An ALS treatment method includes administering to an ALS patient an inhibitor for a target A or a promoter for a target B. The target A is one or more genes selected from the genes in Table 1-1 or a protein encoded by the gene, and the inhibitor for the target A is a substance that inhibits expression of the gene, or a substance that inhibits a function of the protein encoded by the gene. The target B is one or more genes selected from the genes in Table 1-2 or a protein encoded by the gene, and the promoter for the target B is a substance that promotes the expression of the gene, or a substance that promotes a function of the protein encoded by the gene.

An implantable medical device is provided. The device comprises a drug release layer, wherein the drug release layer comprises a naked nucleic acid dispersed within a polymer matrix. The polymer matrix includes an ethylene vinyl acetate copolymer and has a melting temperature of from about 20° C. to about 100° C. as determined in accordance with ASTM D3418-15 and a melt flow index of from about 0.2 to about 100 gram per 10 minutes as determined in accordance with ASTM D1238-20 at a temperature of 190° C. and a load of 2.16 kilograms.

The present disclosure provides methods comprising administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and/or activity and an anti-cancer agent and/or an anti-cancer therapy. Further provided are kits comprising an anti-cancer agent, an agent that decreases or inhibits TIGIT expression and/or activity, or both, as well as instructions for use thereof.

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits activity of a disease allele associated with muscle disease. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

A modified oligonucleotide having an activity of inhibiting Ataxin 3 expression and having any one of the following nucleobase sequences or a nucleobase sequence of 17 contiguous bases contained in the nucleobase sequences:

TABLE-US-00001 (SEQ ID NO: 239) (1) TCGGGTAAGTAGATTTTC, (SEQ ID NO: 240) (2) GAAGTATCTGTAGGCCTA, (SEQ ID NO: 241) (3) GGACTGTATAGGAGATTA, (SEQ ID NO: 242) (4) GGTTATAGGATGCAGGTA, (SEQ ID NO: 243) (5) AGGTTATAGGATGCAGGT, (SEQ ID NO: 244) (6) GAAGCTAAGTAGGTGACT, (SEQ ID NO: 245) (7) TGAAGCTAAGTAGGTGAC, (SEQ ID NO: 246) (8) CCTAGTCACTTTGATAGA, (SEQ ID NO: 247) (9) GGAACATCTTGAGTAGGT, (SEQ ID NO: 248) (10) GGTGTTCAGGGTAGATGT, (SEQ ID NO: 249) (11) GGATACTCTGCCCTGTTC, (SEQ ID NO: 250) (12) GGTGTCAAACGTGTGGTT, (SEQ ID NO: 251) (13) CCGTGTGCTAGTATTTGT, (SEQ ID NO: 252) (14) TAGTAGAGTTTTGCTTGG, (SEQ ID NO: 253) (15) GATGTAGTAGAGTTTTGC, (SEQ ID NO: 254) (16) TGATGTAGTAGAGTTTTG, (SEQ ID NO: 255) (17) CTGATGTAGTAGAGTTTT, (SEQ ID NO: 256) (19) GCAAGTTGGTTTGTGGTA, (SEQ ID NO: 257) (20) TCTAGGCAATTGTGGTGG, (SEQ ID NO: 258) (21) GTAACTCTGCACTTCCCA, (SEQ ID NO: 259) (22) GTCATCCCTATGTCTTAT, (SEQ ID NO: 260) (23) GTCATATGGTCAGGGTAT, (SEQ ID NO: 261) (24) TGTCATATGGTCAGGGTA, (SEQ ID NO: 262) (25) ATGTCATATGGTCAGGGT, and (SEQ ID NO: 263) (26) TATGTCATATGGTCAGGG.

A method for inhibiting expression of an mRNA having an expanded trinucleotide repeat region is provided comprising administering an oligomer comprising a sense strand and an antisense strand wherein: a) the antisense strand comprises a sequence of Formula (I): rGrCrUrGrCrUrGrCX.sup.1X.sup.2rCrUrGrCrUrGrCrUrG (I), wherein X.sup.1 and X.sup.2 are each independently selected from rA, rU, rG, rC, UNA-A, UNA-U, UNA-G, and UNA-C and wherein at least one of X.sup.1 and X.sup.2 is a UNA monomer; b) the oligomer comprises a UNA monomer at the first position at the 5′-end of the sense strand; and the sense strand and the antisense strand each independently include 19-29 monomers. The oligomer can be formulated in a lipid delivery vehicle, and can inhibit expression of Atrophin-1, Huntingtin, Ataxin-1, Ataxin-2, Ataxin-3, Ataxin-7, Alpha1A-voltage-dependent calcium channel subunit, TATA-box binding protein (TBP), Androgen Receptor, PP2A-PR55beta, FMR-1 Protein (FMRP), FMR-2 protein, Frataxin, Dystrophy Protein Kinase (DMPK), or Ataxin-8.

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits expression or activity of DUX4. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

The present disclosure provides methods and compositions relating to gene therapy for treating epilepsy, such as a temporal lobe epilepsy, in a subject in need thereof by targeting Grik2 mRNA. In particular, the present disclosure provides inhibitory RNA constructs capable of inhibiting expression of GluK2 protein and inhibiting epileptiform discharges in hyperexcitable neuronal circuit.

Compositions and methods of use thereof for delivering nucleic acid cargo into cells are provided. The compositions typically include (a) a 3E10 monoclonal antibody or an antigen binding, cell-penetrating fragment thereof; a monovalent, divalent, or multivalent single chain variable fragment (scFv); or a diabody; or humanized form or variant thereof, and (b) a nucleic acid cargo including, for example, a nucleic acid encoding a polypeptide, a functional nucleic acid, a nucleic acid encoding a functional nucleic acid, or a combination thereof. Elements (a) and (b) are typically non-covalently linked to form a complex.

Disclosed herein include compositions and methods of modulating protein expression that utilizes an activator or a repressor of a non-sense mediated RNA decay switch exon (NSE). In some embodiments, also included herein are compositions and methods of modulating protein expression that uses an agent that targets a transposed element.