Isis Pharmaceuticals, Inc.

Ionis Pharmaceuticals, Inc.

Edward Wancewicz

Brett P Monia

Andrew M Siwkowski

Eric E Swayze

Punit P Seth

Sanjay Bhanot

Robert McKay

Richard S Geary

Susan M Freier

William A Gaarde

Lynnetta Watts

Mausumee Guha

Thomas A Leedom

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

Short antisense compounds with gapmer configuration

Compounds and methods for modulating expression of DGAT2

Compounds and methods for modulating expression ApoB

Compounds and methods for modulating expression of PTP1B

Compounds and methods for modulating expression of GCCR

Compounds and methods for modulating expression of SGLT2

The present invention provides antisense compounds and methods for modulating the expression of target genes expressed in the kidney. In particular, this invention provides antisense oligonucleotide compounds optimized for targeting nucleic acid molecules expressed in the kidney. Such compounds are shown herein to efficiently modulate the expression of target genes SGLT2 and connective tissue growth factor (CTGF) in the kidney.

Antisense oligonucleotides optimized for kidney targeting

Compounds and methods for modulating expression of GCGR

Compounds and methods for modulating expression of PCSK9

Compounds, compositions and methods are provided for modulating the expression of SGLT2. The compositions comprise oligonucleotides, targeted to nucleic acid encoding SGLT2. Methods of using these compounds for modulation of SGLT2 expression and for diagnosis and treatment of diseases and conditions associated with expression of SGLT2 are provided.

Modulation of SGLT2 expression

Compounds, compositions and methods are provided for inhibiting E2A-Pbx1 mediated transformation. The compositions comprise antisense compounds targeted to nucleic acids encoding E2A-Pbx1. Methods of using these antisense compounds for inhibition of E2A-Pbx1 expression and for treatment of diseases, particularly cancers, associated with overexpression or constitutive activation of E2A-Pbx1 are provided.

Antisense inhibition of E2A-Pbx1 expression

Antisense compounds, compositions and methods are provided for modulating the expression of TERT. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding TERT. Methods of using these compounds for modulation of TERT expression and for treatment of diseases associated with expression of TERT are provided.

Antisense modulation of TERT expression

Antisense inhibition of tert expression

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Poway, CA, United States of America

Edward Wancewicz