MODIFIED RNA AGENTS WITH REDUCED OFF-TARGET EFFECT

Abstract: one aspect of the present invention relates to double-stranded rna (dsrna) agent capable of inhibiting the expression of a target gene. the antisense strand of the dsrna molecule comprises at least one thermally destabilizing nucleotide occurring at a seed region; the dsrna comprises at least four 2′-fluoro modifications, and the sense strand of the dsrna molecule comprises ligand, wherein the ligand is an asgpr ligand. other aspects of the invention relate to pharmaceutical compositions comprising these dsrna molecules suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsrna molecules, e.g., for the treatment of various disease conditions.

Inventor(s): Mark K. SCHLEGEL, Maja JANAS, Vasant R. JADHAV, Muthiah MANOHARAN, Kallanthottathil G. RAJEEV, Muthusamy JAYARAMAN, Alexander V. KEL'IN, Shigeo MATSUDA, Klaus CHARISSE, Jayaprakash K. NAIR, Martin A. MAIER, Alfica SEHGAL, Christopher BROWN, Christopher THEILE, Stuart MILSTEIN

CPC Classification: A61K31/713 (PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms ; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles ; soap compositions ))

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