Alnylam Pharmaceuticals, Inc.

Sloan-Kettering Institute for Cancer Research

Other

Sirna Therapeutics, Inc.

Technische Universitat Munchen

Laura Sepp-Lorenzino

Vasant R Jadhav

Neal Rosen

Muthiah Manoharan

Samuel J Danishefsky

Kallanthottathil G Rajeev

Martin A Maier

Scott D Kuduk

Gregory Hinkle

Stuart Milstein

Duncan F Brown

Walter R Strapps

Tayeba Khan

Marija Tadin-strapps

Furzhong F Zheng

Ouatek Ouerfelli

Samuel L Graham

Steven R Magnuson

George C Prendergast

Rubina G Parmar

Ouathek Ouerfelli

Svetlana Shulga Morskaya

Allen I Oliff

Ulrike Protzer

Huilei Xu

Jackson B Gibbs

Thomas Michler

Mark M Moasser

Nancy Kohl

The present invention provides methods comprising the in vivo delivery of small nucleic acid molecules capable of mediating RNA interference and reducing the expression of myostatin, wherein the small nucleic acid molecules are introduced to a subject by systemic administration. Specifically, the invention relates to methods comprising the in vivo delivery of short interfering nucleic acid (siNA) molecules that target a myostatin gene expressed by a subject, wherein the siNA molecule is conjugated to a lipophilic moiety, such as cholesterol. The myostatin siNA conjugates that are delivered as per the methods disclosed are useful to modulate the in vivo expression of myostatin, increase muscle mass and/or enhance muscle performance. Use of the disclosed methods is further indicated for treating musculoskeletal diseases or disorders and/or diseases or disorders that result in conditions in which muscle is adversely affected.

Systemic delivery of myostatin short interfering nucleic acids (siNA) conjugated to a lipophilic moiety

The present invention provides methods for the treatment of a subject having a Hepatitis B virus (HBV) infection, e.g., a chronic HBV infection, using a combination of an RNAi agent that targets HBV and an HBV vaccine. It is disclosed a RNAi agent and an HBV vaccine for use in treatment of HBV infection, comprising sequentially administering to the subject having an HBV infection: a) an RNAi agent that inhibits expression of at least three HBV transcripts, wherein the RNAi agent forms a double stranded region; b) a protein-based vaccine comprising a first HBV core antigen (HBcAg) polypeptide, and a first HBV surface antigen (HBsAg) polypeptide; and c) a nucleic acid-based vaccine comprising an expression vector construct encoding a second HBcAg polypeptide, and/or a second HBsAg polypeptide, wherein the second HBcAg polypeptide, and/or the second HBsAg polypeptide, shares at least one epitope with at least one of the first HBcAg polypeptide, and/or the first HBsAg polypeptide.

Methods for the treatment of subjects having a hepatitis b virus (HBV) infection

The present invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the hepatitis B virus (HBV) genome, and methods of using such RNAi agents to inhibit expression of one or more HBV genes and methods of treating subjects having an HBV infection and/or HBV-associated disorder, e.g., chronic hepatitis B infection.

Hepatitis B virus (HBV) iRNA compositions and methods of use thereof

The present invention provides methods comprising the in vivo delivery of small nucleic acid molecules capable of mediating RNA interference and reducing the expression of myostatin, wherein the small nucleic acid molecules are introduced to a subject by systemic administration. Specifically, the invention relates to methods comprising the in vivo delivery of short interfering nucleic acid (siRNA) molecules that target a myostatin gene expressed by a subject, wherein the siRNA molecule is conjugated to a lipophilic moiety, such as cholesterol. The myostatin siRNA conjugates that are delivered as per the methods disclosed are useful to modulate the in vivo expression of myostatin, increase muscle mass or enhance muscle performance. Use of the disclosed methods is further indicated for treating musculoskeletal diseases or disorders or diseases or disorders that result in conditions in which muscle is adversely affected.

Myostatin iRNA compositions and methods of use thereof

The present invention relates to RNAi agents, e.g., double-stranded RNAi agents, targeting the hepatitis D virus (HDV) genome, and methods of using such RNAi agents to inhibit expression of one or more HBV genes and methods of treating subjects having an HDV infection and/or HDV-associated disorder.

Hepatitis D virus (HDV) iRNA compositions and methods of use thereof

Bifunctional molecules comprising two hsp-binding moieties which bind to hspin the pocket to which ansamycin antibiotics bind connected via a linker are effective for inducing the degradation and/or inhibition of HER-family tyrosine kinases. For example, a compound of two geldanamycin moities joined by a four-carbon linker provides selective degradation of HER-family tyrosine kinases, without substantially affecting other kinases. These compounds can be used for treatment of HER-positive cancers with reduced toxicity, since these compounds potently kill cancer cells but affect fewer proteins than geldanamycin.

Methods and compositions for degradation and/or inhibition of HER-family tyrosine kinases

Bifunctional molecules comprising two hsp-binding moieties which bind to hsp90 in the pocket to which ansamycin antibiotics bind connected via a linker are effective for inducing the degradation and/or inhibition of HER-family tyrosine kinases. For example, a compound of two geldanamycin moities joined by a four-carbon linker provides selective degradation of HER-family tyrosine kinases, without substantially affecting other kinases. These compounds can be used for treatment of HER-positive cancers with reduced toxicity, since these compounds potently kill cancer cells but affect fewer proteins than geldanamycin.

The present invention relates to methods of treating cancer using a combination of a compound which is an antineoplastic agent and a compound which is a inhibitor of prenyl-protein transferase, which methods comprise administering to said mammal, either sequentially in any order or simultaneously, amounts of at lest two therapeutic agents selected from a group consisting of a compound which is an antineoplastic agent and a compound which is an inhibitor or prenyl-protein transferase. The invention also relates to methods of preparing such compositions.

Method of treating cancer

Compounds having an ansamycin anitibiotic, or other moiety which binds to hsp90, coupled to a targeting moiety which binds specifically to a protein, receptor or marker can provide effective targeted delivery of the ansamycin antibiotic leading to the degradation of proteins and death of the targeted cells. These compositions may have different specificity than the ansamycin alone, allowing for a more specific targeting of the therapy, and can be effective in instances where the ansamycin alone has no effect. Thus, these compounds provide an entirely new class of targeted chemotherapy agents with application, depending on the nature of the targeting moiety, to treatment of a variety of different forms of cancer. Such agents can further be used to promote selective degradation of proteins associated with the pathogenesis of others diseases, including antigens associated with autoimmune disorders and pathogenic proteins associated with Alzheimer's disease. Exemplary targeting moieties which may be employed in compounds of the invention include testosterone, estradiol, tamoxifen and wortmannin.

Methods and compositions for destruction of selected proteins

This invention provides a process for the preparation of a racemic mixture of dysidiolide a method for inhibiting growth of cancerous cells comprising contracting an amount of the racemic mixture of dysidiolide effective to inhibit the growth of said cells. Further provided is a method for treating cancer in a subject which comprises administering to the subject a therapeutically effective amount of the racemic mixture of dysidiolide.

Synthesis of dysidiolide and uses thereof

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Jenkintown, PA, United States of America

Laura Sepp-Lorenzino