The invention provides a single-stranded oligonucleotide represented by the formula [Xz-Lx].sub.m-X-Y-[Ly-Yz].sub.n, wherein X is represented by Xa-Xb, Xa is coupled with Y, and Xb and Y hybridize. Xa is composed of 1 to 40 nucleotides and contains at least one modified-nucleotide. Xb is composed of 4 to 40 nucleotides and contains at least one modified-nucleotide. Y is composed of 4 to 40 nucleotides and contains at least one ribonucleotide. Xz and Yz are composed of 5 to 40 nucleotides and contain at least one modified-nucleotide. Nucleotide sequences X, Xz and Yz have an antisense sequence capable of hybridizing with a target RNA. Lx and Ly are composed of 0 to 20 nucleotides.

The invention provides a single-stranded oligonucleotide represented by the formula [Xz-Lx].sub.m-X-Y-[Ly-Yz].sub.n, wherein X is represented by Xa-Xb, Xa is coupled with Y, and Xb and Y hybridize. Xa is composed of 1 to 40 nucleotides and contains at least one modified-nucleotide. Xb is composed of 4 to 40 nucleotides and contains at least one modified-nucleotide. Y is composed of 4 to 40 nucleotides and contains at least one ribonucleotide. Xz and Yz are composed of 5 to 40 nucleotides and contain at least one modified-nucleotide. Nucleotide sequences X, Xz and Yz have an antisense sequence capable of hybridizing with a target RNA. Lx and Ly are composed of 0 to 20 nucleotides.

Oligonucleotides are provided herein that inhibit NR1H3 expression. Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders and/or conditions associated with NR1H3 expression.

The present invention relates to antisense oligonucleotides that modulate the expression of and/or function of Tumor Suppressor genes, in particular, by targeting natural antisense polynucleotides of Tumor Suppressor genes. The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of Tumor Suppressor genes.

Molecules are provided for inducing or facilitating exon skipping in forming spliced mRNA products from pre-mRNA molecules in cells. The molecules may be provided directly as oligonucleotides or expression products of vectors that are administered to a subject. High rates of skipping can be achieved. High rates of skipping reduce the severity of a disease like Duchene Muscular Dystrophy so that the disease is more like Becker Muscular Dystrophy. This is a severe reduction in symptom severity and mortality.

Provided herein are methods and compositions for inhibiting p97, for the treatment of a motor neuron disease in a subject, or a symptom thereof. Upon treatment, the motor neuron disease, or a symptom thereof is reduced in the subject.

Disclosed herein are methods for decreasing AlAT mRNA and protein expression and treating, ameliorating, preventing, slowing progression, or stopping progression of fibrosis. Disclosed herein are methods for decreasing A1AT mRNA and protein expression and treating, ameliorating, preventing, slowing progression, or stopping progression of liver disease, such as, A1ATD associated liver disease, and pulmonary disease, such as, A1ATD associated pulmonary disease in an individual in need thereof. Methods for inhibiting AlAT mRNA and protein expression can also be used as a prophylactic treatment to prevent individuals at risk for developing a liver disease, such as, A1ATD associated liver disease and pulmonary disease, such as, A1ATD associated pulmonary disease.

The present disclosure provides a DNA-targeting RNA that comprises a targeting sequence and, together with a modifying polypeptide, provides for site-specific modification of a target DNA and/or a polypeptide associated with the target DNA. The present disclosure further provides site-specific modifying polypeptides. The present disclosure further provides methods of site-specific modification of a target DNA and/or a polypeptide associated with the target DNA The present disclosure provides methods of modulating transcription of a target nucleic acid in a target cell, generally involving contacting the target nucleic acid with an enzymatically inactive Cas9 polypeptide and a DNA-targeting RNA. Kits and compositions for carrying out the methods are also provided. The present disclosure provides genetically modified cells that produce Cas9; and Cas9 transgenic non-human multicellular organisms.

The invention relates to antisense molecules and methods for modulating splicing of polyomavirus T antigen pre-mRNA. In one aspect the invention relates to an antisense oligonucleotide 12 to 30, preferably 17, 18, 19 or 20 to 30 nucleobases in length which comprises a sequence that is the reverse complement of a contiguous stretch of at least 12 nucleobases of a polyomavirus T-antigen pre-mRNA and which antisense oligonucleotide can modulate splicing of said T-antigen pre-mRNA in a cell.

Disclosed herein are methods for inhibiting or activating the transcription of a gene of interest, or inhibiting or activating the transcription of specific mRNA isoforms of a gene by using antisense oligonucleotides and/or small molecules. Also described herein are methods for activating transcription from a promoter and increasing overall gene expression by creating of a new splice site in a gene of a cell.