Alnylam Pharmaceuticals, Inc.

Arbutus Biopharma Corporation

Tekmira Pharmaceuticals Corporation

Verve Therapeutics, Inc.

Takeda Pharmaceutical Company Limited

Isis Pharmaceuticals, Inc.

The Rockefeller University

Ionis Pharmaceuticals, Inc.

Alaylam Pharmacueuticals, Inc.

Alnylam Pharamaceticals, Inc.

University of British Columbia

Genzyme Corporation

Kallanthottathil G Rajeev

Muthiah Manoharan

Martin A Maier

Muthusamy Jayaraman

Klaus Charisse

Jayaprakash K Nair

Akin Akinc

Stuart Milstein

Shigeo Matsuda

Vasant R Jadhav

Brian R Bettencourt

Satyanarayana Kuchimanchi

Pachamuthu Kandasamy

David Butler

Kevin Fitzgerald

Tracy Stage Zimmermann

Venkitasamy Kesavan

Rubina G Parmar

Laxman Eltepu

Alfica Sehgal

Donald Foster

Ivan Zlatev

Jianxin Chen

Gregory Hinkle

James Butler

Michael E Jung

David A Bumcrot

Anna Borodovsky

Philipp Hadwiger

Ivanka Toudjarska

Maria Frank-Kamenetsky

Mark K Schlegel

Eric E Swayze

Antonin De Fougerolles

Thazha P Prakash

Hans-Peter Vornlocher

Laura Sepp-Lorenzino

William Querbes

Punit P Seth

Pieter Rutter Cullis

Don Foster

Satya Kuchimanchi

Jayaprakash K Narayanannair

Steven Ansell

Narayanannair K Jayaprakash

Thomas A Baillie

Alexander V Kel'in

John M Maraganore

Caroline Reiss

Maja Janas

Alexander V Kelin

Rajendra K Pandey

Jie Xia

Alexandra Chadwick

Christopher S Theile

Amy Chan

Souvik Biswas

Ingo Roehl

Christopher Brown

Joseph Robert Dorkin

Xiaojun Qin

William Cantley

Gang Wang

Christopher Cheng

Adam Castoreno

Kirk Brown

Padma Malyala

Marija Prhavc

Lisa N Kasiewicz

Tuyen Nguyen

Sudhakar Rao Takkellapati

Ellen Rohde

Michael J Hope

Steven Michial Ansell

Rajesh Kumar Kainthan

Thomas D Madden

Markus Stoffel

Svetlana Shulga Morskaya

Walter F Lima

Marco A Ciufolini

Sean C Semple

Joseph R Dorkin

Kim F Wong

Huilei Xu

Barbara Mui

Satoru Matsumoto

Mamta Kapoor

Laxmab Eltepu

Muthiah Monaharan

Takeshi Yamada

Chang Geng Peng

Muthusamy Jayraman

Meena

Michael F Jung

Muthiah Mancharan

Scott Lentini

Jeremy Lackey

Laura Sepp-lorenzino

Soma De

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 present disclosure relates to PEG-lipids, cationic and/or ionizable lipids and nucleic acid-lipid particle compositions comprising the same. The present disclosure also relates to methods of making, using and delivering the described lipids and lipid-containing particles.

Lipid formulations for gene editing

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

Provided herein are compositions, methods of making the same, and methods for targeted delivery of therapeutic agents for modifying expression and function of target genes, e.g. proteins involved in lipid and cholesterol metabolism such as PCSK9. Further provided herein are compositions and methods of treating conditions related to coronary disease.

Compositions and methods for targeted RNA delivery

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

Provided herein are compositions and methods for preparation of 5' end region-modified mRNAs. In particular, the instant disclosure relates to novel mRNA 5′ end region motifs and sequence initiators therefore together with assays that are capable of measuring the aspects of the functionality of those motifs and sequence initiators. Further provided herein are compositions and methods of treating conditions related to coronary disease.

Compositions and methods for capping RNAS

Growing community of inventors

Cambridge, MA, United States of America

Kallanthottathil G Rajeev