 increased to 1.14-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-1 increased to 1.22-fold of protein expression in Mut x Mock (FIG.22B). [0410] Protein expression in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-4 was 0.99-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-4 increased to 1.16-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-4 increased to 1.32-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-4 increased to 1.29-fold of protein expression in Mut x Mock (FIG.22C). [0411] Protein expression in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-4 was 0.99-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-4 increased to 1.12-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-4 increased to 1.16-fold of protein expression in Mut x Mock. Protein expression in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-4 increased to 1.15-fold of protein expression in Mut x Mock (FIG.22D). [0412] Neuron Morphology: Phenotypic Response Evaluated as Dendrite Outgrowth Length in Patient-Derived MeCP2 T158M Neurons. [0413] Dendrite outgrowth was measured in MeCP2 T158M neurons stained for Microtubule- associated protein 2 (MAP2), which is the predominant cytoskeletal regulator within neuronal dendrites. Cells were fixed, permeabilized, and labeled: DAPI labeled cell nuclei, and MAP2 and NeuN ("Neuronal Nuclei") labeled neurons. Cell bodies and neurites were identified by staining and size. Skeletonized dendritic outgrowth originating from the cell soma was measured. [0414] The positive staining of MAP2 (denoted as MAP2+) was used as the basis for determining dendrite length in µm for every neuron that also positively stained for NeuN (denoted NeuN+) in each well (µm/NeuN+neuron/well). Each data point is the average of 25 fields of view per well normalized to neuron count (NeuN+)/well. A reduced dendritic length phenotype was observed in neurons derived from patients with reduced or absent levels of MeCP2 protein (e.g., Rett patients), and untreated human MeCP2 T158M neurons displayed such shortened dendrites. [0415] Dendrite outgrowth in each condition was normalized to Mut x Mock. Dendrite outgrowth was generally increased at almost all concentrations of each tested ASO compound. Dendrite outgrowth increased to about 1.20-fold of dendrite outgrowth in Mut x Mock controls when MeCP2 T158M neurons were treated with 1.0 µM of ASO compound 8, and to about 1.25-fold with 10.0 µM of ASO compound 8. Dendrite outgrowth increased to about 1.18-fold of dendrite outgrowth in Mut x Mock controls when MeCP2 T158M neurons were treated with 0.001 µM of ASO compound 8-1. Dendrite outgrowth was increased 1.13-fold relative to dendrite outgrowth in Mut x Mock controls when MeCP2 T158M neurons were treated with 10.0 µM of ASO compound 8-5. [0416] Dendrite outgrowth in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8 was 1.12-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8 was 1.20-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8 increased to 1.25-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8 increased to 1.18-fold of dendrite outgrowth in Mut x Mock (FIG.23A). [0417] Dendrite outgrowth in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-1 was 1.18-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-1 was 1.16-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-1 increased to 1.11-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-1 increased to 1.13-fold of dendrite outgrowth in Mut x Mock (FIG.23B). [0418] Dendrite outgrowth in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-4 was 0.98-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-4 increased to 1.10-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-4 increased to 1.06-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-4 increased to 1.09-fold of dendrite outgrowth in Mut x Mock (FIG.23C). [0419] Dendrite outgrowth in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-4 was 0.99-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-4 increased to 1.06-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-4 increased to 1.13-fold of dendrite outgrowth in Mut x Mock. Dendrite outgrowth in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-4 increased to 1.68-fold of dendrite outgrowth in Mut x Mock (FIG.23D). [0420] Neuron Synapses: Pre-synaptic Synapsin I in Patient-Derived MeCP2 T158M Neurons [0421] MeCP2 T158M neuron synapse number was quantified by staining for MAP2 as described above and positive staining of MAP2 was used as the basis for counting the number of Synapsin I puncta per neuron per well (Synapsin I puncta/neuron/well). Each data point is the sum of 25 fields of view per well normalized to neuron count (NeuN+)/well. A reduced MAP2 expression phenotype was observed in neurons derived from patients with reduced or absent levels of MeCP2 protein (e.g., Rett patients), and untreated human MeCP2 T158M neurons display such reduced MAP2 expression. [0422] Synapsin I puncta count in each condition was normalized to Mut x Mock. Synapsin I puncta count was generally increased at almost all concentrations of each tested ASO compound. Synapsin I puncta count increased to about 1.28-fold of Synapsin I puncta count in Mut x Mock controls when MeCP2 T158M neurons were treated with 10.0 µM of ASO compound 8, to about 1.24-fold with 20.0 µM of ASO compound 8, to about 1.20-fold with 1.0 µM of compound 8-1, to about 1.23-fold with 1.0 µM of compound 8-1, to about 1.37-fold with 20.0 µM of compound 8-1, to about 1.19-fold with 1.0 µM of compound 8-4, and to about 1.20- fold with 10.0 µM of compound 8-4. [0423] Synapsin I puncta count in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8 was 1.06-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8 was 1.17-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8 increased to 1.23-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8 increased to 1.24-fold of Synapsin I puncta count in Mut x Mock (FIG.24A). [0424] Synapsin I puncta count in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-1 was 1.12-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-1 was 1.20-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-1 increased to 1.23-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-1 increased to 1.37-fold of Synapsin I puncta count in Mut x Mock (FIG. 24B). [0425] Synapsin I puncta count in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-4 was 1.07-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-4 increased to 1.19- fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-4 increased to 1.20-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-4 increased to 1.18-fold of Synapsin I puncta count in Mut x Mock (FIG. 24C). [0426] Synapsin I puncta count in MeCP2 T158M neurons treated with 0.001 µM of ASO compound 8-4 was 0.96-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 1.0 µM of ASO compound 8-4 increased to 1.01- fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 10.0 µM of ASO compound 8-4 increased to 1.14-fold of Synapsin I puncta count in Mut x Mock. Synapsin I puncta count in MeCP2 T158M neurons treated with 20.0 µM of ASO compound 8-4 increased to 1.10-fold of Synapsin I puncta count in Mut x Mock (FIG. 24D). [0427] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I): X_AX_N1X_N2X_N3X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇X₁₈X₁₉X₂₀X_C1X_C2X_C3X_B wherein XA is and B_A is when X_N1, X_N2 and X_N3 and X₅ are absent, when X_N1, X_N2 and X_N3 are absent and X₅ is present, when X_N1 and X_N2 are absent and X_N3 and X₅ are present, when X_N1 is absent and X_N2 and X_N3 and X₅ are present, or when X_N1, X_N2 and X_N3 and X₅ are present; X_N1 is or absent, wherein if X_N1 is present X_N2 and X_N3 and X₅ are present; X_N2 is or absent, wherein if X_N2 is present X_N3 and X₅ are present; X_N3 is or absent, wherein if X_N3 is present X₅ is present; X₅ is

or absent; X_C1 is or absent, wherein if X_C1 is present X₂₀ is present; X_C2 is or absent, wherein if X_C2 is present X_C1 and X₂₀ are present; X_C3 is or absent, wherein if X_C3 is present X_C1 and X_C2 and X₂₀ are present; and X_B is and B_B is when X₂₀ and X_C1, X_C2 and X_C3 are present, when X₂₀ and X_C1 and X_C2 are present and X_C3 is absent, (iii) when X₂₀ and X_C1 is present and X_C2 and X_C3 are absent, when X₂₀ is present and X_C1, X_C2 and X_C3 are absent, or when X₂₀ and X_C1, X_C2 and X_C3 are absent. 2. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₆ is X8 is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is 3. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is (v) .

4. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent;

X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

5. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_C2 is absent; X_C3 is absent; and B_B is .

6. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is (v) 7. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is

X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

8. The compound of claim 1, wherein B_A is X_N1 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is (v)

9. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is .

10. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 absent; X_C3 is absent; and B_B is

11. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3

X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

12. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

13. The compound of claim 1, wherein B_A is X_N1 absent; X_N2 absent; X_N3 is absent; X₅ is absent;

14. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₆ is ; ; ; X_C3 is absent; and B_B is (ii)

15. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is X_C2 is absent; X_C3 is absent; and B_B is .

16. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

17. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

18. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₆ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

19. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

20. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

21. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

22. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent;

X_C2 is absent; X_C3 is absent; and B_B is (iii)

23. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is .

24. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 X_C2 is absent; X_C3 is absent; and B_B is

25. The compound of claim 1, wherein B_A is X_N1 absent; X_N2 absent; X_N3 is

26. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₆ is

.

27. The compound of claim 1, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is X_C2 is absent; X_C3 is absent; and B_B is .

28. A compound of Formula (I): X_AX_N1X_N2X_N3X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇X₁₈X₁₉X₂₀X_C1X_C2X_C3X_B wherein X_A is and B_A is when X_N1, X_N2 and X_N3 and X₅ are absent, when X_N1, X_N2 and X_N3 are absent and X₅ is present, when X_N1 and X_N2 are absent and X_N3 and X₅ are present, when X_N1 is absent and X_N2 and X_N3 and X₅ are present, or when X_N1, X_N2 and X_N3 and X₅ are present; X_N1 is or absent, wherein if X_N1 is present X_N2 and X_N3 and X₅ are present; X_N2 is or absent, wherein if X_N2 is present X_N3 and X₅ are present; X_N3 is or absent, wherein if X_N3 is present X₅ is present; X₅ is X_C1 is or absent, wherein if X_C1 is present X₂₀ is present; X_C2 is or absent, wherein if X_C2 is present X_C1 and X₂₀ are present; X_C3 is or absent, wherein if X_C3 is present X_C1 and X_C2 and X₂₀ are present; and X_B is and B_B is when X_C1, X_C2 and X_C3 and X₂₀ are present, when X_C1 and X_C2 and X₂₀ are present and X_C3 is absent, when X_C1 and X₂₀ are present and X_C2 and X_C3 are absent, when X₂₀ is present and X_C1, X_C2 and X_C3 are absent, or when X₂₀ and X_C1, X_C2 and X_C3 are absent.

29. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is

X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B

30. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X_C2 is absent; X_C3 is absent; and B_B is

31. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; X₅ is absent; X₆ is ; X10 is ; X11 is ; X12 is ; X13 is ; X₁₄ is ; X₁₅ is ; X₁₆ is ; X₁₇ is X_C1 is X_C2 is absent; X_C3 is absent; and B_B is

32. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is

X_C3 is absent; and B_B is

33. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is .

34. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B

35. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 absent; X_C2 is absent; X_C3 is absent; and B_B is

36. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_N3 is absent; ; ; X_C2 is absent; X_C3 is absent; and B_B is

37. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B

38. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; ; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

39. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is absent; X_C2 is absent; X_C3 is absent; and B_B is

40. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B (v)

41. The compound of claim 28, wherein B_A is X_N1 is absent; X_N2 is X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B is

42. The compound of claim 28, wherein B_A is X_N1 is X_N2 is X₂₀ is absent; X_C1 is absent; X_C2 is absent; X_C3 is absent; and B_B (v)

43. A compound selected from the group consisting of: ,



44. A compound that is an antisense oligonucleotide (ASO) having a sequence according to SEQ ID NO: 103 or 211, wherein the ASO comprises a backbone modification comprising a phosphoryl guanidine diester or derivative thereof.

45. The compound of claim 44, wherein the ASO comprises CnTACAGAAGCAAGGTG, CTnACAGAAGCAAGGTG, CTnACAGAAGCAAGGTG, CTACnAGAAGCAAGGTG, CTACAnGAAGCAAGGTG, CTACAGnAAGCAAGGTG, CTACAGAnAGCAAGGTG, CTACAGAAnGCAAGGTG, CTACAGAAGnCAAGGTG, CTACAGAAGCnAAGGTG, CTACAGAAGCAnAGGTG, CTACAGAAGCAAnGGTG, CTACAGAAGCAAGnGTG, CTACAGAAGCAAGGnTG, CTACAGAAGCAAGGTnG, CnTnACAGAAGCAAGGTnG, CTnAnCAGAAGCAAGGTnG, CTAnCnAGAAGCAAGGTnG, CTACnAnGAAGCAAGGTnG, CTACAnGnAAGCAAGGTnG, CTACAGnAnAGCAAGGTnG, CTACAGAnAnGCAAGGTnG, CTACAGAAnGnCAAGGTnG, CTACAGAAGnCnAAGGTnG, CTACAGAAGCnAnAGGTnG, CTACAGAAGCAAnGnGTnG, CTACAGAAGCAnAnGGnTG, CTACAGAAGCnAnAGnGTG, CnTnACnAGAAGCAAGGTG, CTnACnAnGAAGCAAGGTG, CTAnCAnGnAAGCAAGGTG, CTACnAGnAnAGCAAGGTG, CTACAnGAnAnGCAAGGTG, CnTACAGAAGCAAGGTnG, CTnACAGAAGCAAGGnTG, CTACAGAAGCAAGGnTG or CTACAGAAGCAAGGTnG, wherein n is the phosphoryl guanidine diester or derivative thereof.

46. The compound of claim 44 or 45, wherein the ASO further comprises a backbone modification comprising a phosphorothioate (PS) linkage or a phosphoroamidate linkage.

47. The compound of any one of claims 44-46, wherein the phosphoryl guanidine diester or derivative thereof comprises a (1,3-dimethylimididazolidin-2-ylidene) phosphoramidate; ((4-acetamidophenyl) sulfonyl) phosphoramidate; ((1,3-dimethyltetrahydropyrimidin- 2(1H)-ylidene) phosphoramidate; (1,3-dimethyl-1,3-diazepan-2-ylidene) phosphoramidate; or (did(pyrrolidin-1-yl)methylene) phosphoramidate.

48. The compound of any one of claims 44-47, wherein the ASO comprises a 2'- O-methyl, 2'- Fluoro, and/or a 2'-O-methoxyethyl moiety.

49. The compound of any one of claims 44-48, wherein the ASO comprises at least one modified sugar moiety.

50. The compound of any one of claims 1-49, wherein the compound is conjugated to a lipid.

51. A compound that is an antisense oligonucleotide (ASO) having a sequence according to SEQ ID NO: 103 or 211, wherein the ASO is conjugated to a lipid.

52. The compound of claim 50 or 51, wherein the lipid is conjugated to a 5' end or 3' end of the compound.

53. The compound of any one of claims 50-52, wherein the lipid is conjugated to the compound via a phosphate, a phosphoroamidate, or a phosphorothioate.

54. The compound of any one of claims 50-53, wherein the lipid is conjugated to the compound via a linker.

55. The compound of claim 54, wherein the linker is selected from the group consisting of a proline-based linker, an aminohexyl linker, and a glycerol-based linker.

56. The compound of claim 55, wherein the linker is a linker selected from the group consisting

57. The compound of any one of claims 50-56, wherein the lipid is selected from the group consisting of stearic acid, oleic acid, elaidic acid, linoleic acid, linoleaidic acid, linolenic acid, arachidic acid, myristic acid, capric acid, caprylic acid, lauric acid, palmitic acid, arachidonic acid, and eicosenoic acid.

58. The compound of claim 57, wherein the lipid is stearic acid.

59. The compound of any one of claims 44-58, wherein the compound has a structure according to formula (I): lipid-linker-ASO.

60. The compound of claim 59, wherein the compound has a structure selected from the group consisting of:

61. The compound of any one of claims 44-58, wherein the compound has a structure according to formula (II): ASO-linker-lipid.

62. The compound of claim 61, wherein the compound has a structure selected from the group consisting of: