One aspect described herein is use of a compound to modulate the production of one or more mature RNA isoforms from a gene transcript in a cell. Another aspect described herein is use of a compound in a method to modulate exon inclusion or exon exclusion in one or more mature mRNA isoforms from a gene transcript in a cell.

This disclosure concerns an engineered polynucleotide that interacts with a pre-mRNA and a spliceosome to regulate gene expression. The engineered polynucleotide may have stem-loop structure that recruits the spliceosome and targeting sequences that are complementary to a target sequence at an exon-intron splice junction and may include nucleotides with 2′ modifications and phorphorothioate linkages.

The present disclosure provides antisense oligonucleotides, compositions, and methods that target ATP7B exon 6 or a flanking intron, thereby modulating splicing of ATP7B pre-mRNA to increase the level of ATP7B mRNA molecules having exon 6, e.g., to provide a therapy for Wilson disease. The present disclosure provides an antisense oligonucleotide including a nucleobase sequence at least 70% complementary to an ATP7B target sequence in exon 6, a 5′-flanking intron, a 3′-flanking intron, or a combination of exon 6 and the 5′-flanking or 3′-flanking intron.

The present disclosure provides, among other things, improved compositions and methods for treating muscular dystrophy. For example, the disclosure provides methods for treating Duchenne muscular dystrophy patients having a mutation in the DMD gene that is amenable to exon 53 skipping by administering an effective amount of golodirsen.

The present specification provides an antisense oligomer capable of causing simultaneous skipping of a plurality of exons in pre-mRNA of interest, and a pharmaceutical composition comprising the oligomer. The present specification also provides an antisense oligomer or a pharmaceutically acceptable salt thereof, or hydrate thereof which causes simultaneous skipping of two or more numerically consecutive exons from pre-mRNA of interest, the antisense oligomer comprising a base sequence complementary to a base sequence of a region including the vicinity of a donor of any intron in the pre-mRNA of interest, or a region including the vicinity of an acceptor of any intron in the pre-mRNA of interest, or a partial base sequence thereof.

A modified antisense oligonucleotide of about 10 to about 40 nucleobases is disclosed. The oligonucleotide comprises a targeting sequence having a region complementary to at least one string of three or more identical contiguous nucleobases in a target sequence, wherein the target sequence comprises at least one additional nucleobase compared to the region of the targeting sequence and the at least one additional nucleobase has no complementary nucleobase in the region of the targeting sequence, and wherein the targeting region complementary to the at least one string of three or more identical contiguous nucleobases is internal to the targeting sequence.

Disclosed herein are methods for inhibiting or activating the transcription of a gene of interest, or inhibiting or activating the transcription of specific mRNA isoforms of a gene by using antisense oligonucleotides and/or small molecules. Also described herein are methods for activating transcription from a promoter and increasing overall gene expression by creating of a new splice site in a gene of a cell.

An antisense molecule capable of binding to a selected target site to induce exon skipping in the dystrophin gene, as set forth in SEQ ID NO: 1 to 214.

Antisense molecules capable of binding to a selected target site in the human dystrophin gene to induce exon 53 skipping are described.

Disclosed herein are methods, compositions, polynucleic acid polymers, assays, and kits for inducing processing of a partially processed mRNA transcript to remove a retained intron to produce a fully processed mRNA transcript that encodes a full-length functional form of a protein. Also described herein are methods and compositions for treating a disease or condition characterized by impaired production of a full-length functional form of a protein or for treating a disease or condition characterized by a defective splicing in a subject.