Arrowhead Pharmaceuticals, Inc.

Arrowhead Madison, Inc.

Jonathan D Benson

David B Rozema

Andrei V Blokhin

Darren H Wakefield

Jeffrey Carlson

David L Lewis

Aaron Almeida

Jon Asher Wolff

Peter Mohr

Philipp Hadwiger

Torsten Hoffmann

Eric Argirios Kitas

Hans Martin Mueller

Steven B Kanner

Zhen Li

Lauren Almeida

Ingo Roehl

So Wong

Anthony Nicholas

Weijun Cheng

Kerstin Jahn-Hofmann

Guenther Ott

Justin Woods

Jeffrey C Carlson

Tao Pei

Fred J Fleitz

Eric A Kitas

Rui Zhu

Erik W Bush

Matthew Fowler-Watters

Xiaokai Li

Ingo Röhl

Patrick Shao

Dongxu Shu

Günther Ott

Torsten Hoffman

Kerstin Jahn-Hoffmann

Jon A Wolff

Anthony L Nicholas

Weijun Chen

Lauren J Almeida

Described are novel targeting ligands that may be linked to compounds, such therapeutic compounds, that are useful in directing the compounds to the target in vivo. The targeting ligands disclosed herein can serve to target expression-inhibiting oligomeric compounds, such as RNAi agents, to liver cells to modulate gene expression. The targeting ligands disclosed herein, when conjugated to an expression-inhibiting oligomeric compound, may be used in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Compositions including the targeting ligands disclosed herein when linked to expression-inhibiting oligomeric compounds are capable of mediating expression of target nucleic acid sequences in liver cells, such as hepatocytes, which may be useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.

Targeting ligands for therapeutic compounds

RNA interference (RNAi) triggers and RNAi trigger conjugates for inhibiting the expression of Hif2&#x3b1; (EPAS1) gene are described. Pharmaceutical compositions comprising one or more Hif2&#x3b1; RNAi triggers optionally with one or more additional therapeutics are also described. Delivery of the described Hif2&#x3b1; RNAi triggers to tumor cells in vivo provides for inhibition of Hif2&#x3b1; gene expression and treatment of cancer.

Compositions and methods for inhibiting gene expression of Hif2alpha

Synthetic &#x3b1;v&#x3b2;6 integrin ligands of Formula I having serum stability and affinity for integrin &#x3b1;v&#x3b2;6, which is a receptor expressed in a variety of cell types, are described. The described ligands are useful for delivering cargo molecules, such as RNAi agents or other oligonucleotide-based compounds, to cells that express integrin &#x3b1;v&#x3b2;6, and thereby facilitating the uptake of the cargo molecules into these cells. Compositions that include &#x3b1;v&#x3b2;6 integrin ligands and methods of use are also described. 

Integrin ligands and uses thereof

We describe anhydride compounds suitable for physiologically labile modification of amine-containing molecules. The described anhydrides form reversible linkages having desirable kinetics for in vivo delivery of biologically active molecules. Also described are endosomolytic polymers formed by modification of membrane active polyamines with the described anhydrides.

Disubstituted maleic anhydrides with altered kinetics of ring closure

Described are improved disulfide-containing alkyne linking agents having have branched disulfides. The improved linking agents exhibit improved stability. The linking agents are useful for attachment of oligonucleotides to targeting groups or delivery agents.

Disulfide-containing alkyne linking agents

The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted melittin delivery peptides. Delivery peptides provide membrane penetration function for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery peptides.

Peptide-based in vivo siRNA delivery system

The present invention is directed compositions for delivery of RNA interference (RNAi) polynucleotides to cells in vivo. The compositions comprise amphipathic membrane active polyamines reversibly modified with enzyme cleavable dipeptide-amidobenzyl-carbonate masking agents. Modification masks membrane activity of the polymer while reversibility provides physiological responsiveness. The reversibly modified polyamines (dynamic polyconjugate or DPC) are further covalently linked to an RNAi polynucleotide or co-administered with a targeted RNAi polynucleotide-targeting molecule conjugate.

In vivo polynucleotide delivery conjugates having enzyme sensitive linkages

Growing community of inventors

Stoughton, WI, United States of America

Jonathan D Benson