Alnylam Pharmaceuticals, Inc.

Isis Pharmaceuticals, Inc.

Arbutus Biopharma Corporation

Tekmira Pharmaceuticals Corporation

Degussa Aktiengesellschaft

Alnylam Pharamaceticals, Inc.

University of British Columbia

Genzyme Corporation

Martin A Maier

Kallanthottathil G Rajeev

Muthiah Manoharan

Stuart Milstein

Klaus Charisse

Vasant R Jadhav

Akin Akinc

Jayaprakash K Nair

Muthusamy Jayaraman

Satyanarayana Kuchimanchi

Kevin Fitzgerald

Brian R Bettencourt

Shigeo Matsuda

Gregory Hinkle

James Butler

Pachamuthu Kandasamy

Donald Foster

Rubina G Parmar

Tracy Stage Zimmermann

Alfica Sehgal

Don Foster

Satya Kuchimanchi

William Querbes

Mark K Schlegel

Anna Borodovsky

Ivanka Toudjarska

Stephanie Williams

David Butler

Ivan Zlatev

Maria Frank-Kamenetsky

Adam Castoreno

Laxman Eltepu

Laura Sepp-Lorenzino

Phillip Dan Cook

Haoyun An

Eric E Swayze

Richard Holmes Griffey

Pieter Rutter Cullis

Michael J Hope

Andrei P Guzaev

Thomas D Madden

Thomas A Baillie

John M Maraganore

Narayanannair K Jayaprakash

Alexander V Kel'in

Maja Janas

Abigail Liebow

Christopher S Theile

Amy Chan

Christopher Brown

Shannon Fishman

Kirk Brown

Jayaprakash K Narayanannair

Jingxuan Liu

Tuyen Nguyen

Svetlana Shulga Morskaya

Garth A Kinberger

Guo He

Mark Keating

Huilei Xu

Kallanthottahil G Rajeev

Varun Kumar

Mangala Meenakshi Soundarapandian

Ernst Bayer

Michael Gerster

Pushkal Garg

Jae Kim

Muthiah Monaharan

Jens Schewitz

Hans Fritz

Hartmut Ingo Jahns

Nate Taneja

Muthusamy Jayraman

Scott Lentini

Patrick Haslett

Laura Sepp-lorenzino

Haripriya Addepalli

Rajeev G Kallanthottathil

Svetlana Shulga-Morskaya

Ismail Mahmoud Hafez

The invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the PCSK9 gene, and methods of using such RNAi agents to inhibit expression of PCSK9 and methods of treating subjects having a lipid disorder, such as a hyperlipidemia.

PCSK9 iRNA compositions and methods of use thereof

The invention relates to a method of gene silencing, comprising administering to a cell or a subject in need thereof a therapeutically effective amount of the lipophilic moieties-conjugated double-stranded iRNAs at one or more internal positions on at least one strand, optionally via a linker or carrier.

Extrahepatic delivery

One aspect of the present invention relates to double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene. The sense strand of the dsRNA agent comprises at least one thermally destabilizing nucleotide, and at least one said thermally destabilizing nucleotide occurring at a site opposite to the seed region (positions 2-8) of the antisense strand; and the antisense strand of the dsRNA agent comprises at least two modified nucleotides that provide the nucleotide a steric bulk that is less than or equal to the steric bulk of a 2'-OMe modification, wherein said modified nucleotides are separated by 11 nucleotides in length. Other aspects of the invention relates to pharmaceutical compositions comprising these dsRNA agents suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA agents, e.g., for the treatment of various disease conditions.

Modified double-stranded RNA agents

One aspect of the present invention relates to double-stranded RNA (dsRNA) agent capable of inhibiting the expression of a target gene. The sense strand of the dsRNA agent comprises at least one thermally destabilizing nucleotide, and at least one said thermally destabilizing nucleotide occurring at a site opposite to the seed region (positions 2-8) of the antisense strand; and the antisense strand of the dsRNA agent comprises.at least two modified nucleotides that provide the nucleotide a steric bulk that is less than or equal to the steric bulk of a 2'-OMe modification, wherein said modified nucleotides are separated by 11 nucleotides in length. Other aspects of the invention relates to pharmaceutical compositions comprising these dsRNA agents suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA agents, e.g., for the treatment of various disease conditions.

The present invention relates to a cationic lipid having one or more biodegradable groups located in a lipidic moiety (e.g., a hydrophobic chain) of the cationic lipid. These cationic lipids may be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid. The invention also relates to lipid particles comprising a neutral lipid, a lipid capable of reducing aggregation, a cationic lipid of the present invention, and optionally, a sterol. The lipid particle may further include a therapeutic agent such as a nucleic acid.

Biodegradable lipids for the delivery of active agents

The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting the Kallikrein B, Plasma (Fletcher Factor) 1 (KLKB1) gene, the Factor XII (Hageman Factor (F12) gene, or the Kininogen 1 (KNG1) gene, and methods of using such RNAi agents to inhibit expression of a KLKB1 gene, an F12 gene, and/or a KNG1 gene, and methods of treating subjects having an hereditary angioedema (HAE) and/or a contact activation pathway-associated disorder.

Factor XII (hageman factor) (F12), kallikrein B, plasma (fletcher factor) 1 (KLKB1), and kininogen 1 (KNG1) iRNA compositions and methods of use thereof

One aspect of the present invention relates to double-stranded RNAi (dsRNA) duplex agent capable of inhibiting the expression of a target gene. The dsRNA duplex comprises one or more motifs of three identical modifications on three consecutive nucleotides in one or both strand, particularly at or near the cleavage site of the strand. Other aspects of the invention relates to pharmaceutical compositions comprising these dsRNA agents suitable for therapeutic use, and methods of inhibiting the expression of a target gene by administering these dsRNA agents, e.g., for the treatment of various disease conditions.

Modified RNAi agents

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.

Modified RNA agents with reduced off-target effect

The present invention relates, in general to agents that modulate the pharmacological activity of conjugated siRNAs.

REVERSIR™ compounds

The present invention relates, in general to, compounds, compositions and methods useful for modulating gene expression of multiple target nucleic acids by a single chemical entity.

Multi-targeted single entity conjugates

Growing community of inventors

Belmont, MA, United States of America

Martin A Maier