Alnylam Pharmaceuticals, Inc.

Arrowhead Madison, Inc.

Axolabs Gmbh

Mpeg La, L.l.c.

Hoffmann-la Roche Inc.

Arrowhead Pharmaceuticals, Inc.

Alnylam Europe Ag

F. Hoffmann-la Roche Ag

Arrowhead Research Corporation

Philipp Hadwiger

Hans-Peter Vornlocher

Ingo Roehl

Peter Mohr

David B Rozema

David L Lewis

Torsten Hoffmann

Eric Argirios Kitas

Anke Geick

Darren H Wakefield

Hans Martin Mueller

Muthiah Manoharan

Kallanthottathil G Rajeev

Pamela Tan

Stefan Limmer

Kerstin Jahn-Hofmann

Guenther Ott

Sayda Mahgoub Elbashir

Dinah Wen-Yee Sah

Maria Frank-Kamenetsky

Roland Kreutzer

Birgit Bramlage

Juergen Soutschek

Rainer Constien

Ludger Ickenstein

Carla Alexandra Hernandez Prata

Timo Weide

Andrea Schuster

Torsten Haneke

Eric A Kitas

Jon Asher Wolff

Antonin De Fougerolles

Akin Akinc

David A Bumcrot

Henrik Frydenlund Hansen

Andrei V Blokhin

Jeffrey Carlson

Jonathan D Benson

Jonathan Miles Brown

Sylvia Limmer

Linda Valis

Kristin K H Neuman

Tracy Stage Zimmermann

Olaf Heidenreich

Jacob Ravn

James E Dahlman

Søren Ottosen

Andrea Forst

Matthias John

Morten Lindow

Susanne Kammler

Detlef Schuppan

Monika Krampert

Wilma Thuer

Jeffrey C Carlson

Dinah Sah

Ingo Röhl

Christoph Herold

Matthias Ocker

Torsten Hoffman

Claudia Woppmann

Erik Kitas

Heiko Van Der Kuip

Kerstin Jahn-Hoffmann

Günther Ott

Jon A Wolff

Linda Christine Valis

Nanna ALBÆK

Christina Lorenz

Mark Turner

Henrik Ørum

The present invention relates to methods of administering to a subject multimeric oligonucleotides having monomeric subunits joined by linkers. The multimeric oligonucleotides have a molecular weight of at least about 45 kD and other characteristics, such that their clearance due to glomerular filtration is reduced. The present invention also relates to such multimeric oligonucleotides and methods of synthesizing such multimeric oligonucleotides.

Multimeric oligonucleotides having decreased kidney clearance

Defined multi-conjugate oligonucleotides can have predetermined sizes and compositions. For example, in various embodiment, defined multi-conjugate oligonucleotides can have advantageous properties, for example in the form of defined multi-conjugate siRNA (i.e., including two, three or more siRNA) having enhanced intracellular delivery and/or multi-gene silencing effects. In various embodiment, the defined multi-conjugate oligonucleotides can be synthesized via new synthetic intermediates and methods. The defined multi-conjugate oligonucleotides can be used, for example, in reducing gene expression, biological research, treating or preventing medical conditions, or to produce new or altered phenotypes in cells or organisms.

Defined multi-conjugates oligonucleotides

Defined multi-conjugate oligonucleotides

The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to hepatocytes in vivo. Targeted RNAi polynucleotides are administered together with co-targeted delivery polymers. Delivery polymers provide membrane penetration function for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness to the delivery polymers.

Compositions for targeted delivery of siRNA

The present invention relates to agents, compositions and methods for inhibiting the expression of a target gene, comprising an RNAi agent bearing at least one galactosyl moiety. These are useful for delivering the gene expression inhibiting activity to cells, particularly hepatocytes, and more particularly in therapeutic applications.

Glycoconjugates of RNA interference agents

The invention provides novel compounds and conjugates of these compounds useful for the delivery of biologically active substances. Further novel design criteria for chemically stabilized siRNA particular useful when covalently attached to a delivery polymer to achieve in vivo mRNA knock down are disclosed therein.

Small molecule conjugates for intracellular delivery of biologically active compounds

The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to cell in vivo. The pharmacokinetic modulator improve in vivo targeting compared to the targeting ligand alone. Targeting ligand-pharmacokinetic modulator targeting moiety targeted RNAi polynucleotides can be administered in vivo alone or together with co-targeted delivery polymers.

Galactose cluster-pharmacokinetic modulator targeting moiety for siRNA

The present invention provides novel amino-lipids, compositions comprising such amino-lipids and methods of producing them. In addition, lipid nanoparticles comprising the novel amino-lipids and a biologically active compound are provided, as well as methods of production and their use for intracellular drug delivery.

Lipids and compositions for intracellular delivery of biologically active compounds

The present invention relates to a double-stranded ribonucleic acid (dsRNA) having a nucleotide sequence which is substantially identical to at least a part of a target gene and which is no more than 49, preferably less than 25, nucleotides in length, and which comprises a complementary (antisense) RNA strand having a 1 to 4 nucleotide overhang at the 3'-end and a blunt 5&#x2032;-end. The invention further relates to a pharmaceutical composition comprising the dsRNA and a pharmaceutically acceptable carrier. The pharmaceutical compositions are useful for inhibiting the expression of a target gene, as well as for treating diseases caused by expression of the target gene, at low dosages (i.e., less than 5 milligrams, preferably less than 25 micrograms, per kg body weight per day). The invention also relates to methods for inhibiting the expression of a target gene, as well as methods for treating diseases caused by the expression of the gene.

Compositions and methods for inhibiting expression of a target gene

The invention provides use of novel compounds for delivery of nucleic acids, and conjugates of these compounds with nucleic acids. Further novel design criteria for chemically stabilized siRNA particular useful when covalently attached to said compounds and co-administered with a delivery polymer to achieve mRNA knock down in vivo are disclosed therein.

Small molecule conjugates for intracellular delivery of nucleic acids

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Altenkunstadt, Germany

Philipp Hadwiger