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 present invention provides methods and compositions for stable genetic modification of cultured mammalian cells. The genetic modifications can be used to produce cultured mammalian cells for therapeutic or diagnostic purposes.

The present invention relates to an oligonucleotide conjugate K of the structure RNA1-B-RNA2 RNA3 RNA4 or a pharmaceutically active salt thereof, wherein each RNA1, RNA2, RNA3 and RNA4 is a strand of a ribonucleic acid or of an analogue or of a derivative thereof, wherein B is a divalent linker that covalently bonds the 5′ terminus of RNA1 to the 5′ terminus of RNA2 or the 3′ terminus of RNA1 to the 3′ terminus of RNA2, and wherein RNA3 and RNA4 are not covalently bonded to each other. The invention further relates to the medical and non-medical use of such an oligonucleotide conjugate K and to corresponding manufacturing methods.

Embodiments of the disclosure include compositions and methods for generating RNA nanostructures, particularly in a cell. In particular embodiments, RNA subunits comprising at least one three-way junction and at least one kissing loop are configured such that multiple RNA subunits can polymerize into a specific structure. In particular embodiments, the RNA subunits are configured such that sequence of at least one kissing loop is complementary to sequence of another kissing loop, such as on another RNA subunit, and the summation of multiple RNA subunits having specific individual structures results in a combined polymerized structure of a defined shape. In specific embodiments, an RNA nanostructure generated from methods herein is utilized for an application, such as manufacturing or genetic modifications in a cell.

This disclosure relates to novel MLH3 targeting sequences. Novel MLH3 targeting oligonucleotides for the treatment of neurodegenerative diseases are also provided.

The present invention provides methods and compositions for stable genetic modification of cultured mammalian cells. The genetic modifications can be used to produce- cultured mammalian cells for therapeutic of diagnostic purposes.

The present invention relates to a RNA molecule comprising a first ribozyme, a first ligation sequence, an effector molecule, a second ligation sequence, and a second ribozyme. Methods of producing circular RNA molecules and treatment methods are also disclosed.

Orthogonally linked multi-conjugates (such as multimeric oligonucleotides) are disclosed, along with methods of synthesizing them using orthogonal linking strategies to join together subunits that are biological moieties.

The present invention is directed to compositions and methods for the aptamer-driven surface formulation of self-forming polynucleotide nanoparticles, and the use of such moiety-coated nanoparticle complexes for use in a variety of organisms.

Morpholino antisense oligos (Morpholinos) are a class of synthetic non-ionic molecules, each designed to very specifically bind to a selected complementary RNA sequence (targeted RNA transcript). Custom-sequence Morpholinos are used in a broad range of biological research areas, as well as for therapeutic applications in vivo (in living animals such as humans).

For most in vivo applications the “bare” Morpholino (FIG. 1a) is linked to a cationic delivery component to give a “delivery-enabled” Morpholino (FIG. 1b) with significantly improved delivery efficiency. However, cytosolic delivery was still markedly less than expected. Then recently we discovered that by adding a special disconnect component between the Morpholino component and the cationic delivery component (FIG. 1c), the cytosolic delivery efficiency for the Morpholino was dramatically increased (about a 1,000% increase in delivery efficiency).

This patent application describes designing, making, and using such delivery-enabled Morpholinos containing a key disconnect component.