This invention relates to interfering RNA (iRNA) molecules and their applications, especially multi-targets iRNA molecules and their applications. The said multi-targets iRNA molecules comprised of a sense strand annealed onto at least one antisense strand, each strand is at least 30 nucleotides in length, the sense or antisense strand has at least two segments, which can target at least two RNAs of different genes, or can target at least two portions of an RNA, and wherein the iRNA does not induce an interferon-response when transfected into a cell. The iRNA molecule can interfere with the translation procedure post-transcription, and the target gene is inhibited or blocked, the iRNA does not induce an interferon-response in vivo. The RNA molecules are the active ingredient in preparation of the drug which can regulate one or many genes function.

This disclosure relates to novel huntingtin targets. Novel oligonucleotides for the treatment of Huntington's disease are also provided.

Oligonucleotide constructs are described, each comprising a functional element and a coding element, wherein the functional element comprises a functional sequence, the functional sequence comprising a sequence of nucleotides in which one or more, or each, nucleotide is modified and the coding element comprises a coding sequence, the coding sequence comprising a sequence of nucleotides which do not contain the modifications of the functional sequence, wherein the coding sequence encodes the sequence structure of the functional sequence.

Provided herein are branched oligonucleotides exhibiting efficient and specific tissue distribution, cellular uptake, minimum immune response and off-target effects, without formulation.

This disclosure relates to novel huntingtin targets. Novel oligonucleotides for the treatment of Huntington's disease are also provided.

Double stranded RNAi agents for inhibiting PCSK9 gene expression are provided. Complexes in which the siRNA agents are covalently conjugated to a peptide docking vehicle (PDoV), and further covalently linked to one or more targeting ligands also are provided. Pharmaceutical compositions containing the RNAi agents and complexes are provided, together with methods for their use.

Provided herein are methods, compounds, and compositions for reducing expression of transthyretin mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate transthyretin amyloidosis, or a symptom thereof.

Microglia are an essential part of the immune system in the central nervous system, as well as potential sources of disease. Gene silencing employs short interfering RNA (siRNA) to selectively target genes that are the source of such diseases. By employing branched siRNA, distribution of the siRNA throughout the CNS, including to the resident microglial cells, may be enhanced as compared to unbranched siRNA. Methods and compositions for the use of branched siRNA in a therapy are contained herein.

Novel oligonucleotides that enhance silencing of the expression of a gene containing a single nucleotide polymorphism (SNP) relative to the expression of the corresponding wild-type gene are provided. Methods of using novel oligonucleotides that enhance silencing of the expression of a gene containing a SNP relative to the expression of the corresponding wild-type gene are provided.

The instant invention provides RNA nanoparticles and R/DNA chimeric nanoparticles comprising one or more functionalities. The multifunctional RNA nanoparticles are suitable for therapeutic or diagnostic use in a number of diseases or disorders.