The invention relates to iRNA, e.g., double stranded ribonucleic acid (dsRNA), compositions targeting the complement component C5 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of C5 and to treat subjects having a complement component C5-associated disease, e.g., paroxysmal nocturnal hemoglobinuria.

Compositions and methods for enhancing targeted gene editing and methods of use thereof are disclosed. In the most preferred embodiments, gene editing is carried out utilizing a gene editing composition such as triplex-forming oligonucleotides, CRISPR, zinc finger nucleases, TALENS, or others, in combination with a gene modification potentiating agent such as stem cell factor (SCF), a CHK1 or ATR inhibitor, or a combination thereof. A particular preferred gene editing composition is triplex-forming peptide nucleic acids (PNAs) substituted at the γ position for increased DNA binding affinity. Nanoparticle compositions for intracellular delivery of the gene editing composition are also provided and particular advantageous for use with in vivo applications.

This invention relates generally to pharmaceutical compositions and preparations of circular polyribonucleotides and uses thereof.

The invention relates to a method of treating a cardiovascular disease, such as heart failure, in a subject in need comprising the step of administering an inhibitor of bZIP repressor or an activator of p38 or a combination thereof to a subject in need thereby treating the cardiovascular disease. The inhibitor to bZIP repressor is: an inhibitor of ATF3; an inhibitor of JDP2; a co-inhibitor to both ATF3 and JDP2; or a combination of an inhibitor of ATF3 and an inhibitor of JDP2.

Disclosed herein are methods and agents for the treatment of cancer using p53-independent apoptosis to reduce the number of cancer cells that have an amplified HER2 gene, such as p53-depleted or p53-mutated cancer cells that have an amplified HER2 gene. Also disclosed herein are methods and agents for the treatment of HER2-positive cancer in individuals with Li-Fraumeni Syndrome.

A method of reducing the level of a transcription product in a cell comprising contacting with the cell a composition comprising a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, wherein: (i) the first nucleic acid strand hybridizes to the transcription product and comprises (a) a region consisting of at least 4 consecutive nucleotides that are recognized by RNase H when the strand is hybridized to the transcription product, (b) one or more nucleotide analogs located on 5′ terminal side of the region, (c) one or more nucleotide analogs located on 3′ terminal side of the region and (d) a total number of nucleotides and nucleotide analogs ranging from 8 to 35 nucleotides and (ii) the second nucleic acid strand comprises (a) nucleotides and optionally nucleotide analogs and (b) at least 4 consecutive RNA nucleotides.

The invention relates to iRNA, e.g., double stranded ribonucleic acid (dsRNA), compositions targeting the complement component C5 gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of C5 and to treat subjects having a complement component C5-associated disease, e.g., paroxysmal nocturnal hemoglobinuria.

Provided herein are tools for understanding and engineering dynamics of synthetic genetic circuits which utilize CRISPR components. More particularly, methods, systems, and compositions for directing Cas9 activity using a fluorescent guide RNA (fgR-NA) which fluoresces in the presence of small molecules (e.g., DFHBI-IT) are described and illustrated in the present provisional application.

A circular RNA molecule generally includes at least one coding region and an internal ribosome entry site (IRES) operably linked to the coding region. The RNA may be more resistant to digestion by an RNA endonuclease that a linear form of the circular RNA. In another aspect, a polynucleotide generally includes a transcription unit and a promoter operably linked to the transcription unit. The transcription unit includes a circularizing element, at least one coding region and an internal ribosome entry site (IRES) operably linked to the coding region. When transcribed by a cell, the transcribed RNA forms a circular RNA molecule.

Disclosed herein are methods and agents for the treatment of cancer using p53-independent apoptosis to reduce the number of p53-depleted or p53-mutated cancer cells that have amplified HER2 gene. Also disclosed herein are methods and agents for the treatment of HER2-positive cancer in individuals with Li-Fraumeni Syndrome.