The present invention relates to oligonucleotides that upregulate or restore the expression of progranulin in cells by targeting the promoter region of the progranulin gene. The invention further relates to pharmaceutical compositions and methods for the treatment of diseases associated with progranulin, specifically progranulin haploinsufficiency and neurological disorders.

The present invention provides refillable drug delivery systems, as well as methods of refilling the systems, and methods of using them to treat diseases.

Disclosed herein are antisense compounds and methods for decreasing LDL-C in an individual having elevated LDL-C. Additionally disclosed are antisense compounds and methods for treating, preventing, or ameliorating hypercholesterolemia and/or atherosclerosis. Further disclosed are antisense compounds and methods for decreasing coronary heart disease risk. Such methods include administering to an individual in need of treatment an antisense compound targeted to a PCSK9 nucleic acid. The antisense compounds administered include gapmer antisense oligonucleotides.

The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of gene expression and/or activity, and/or modulate a gene expression pathway. Specifically, the invention relates to double-stranded nucleic acid molecules including small nucleic acid molecules, such as short interfering nucleic acid (siNA) molecules that are capable of mediating or that mediate RNA interference (RNAi) against target gene expression.

Provided is a single-stranded oligonucleotide that is capable of controlling a target gene with high efficiency and can be easily produced. The single-stranded oligonucleotide is represented by the formula X-L-Y wherein X and Y hybridize by a first nucleotide sequence portion and a second nucleotide sequence portion. X is composed of 7 to 100 nucleotides, contains at least one modified nucleotide, and has a first nucleotide sequence that is capable of hybridizing with a second oligonucleotide and contains at least four contiguous nucleotides recognized by RNase H. Y is composed of 4 to 100 nucleotides, and has a second nucleotide sequence that is capable of hybridizing with a second oligonucleotide and contains at least one ribonucleotide. At least one of nucleotide sequence X and nucleotide sequence Y has an antisense sequence capable of hybridizing with a target RNA. L is a group derived from a third oligonucleotide that is degraded under physiological conditions.

Provided are a siRNA for inhibiting the expression of hepatitis B virus gene, and a pharmaceutical composition and conjugate containing the siRNA. Each nucleotide in the siRNA is independently a modified nucleotide. The siRNA comprises a sense strand and an antisense strand. The sense strand of the siRNA comprises a nucleotide sequence 1 having the same length and no more than three nucleotides different from the nucleotide sequence shown in SEQ ID NO: 155, and the antisense strand of the siRNA comprises a nucleotide sequence 2 having the same length and no more than three nucleotides different from the nucleotide sequence shown in SEQ ID NO: 156.

Described are RNAi agents, compositions that include RNAi agents, and methods for inhibition of a Receptor for Advanced Glycation End-products (AGER or RAGE) gene. The RAGE RNAi agents and RNAi agent conjugates disclosed herein inhibit the expression of an AGER gene. Pharmaceutical compositions that include one or more RAGE RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the described RAGE RNAi agents to pulmonary cells, in vivo, provides for inhibition of AGER gene expression and a reduction in membrane RAGE activity, which can provide a therapeutic benefit to subjects, including human subjects, for the treatment of various diseases including pulmonary inflammation diseases such as severe asthma.

The present invention provides oligonucleotides comprising 2′-O-methyl (2′-OMe) and 2′-deoxy-2′-fluoro (2′-F) modifications, compositions thereof, and methods of use for reducing the expression or activity of a gene.

siRNA compositions are provided that contain gemcitabine (GEM) in place of cytosine moieties within the siRNA sequence. Pharmaceuticals compositions containing these siRNA molecules, and methods of using the compositions for treating diseases such as cancer are provided.

Provided herein are certain nucleic acids (e.g., double stranded siRNA molecules), as well as conjugates that comprise a targeting moiety, a double stranded siRNA, and optional linking groups. Certain embodiments also provide synthetic methods useful for preparing the conjugates. The conjugates are useful to treat certain diseases, such as liver fibrosis, e.g., in the setting of NASH or ASH.