In vivo gene silencing by chemically modified and stable sirna

C - Chemistry – Metallurgy – 07 – H

Patent

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Details

C07H 21/04 (2006.01) C07D 213/69 (2006.01) C12N 15/11 (2006.01) C12N 15/85 (2006.01) C12N 15/86 (2006.01) C12P 19/34 (2006.01) A61K 38/00 (2006.01) A61K 48/00 (2006.01)

Patent

CA 2500224

The present invention provides compositions for RNA interference and methods of use thereof. In particular, the invention provides small interfering RNAs (siRNAs) having modification that enhance the stability of the siRNA without a concomitant loss in the ability of the siRNA to participate in RNA interference (RNAi). The invention also provides siRNAs having modification that increase targeting efficiency. Modifications include chemical crosslinking between the two complementary strands of an siRNA and chemical modification of a 3' terminus of a strand of an siRNA. Preferred modifications are internal modifications, for example, sugar modification, nucleobase modification and/or backbone modifications. Such modifications are also useful, e.g., to improve uptake of the siRNA by a cell. Functional and genomic and proteomic methods are featured. Therapeutic methods are also featured.

La présente invention concerne des compositions d'interférence d'ARN ainsi que des procédés d'utilisation associés. Cette invention concerne en particulier des petits ARN interférants (siARN) présentant une modification qui renforce la stabilité du siARN sans entraîner la perte concomitante de l'aptitude du siARN à intervenir dans l'interférence d'ARN (RNAi). Cette invention concerne également des siARN présentant une modification qui accroît l'efficacité du ciblage. Parmi ces modifications figurent la réticulation chimique entre les deux brins complémentaires d'un siARN et la modification chimique d'une extrémité 3' d'un brin d'un siARN. Les modifications préférées de cette invention sont des modifications internes, telles qu'une modification des glucides, une modification des nucléobases et/ou des modifications du squelette. Ces modifications sont également utilisées, par exemple, pour améliorer l'absorption du siARN par une cellule. Cette invention concerne également des procédés fonctionnels, génomiques et protéomiques ainsi que des méthodes thérapeutiques.

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