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 specification provides a drug that causes highly-efficient skipping of exon 51 in the human dystrophin gene. The present specification provides an antisense oligomer having an activity to induce skipping of exon 51 in the human dystrophin gene.

The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting an RPS25 gene, as well as methods of inhibiting expression of an RPS25 gene and methods of treating subjects having an RPS25-associated disease or disorder, such as a nucleotide repeat expansion disorder, e.g., c9orf72 amyotrophic lateral sclerosis (ALS)/frontotemporal demential (FTD) and Huntington-Like Syndrome Due To C9orf72 Expansions, using such dsRNAi agents and compositions.

Compositions related to spherical nucleic acids (SNAs) with antisense oligonucleotides and methods of treatment of diseases and disorders are disclosed therein. In particular, the antisense oligonucleotides are targeted to a region in a pre-mRNA of interest to regulate pre-mRNA splicing.

An isolated or purified antisense oligomer with a modified backbone structure for modifying pre-mRNA splicing in the parkin gene transcript or part thereof.

An isolated or purified antisense oligomer with a modified backbone structure for modifying pre-mRNA splicing in the parkin gene transcript or part thereof.

Improved compositions and methods for treating a disease or disorder through target exon skipping, and preferably muscular dystrophy by administering antisense thiomorpholino molecules capable of binding to a selected target site in the human dystrophin gene to induce exon skipping to produce a functional Dystrophin protein.

Among the various aspects of the present disclosure is the provision of compositions and methods for selectively reducing pathogenic isoforms (e.g., DNAJB6) in a subject having a neuromuscular disorder. An aspect of the present disclosure provides for selectively reducing DNAJB6 in a subject having a neuromuscular disorder (e.g., limb-girdle muscular dystrophy D1 (LGMD-D1)) comprising administering an amount of a DNAJB6-targeting antisense oligonucleotide (ASO) sufficient to reduce the expression of DNAJB6 compared to the subject prior to being administered the DNAJB6-targeting ASO.

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.

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.