The lack of blood-brain barrier (BBB) penetrating ability has hindered the delivery of many therapeutic agents for tauopathy therapeutic treatment. A circular bifunctional aptamer reported here has been able to enhance the in vivo BBB penetration for improved therapy. The circular aptamer includes one transferrin receptor (TfR) aptamer to facilitate TfR-aptamer recognition-induced transcytosis across BBB endothelial cells, and one Tau protein aptamer selected to inhibit Tau phosphorylation and other tauopathy-related pathological events in the brain. This bispecific construct exhibits strong specificity towards Tau and enhanced plasma stability in comparison to linear Tau aptamer. In vivo administration of circular Tau-TfR aptamer results in a rapid uptake into relevant brain regions after crossing the BBB, such as hippocampus and cortex. A Y-shaped trispecific aptamer including one aptamer for L1CAM, one aptamer for Tau and one aptamer for TfR reported here has enhanced BBB and neuron cell membrane permeation. Bispecific and trispecific Tau aptamer coupled to a signaling moiety (such as dodecane tetraacetic acid (DOTA) or DOTA complexed to Gd+3) for neuroimaging, and bispecific or trispecific Tau aptamer coupled to protein aggregate binding moiety (such as methylene blue) for enhanced ability to disrupt tau aggregation are also contemplated in this invention.

The present disclosure relates to methods of administering, subcutaneously, to a subject, multimeric oligonucleotides having monomeric subunits joined by covalent linkers. The multimeric oligonucleotides have a molecular weight and/or size configured to increase in vivo activity of one or more subunits within the multimeric oligonucleotide relative to in vivo activity of the same subunit when administered in monomeric form of at least about 45 kD and other characteristics, such that their clearance due to glomerular filtration is reduced. The present disclosure also relates to such multimeric oligonucleotides and methods of synthesizing such multimeric oligonucleotides.

Disclosed herein is the use of DNA aptamer assemblies of varying DNA length, structure, and sequence to both bind to collagen and other proteins, to then act as a biocompatible, degradable, reversible, or permanent 3D crosslinkers between proteins, and to service as a biologically functional material when using the appropriate aptamer sequence. Therefore, disclosed herein are compositions comprising collagen fibers crosslinked with DNA aptamers. Also disclosed are devices and implants made from or coated with collagen fibers crosslinked with DNA aptamers. Also disclosed are methods of making collagen fibers. Also disclosed are kits for producing collagen fibers. Also disclosed herein are compositions DNA aptamers in a collagen fiber matrix that stabilizes the DNA aptamer.

The present invention relates to a multi-conjugate of small interfering RNA (siRNA) and a preparing method of the same, more precisely a multi-conjugate of siRNA prepared by direct binding of double stranded sense/antisense siRNA monomers or indirect covalent bonding mediated by a cross-linking agent or a polymer, and a preparing method of the same. The preparing method of a siRNA multi-conjugate of the present invention is characterized by simple and efficient reaction and thereby the prepared siRNA multi-conjugate of the present invention has high molecular weight multiple times the conventional siRNA, so that it has high negative charge density, suggesting that it has excellent ionic interaction with a cationic gene carrier and high gene delivery efficiency.

The present disclosure relates to miRNA expression constructs, such as for expression of multiple miRNAs and use thereof to knockdown target gene expression. In some aspects, the expression constructs include a promoter element, a spacer sequence and a miRNA coding sequence. In some aspects, constructs provide enhanced immune cell function.

Compositions and methods for treatment of a respiratory infection by a virus are disclosed herein. In some embodiments, the composition comprises pulmonary administration of a plasmid encoding a GM-CSF sequence and a bifunctional shRNA capable of inhibiting furin expression. In some embodiments, the virus is SARS-CoV-2.

The present disclosure relates to multimeric oligonucleotides comprising subunits, each of the subunits independently comprises a single-stranded or double-stranded oligonucleotide. Each of the subunits is joined to another subunit by a covalent linker, and at least one subunit comprises at least one partial single-stranded oligonucleotide. The present disclosure also relates to methods of synthesizing the multimeric oligonucleotides and the methods of using the multimeric oligonucleotides disclosed herein.

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 is related to the field of cardiovascular thrombosis. In particular, compositions and methods that modulate gene regulation of cardiovascular thrombosis. For example, such gene regulation may be controlled by modulating microRNA binding. The present invention contemplates inhibitor compounds, such as antisense inhibitors, that compete with miRNA binding to specific gene regulatory sites on the SERPINC1 gene.

Described herein are methods and compositions of combinations of microRNAs that enhance the sensitivity of cancer cells to chemotherapeutic agents or reduce proliferation of cancer cells. Also described herein are methods for the identification of combinations of microRNAs that result in desired effects.