Isis Pharmaceuticals, Inc.

Ionis Pharmaceuticals, Inc.

Andrew M Siwkowski

Brett P Monia

Eric E Swayze

Punit P Seth

Edward Wancewicz

Sanjay Bhanot

Robert McKay

Richard S Geary

Susan M Freier

Thazha P Prakash

Balkrishen Bhat

Hong Zhang

Charles Allerson

Shuling Guo

Jeffrey R Crosby

Chenguang Zhao

Lynnetta Watts

C Frank Bennett

Lex M Cowsert

Mausumee Guha

Thomas A Leedom

Robert Mckay

Provided herein are methods, compounds, and compositions for reducing expression of transthyretin mRNA and protein in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate transthyretin amyloidosis, or a symptom thereof.

Modulation of transthyretin expression

Disclosed herein are antisense compounds and methods for decreasing Factor 11 and treating or preventing thromboembolic complications in an individual in need thereof. Examples of disease conditions that can be ameliorated with the administration of antisense compounds targeted to Factor 11 include thrombosis, embolism, and thromboembolism, such as, deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke. Antisense compounds targeting Factor 11 can also be used as a prophylactic treatment to prevent individuals at risk for thrombosis and embolism.

Modulation of factor 11 expression

The present disclosure describes short antisense compounds, including such compounds comprising chemically-modified high-affinity monomers 8-16 monomers in length. Certain such short antisense compound are useful for the reduction of target nucleic acids and/or proteins in cells, tissues, and animals with increased potency and improved therapeutic index. Thus, provided herein are short antisense compounds comprising high-affinity nucleotide modifications useful for reducing a target RNA in vivo. Such short antisense compounds are effective at lower doses than previously described antisense compounds, allowing for a reduction in toxicity and cost of treatment. In addition, the described short antisense compounds have greater potential for oral dosing.

Compounds and methods for modulating gene expression

The present disclosure provides tricyclic nucleosides, oligomeric compounds comprising at least one of the tricyclic nucleosides and methods of using the oligomeric compounds. The methods provided herein include contacting a cell or administering to an animal at least one of the oligomeric compounds. In certain embodiments, the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Oligomeric compounds comprising tricyclic nucleosides and methods for their use

Short antisense compounds with gapmer configuration

The present disclosure describes tetrahydropyran nucleoside analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, tetrahydropyran nucleoside analogs are provided, having one or more chiral substituents, that are useful for enhancing properties of oligomeric compounds including nuclease resistance and binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Tetrahydropyran nucleic acid analogs

Oligomeric compounds comprising tricyclic nucelosides and methods for their use

Compounds and methods for modulating expression of DGAT2

In certain embodiments, the present invention provides oligomeric compounds having favorable toxicity profiles and therapeutic indexes. Compounds of the present invention comprise bicyclic nucleosides. Certain such bicyclic nucleosides are pyrimidines that do not include a methyl group at the 5-carbon. Oligomeric compounds comprising such nucleosides are less toxic than compounds comprising bicyclic nucleosides that do include a methyl group at the 5-carbon. In certain embodiments, the present invention provides methods of preparing and using such compounds.

Oligomeric compounds comprising bicyclic nucleosides and having reduced toxicity

Diagnosis and treatment of disease

Compounds and methods for modulating expression ApoB

Growing community of inventors

Carlsbad, CA, United States of America

Andrew M Siwkowski