Arrowhead Pharmaceuticals, Inc.

Mirus Bio Corporation

Arrowhead Madison, Inc.

Roche Madison Inc.

Mirus Corporation

F. Hoffmann-la Roche Ag

So Wong

Darren H Wakefield

Jon Asher Wolff

David B Rozema

James E Hagstrom

Steven B Kanner

Jason Klein

David L Lewis

Zhen Li

Jeffrey Carlson

Rui Zhu

Vladimir G Budker

Vladimir S Trubetskoy

Andrei V Blokhin

Anthony Nicholas

Aaron Almeida

Weijun Cheng

Sean D Monahan

Tao Pei

Lauren Almeida

Jonathan D Benson

Justin Woods

Lori Higgs

Alexander V Sokoloff

James Ludtke

Magdolna G Sebestyén

Xiaokai Li

Matthew Fowler-Watters

Erich Altenhofer

Dongxu Shu

Bo Chen

Aaron M Almeida

Andrei Blokhin

Vladimir Trubetskoy

Hans Herweijer

Jeffrey C Carlson

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, capable of inhibiting Apolipoprotein C-III (also called APOC3, apoC-III, APOC-III, and APO C-III) gene expression, and compositions that include APOC3 RNAi agents. The APOC3 RNAi agents disclosed herein may be conjugated to targeting ligands, including ligands that include N-acetyl-galactosamine, to facilitate the delivery to cells, including to hepatocytes. Pharmaceutical compositions that include one or more APOC3 RNAi agents, optionally with one or more additional therapeutics, are also described. Delivery of the APOC3 RNAi agents in vivo provides for inhibition of APOC3 gene expression, and can result in lower triglycerides and/or cholesterol levels in the subject. The APOC3 RNAi agents can be used in methods of treatment of APOC3-related diseases and disorders, including hypertriglyceridemia, cardiovascular disease, and other metabolic-related disorders and diseases.

RNAi agents and compositions for inhibiting expression of apolipoprotein C-III (APOC3)

The present disclosure relates to RNAi agents, for example, double stranded RNAi agents, able to inhibit HIF-2 alpha (EPAS1) gene expression. Also disclosed are pharmaceutical compositions that include HIF-2 alpha RNAi agents and methods of use thereof. The HIF-2 alpha RNAi agents disclosed herein may be linked or conjugated to targeting ligands (such as compounds that have affinity for integrins, including alpha-v-beta-3 and alpha-v-beta-5 integrins) and pharmacokinetic (PK) enhancers, to facilitate the delivery to cells and tissues, including to clear cell renal cell carcinoma (ccRCC) cells and tumors. Delivery of compositions comprising the HIF-2 alpha RNAi agents in vivo provides for inhibition of HIF-2 alpha gene expression. The HIF-2 alpha RNAi agents can be used in methods of treatment of various diseases and disorders, including ccRCC.

RNAi agents for inhibiting expression of HIF-2 alpha (), compositions thereof, and methods of use

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

The present disclosure relates to RNAi agents, e.g., double stranded RNAi agents, able to inhibit Angiopoietin-like 3 (also called ANGPTL3, ANGPL3, angiopoietin-like protein 3) gene expression, and compositions that include ANGPTL3 RNAi agents. Also disclosed are methods of use of ANGPTL3 RNAi agents and compositions. The ANGPTL3 RNAi agents disclosed herein may be conjugated to targeting ligands to facilitate the delivery to cells, including to hepatocytes. Pharmaceutical compositions that include one or more ANGPTL3 RNAi agents, optionally with one or more additional therapeutics, are described. Delivery of the ANGPTL3 RNAi agents in vivo provides for inhibition of ANGPTL3 gene expression, and can result in lower triglycerides and/or cholesterol levels in the subject. The RNAi agents can be used in methods of treatment of ANGPTL3-related diseases and disorders, including cardiometabolic diseases such as hypertriglyceridemia and hyperlipidemia.

RNAi agents and compositions for inhibiting expression of angiopoietin-like 3 (ANGPTL3), and methods of use

The present invention is directed compositions for delivery of RNA interference (RNAi) triggers to integrin positive tumor cells in vivo. The compositions comprise RGD ligand-targeted 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 conjugate) are further covalently linked to an RNAi trigger.

Polyconjugates for delivery of RNAi triggers to tumor cells in vivo

The present invention is directed to compounds, compositions, and methods useful for delivering polynucleotides or other cell-impermeable molecules to mammalian cells. Described are polyconjugates systems that incorporate targeting, anti-opsonization, anti-aggregation, and transfection activities into small biocompatible in vivo delivery vehicles. The use of multiple reversible or labile linkages connecting component parts provides for physiologically responsive activity modulation.

Polyconjugates for in vivo delivery of polynucleotides

The present invention is directed to compounds, compositions, and methods useful for delivering polynucleotides or other cell-impermeable molecules to mammalian cells. Described are polyconjugates systems that incorporate targeting, anti-opsonization, anti-aggregation, and transfection activities into small biocompatible in vivo delivery vehicles. The use of multiple reversible linkages connecting component parts provides for physiologically responsive activity modulation.

We describe compounds that bind to and are internalized by hepatocytes. Association of these compounds to other molecules or complexes can be used to target the molecules or complexes to hepatocytes in vivo or in vitro.

Compounds for targeting hepatocytes

Polyampholyte are able to condense nucleic acid to form small complexes which can be utilized in the delivery of nucleic acid to mammalian cells. The polyampholytes can be formed prior to interaction with nucleic acid or they can be formed in the presence of nucleic acid. Stabilized polycation/nucleic acid complexes can be modified to reduce the positive charge of the polycation and add targeting ligands without destabilizing the complex. The resultant particles retain their small size and are more effective in delivery of nucleic acid to cells in vivo.

Formation of polyampholytes in the presence of a polyion

Compounds for targeting hepatocytes in vivo

Growing community of inventors

Oregon, WI, United States of America

So Wong