Alnylam Pharmaceuticals, Inc.

Isis Pharmaceuticals, Inc.

Arbutus Biopharma Corporation

Tekmira Pharmaceuticals Corporation

Ionis Pharmaceuticals, Inc.

Other

Mcgill University

Eth Zurich

Medtronic, Inc.

Takeda Pharmaceutical Company Limited

The Rockefeller University

Alaylam Pharmacueuticals, Inc.

Alnylam Pharamaceticals, Inc.

University of British Columbia

Genzyme Corporation

Muthiah Manoharan

Kallanthottathil G Rajeev

Martin A Maier

Muthusamy Jayaraman

Phillip Dan Cook

Jayaprakash K Nair

Akin Akinc

Klaus Charisse

Stuart Milstein

Vasant R Jadhav

Satyanarayana Kuchimanchi

Kevin Fitzgerald

David Butler

Thazha P Prakash

Balkrishen Bhat

Brian R Bettencourt

Michael E Jung

Eric E Swayze

Gregory Hinkle

Vasulinga T Ravikumar

Brenda F Baker

Richard Holmes Griffey

David A Bumcrot

Douglas L Cole

Philipp Hadwiger

William Querbes

Maria Frank-Kamenetsky

Brett P Monia

Lex M Cowsert

David J Ecker

Antonin De Fougerolles

Stanley T Crooke

Rachel E Meyers

Hans-Peter Vornlocher

Sayda Mahgoub Elbashir

Susan M Freier

C Frank Bennett

Punit P Seth

Pieter Rutter Cullis

Shigeo Matsuda

Andrei P Guzaev

Pachamuthu Kandasamy

Rubina G Parmar

Venkitasamy Kesavan

Laxman Eltepu

Tracy Stage Zimmermann

Don Foster

Andrew Mamoru Kawasaki

James Butler

Alfica Sehgal

Clarence Frank Bennett

Donald Foster

Ivan Zlatev

Anne Bettina Eldrup

Jianxin Chen

Anna Borodovsky

Venkatraman Mohan

P Dan Cook

Mark K Schlegel

Daniel C Capaldi

Charles Allerson

Achim H Krotz

Charles John Guinosso

Laura Sepp-Lorenzino

Haoyun An

Ingo Roehl

Markus Stoffel

Yogesh S Sanghvi

Thomas W Bruice

Adam Castoreno

Harri Salo

John S Kiely

Jacqueline R Wyatt

Nicholas M Dean

Gilles J Gosselin

William Frederick Kaemmerer

Robert McKay

Michael Egholm

Zhili Xin

Michael J Hope

Peter Eigil Nielsen

Jean-Louis Imbach

Brian Dale Nelson

Jesper Lohse

Steven Michial Ansell

Eric Marsault

Rajesh Kumar Kainthan

Yi Jin

Thomas D Madden

Kelly G Sprankle

Ole Buchardt

James G Karras

Ivanka Toudjarska

Walter F Lima

Svetlana Shulga Morskaya

Marco A Ciufolini

Bruce S Ross

Sean C Semple

Matthew H Adams

Jens Harborth

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 present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure wherein:

Lipids and compositions for the delivery of therapeutics

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

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

Cambridge, MA, United States of America

Muthiah Manoharan