Abstract: The present invention includes compositions and methods for making and using a RNAi capable of reducing expression of two or more genes, comprising: a first RNAi molecule that reduces the expression of a first target gene; a second RNAi molecule that reduces the expression of the first or a second target gene; and optionally a third RNAi molecule that reduces the expression of the first, the second, or a third target gene, wherein the RNAi molecules reduce the expression level of, e.g., mutated KRAS, SRC-3, EGFR, PIK3, NCOA3, or ERalpha1, and can be, e.g., miRNAs, shRNAs, or bifunctional shRNAs.

Abstract: The present invention relates to certain novel shRNA molecules and methods of use thereof. According to certain embodiments of the present invention, methods for reducing the expression level of a target gene are provided. Such methods generally comprise providing a cell with one or more precursor nucleic acid sequences that encode two or more RNA molecules. A first RNA molecule comprises a double stranded sequence, which includes a guide strand sequence that is complementary to a portion of an mRNA transcript encoded by the target gene. In addition, a second RNA molecule comprises a second double stranded sequence, which includes a second guide strand sequence that is partially complementary to a portion of the mRNA transcript encoded by the target gene. Preferably, the second guide strand sequence comprises one or more bases that are mismatched with a nucleic acid sequence of the mRNA transcript encoded by the target gene.

Abstract: The present invention includes compositions and methods for making and using a bifunctional shRNAs capable of reducing an expression of a K-ras gene, e.g., a mutated K-ras gene, wherein at least one target site sequence of the bifunctional RNA molecule is located within the K-ras gene and wherein the bifunctional RNA molecule is capable of activating a cleavage-dependent and a cleavage-independent RNA-induced silencing complex for reducing the expression level of K-ras.

Abstract: A method for designing a bi-shRNA expression cassette encoding a bi-shRNA comprising: selecting one or more target site sequences; providing a backbone sequence comprising a first and a second stem-loop structure, inserting a first passenger strand and a second passenger strand and providing for synthesis of the bi-shRNA expression cassette.

Abstract: According to certain embodiments of the present invention, methods for modulating the production of sialic acid in a system are provided, which comprise providing the system with a wild-type GNE-encoding nucleic acid sequence. According to such embodiments, the system may comprise a cell, muscular tissue, or other desirable targets. Similarly, the present invention encompasses methods for producing wild-type GNE in a system that comprises a mutated endogenous GNE-encoding sequence. In other words, the present invention includes providing, for example, a cell or muscular tissue that harbors a mutated (defective) GNE-encoding sequence with a functional wild-type GNE encoding sequence.

Abstract: Compositions and methods for tissue-specific targeted delivery of therapeutic agents through the use of tissue-specific peptidomimetic ligands are disclosed herein. The ligand comprises a composition of formula A-scaffold-A? and one or more hydrophobic anchors covalently linked to the scaffold. The A and A? compounds linked to the scaffold comprise monovalent peptidomimetic compounds wherein each monovalent peptidomimetic compound is selected from the group consisting of fragments IKs, GKs, IDs, GSs, GTs, VSs, TKs, KTs, ARs, KIs, KEs, AEs, GRs, YSs, IRs, and morpholino.

Abstract: A bifunctional shRNA-based composition and methods for knocking down the expression of the PDX-1 oncogene in target cells is described herein. The invention also provides methods to deliver the shRNA-containing expression vectors to target tissues overexpressing the PDX-1 oncogene.