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

The present invention concerns methods and reagents useful in modulating gene expression in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Specifically, the invention relates to synthetic chemically modified small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi) against target nucleic acid sequences. The small nucleic acid molecules are useful in the treatment of any disease or condition that responds to modulation of gene expression or activity in a cell, tissue, or organism.

A method of generating neural stem cells or motor neurons is disclosed, the method comprising up-regulating a level of at least one exogenous miRNA and/or down-regulating at least one miRNA using an agent which hybridizes to the miRNA in mesenchymal stem cells (MSCs) or down-regulating Related to testis-specific, vespid and pathogenesis protein 1 (RTVP-1).

A method for screening interfering nucleic acids enhancing the expression or the activity of expressed gene sequences is described. The method includes a step of introducing, into a cell, a hybrid nucleic acid molecule having: a first non-coding sequence intended to initiate translation; a second sequence complementary to the interfering nucleic acids to be screened; and, optionally, a third nucleotide sequence encoding at least one pre-determined peptide, the first sequence being modified such that the translation level of the at least one peptide is reduced by at least 10%.

RNAi constructs directed to MAP4K4 that demonstrate unexpectedly high gene silencing activities, and uses thereof are disclosed. The blunt-ended constructs have a double-stranded region of 19-49 nucleotides. The constructs have selective minimal modifications to confer an optimal balance of biological activity, toxicity, stability, and target gene specificity. For example, the strands may be modified (e.g., one or both ends of the sense strand is modified by 2′-O-methyl groups), such that the construct is not cleaved by Dicer or other RNAse III, the antisense strand may also be modified by a 2′-O-methyl group at the penultimate 5′-end nucleotide to greatly reduce off-target silencing.

The invention relates to a method of identifying or producing an aptamer, and a reagent comprising a nucleic acid ligand capable of binding a target sample, wherein the nucleic acid ligand comprises at least one nucleobase modified to contain an azide-alkyne chemical group.

The oligonucleotide compositions of the present invention make use of combinations of oligonucleotides. In one aspect, the invention features an oligonucleotide composition including at least 2 different oligonucleotides targeted to a target gene. This invention also provides methods of inhibiting protein synthesis in a cell and methods of identifying oligonucleotide compositions that inhibit synthesis of a protein in a cell.

Efficient sequence specific gene silencing is possible through the use of siRNA technology. By selecting particular siRNAs by rational design, one can maximize the generation of an effective gene silencing reagent, as well as methods for silencing genes. Methods, compositions, and kits generated through rational design of siRNAs are disclosed including those directed to nucleotide sequences for TTR.

The present invention relates to RNAi constructs for reducing expression of the MARC1 gene. Methods of using such RNAi constructs to treat or prevent liver fibrosis and fatty liver diseases, such as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, are also described.

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