The present invention relates to composition comprising an inhibitor of miR-379 or a portion or fragment thereof and an inhibitor of miR-541 or a portion or fragment thereof, and/or an inhibitor of the target site of miR-379 or a portion or fragment thereof and an inhibitor of the target site of miR-541 or a portion or fragment thereof, and/or a combination of an inhibitor of miR-379 or a portion or fragment thereof and an inhibitor of the target site of miR-541 or a portion or fragment thereof or a combination of an inhibitor of the target site of miR-379 or a portion or fragment thereof and an inhibitor of miR-541 or a portion or fragment thereof. The present invention also relates to the respective composition for use in treating or preventing a metabolic disease, a disease related to a metabolic disorder, and/or cancer.

Disclosed herein are methods to treat a neurodegenerative disease comprising administering to a subject with a neurodegenerative disease a therapeutically effective amount of a polynucleotide that binds a nucleic acid-binding polypeptide, wherein the nucleic acid-binding polypeptide can aggregate in cells and is associated with a neurodegenerative disease. Also disclosed are methods to inhibit protein aggregation in a cell comprising contacting the cell with a composition comprising a polynucleotide that binds a nucleic acid-binding polypeptide, wherein the nucleic acid-binding polypeptide can aggregate in cells and is associated with a neurodegenerative disease. Additionally disclosed are compositions comprising a polynucleotide that binds a nucleic acid-binding polypeptide, wherein the nucleic acid-binding polypeptide can aggregate in cells and is associated with a neurodegenerative disease.

Disclosed herein are methods of treating neurodevelopmental disorders such as schizophrenia (SCZ), bipolar disorder or depression. The methods entail inhibiting expression of miR-219 or overexpressing TLX thereby promoting proliferation of neural stem cells (NSCs) in the subjects.

The invention provides methods and pharmaceutical compositions for treating a metabolic disease in a subject. In some aspects, the invention comprises administering to the subject a therapeutically effective amount of a miR-22 inhibitor. In some embodiments, the invention further comprises administering to the subject a metabolism-enhancing agent such as a miR-22 inducer.

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.

Some embodiments of the invention include a nucleic acid molecule comprising natural nucleotides, non-natural nucleotides, an LNA which comprises one or more RNA core molecules, or an RNA molecule which comprises more than one RNA core molecule. Some embodiments of the invention include a nucleic acid molecule comprising an RNA molecule which comprises more than one RNA core molecule. Other embodiments of the invention include a nucleic acid molecule comprising a DNA molecule encoding the RNA molecule (e.g., vector or viral vector). Other embodiments include compositions or pharmaceutical compositions that comprise the nucleic acid molecule. Some embodiments of the invention comprise reducing miR-143 in a cell. Other embodiments of the invention include methods to deliver a protein across the BBB. Other embodiments include methods for treating disease (e.g., LSD, neuronopathic disease, neurodegenerative disease, Hurler syndrome, or MPS I). Additional embodiments of the invention are also discussed herein.

The disclosure in some aspects, relates to nucleic acids, compositions and kits useful for gene therapy with reduced immune response to transgene products.

The disclosure in some aspects, relates to nucleic acids, compositions and kits useful for gene therapy with reduced immune response to transgene products.

Described herein are compositions that inhibit/degrade STAT3, and methods of using such compositions for chemoprevention of non-small cell lung cancer (NSCLC).

The present invention is related to a ribonucleic acid comprising a double stranded structure whereby the double-stranded structure comprises a first strand and a second strand, whereby the first strand comprises a first stretch of contiguous nucleotides and whereby said first stretch is at least partially complementary to a target nucleic acid, and the second strand comprises a second stretch of contiguous nucleotides whereby said second stretch is at least partially identical to a target nucleic acid, and whereby the double stranded structure is blunt ended.