Provided herein are processes for preparing an oligomer (e.g., a morpholino oligomer). The synthetic processes described herein may be advantageous to scaling up oligomer synthesis while maintaining overall yield and purity of a synthesized oligomer.

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.

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.

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.

The present invention relates to a novel morpholino oligonucleotide comprising at least one type of morpholino nucleotide monomer having pyrrolocytosine (pC) among unnatural cytosines, and relates to a morpholino oligonucleotide capable of more selectively binding to a target RNA and exhibiting excellent cell penetration compared to an MPO having a natural cytosine, and thus being capable of greatly contributing to the development of a therapeutic agent for incurable diseases in the area of morpholino oligonucleotides.

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 promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.