Alnylam Pharmaceuticals, Inc.

Christopher S Theile

Kallanthottathil G Rajeev

Martin A Maier

Jayaprakash K Nair

Muthiah Manoharan

Stuart Milstein

Muthusamy Jayaraman

Vasant R Jadhav

Klaus Charisse

Alexander V Kel'in

Kevin Fitzgerald

Rubina G Parmar

Adam Castoreno

Kirk Brown

Shigeo Matsuda

Mark K Schlegel

Alfica Sehgal

Donald Foster

Ivan Zlatev

Maja Janas

Christopher Brown

Scott Lentini

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 a double stranded iRNA agent comprising an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic moieties conjugated to one or more internal positions on at least one strand, optionally via a linker or carrier. Another aspect of 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.

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 relates 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 disclosure relates generally to cleavable linkers and uses thereof.

Endosomal cleavable linkers

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Cambridge, MA, United States of America

Christopher S Theile