University of Texas System

Ionis Pharmaceuticals, Inc.

David R Corey

Jiaxin Hu

Thazha P Prakash

Jerry W Shay

Woodring E Wright

John Dorrance Minna

Mieczyslaw A Piatyszek

Bethany Ann Janowski

James C Norton

David S Shames

Eric E Swayze

Frank Rigo

Masayuki Matsui

Dongbo Yu

Jing Liu

Dinah W Y Sah

Venkateswara V Mootha

Liande Li

Xuan Yue

Scott T Younger

Rachel S Greer

Provided herein are compositions and methods for reducing expression of C9orf72 transcripts in cells containing expanded intronic GGGGCC regions, including those in subjects having or at risk of developing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Allele selective inhibition of mutant C9orf72 foci expression by duplex RNAs targeting the expanded hexanucleotide repeat

Described are compounds and methods useful for the treatment and investigation of Friedreich's Ataxia.

Compositions and methods for treatment of Friedreich's Ataxia

Described are compounds and methods useful in the treatment of Fuchs' Endothelial Corneal Dystrophy (FECD).

Treatment of Fuchs' endothelial corneal dystrophy

Certain embodiments are directed to methods and compounds for increasing FXN. Such methods and compounds are useful for increasing expression of FXN in cells and animals.

Modulation of frataxin expression

Disclosed herein are compounds and methods for modulating C9orf72 transcript. Such compounds and methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof.

Compounds and methods for modulating C90RF72

Provided herein are compositions and methods for reducing expression of C9orf72 transcripts in cells containing expanded intronic GGGGCC regions, including those in subjects having or at risk of developing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Provided herein are a double-stranded oligonucleotides of 13 to 22 nucleobases in length targeting a GGGGCC expanded repeat region in an intron of C9orf72, comprises (a) 3-5 central mismatches (within bases 9-14) within a target sequence comprising the expanded repeat sequence, or (h) 3-5 mismatches outside of the seed sequence (bases 2-8 within the guide strand complementary to the expanded repeat sequence).

Allele selective inhibition of mutant C9orf72 foci expression by duplex RNAS targeting the expanded hexanucleotide repeat

Described are compounds and methods useful for the treatment and investigation of diseases and disorders associated with expanded repeat-containing RNA molecules. In certain embodiments, compounds and methods useful for the modulation of ATXN-3 pre-mRNA are described. In certain embodiments, compounds and methods useful for the modulation of ATN-1 mRNA are described.

Methods and compounds useful in conditions related to repeat expansion

Described are compounds and methods useful for the treatment and investigation of diseases and disorders associated with expanded repeat-containing RNA molecules.

The present invention relates to the selective inhibition of protein expression of CAG repeat-related disease proteins such as Huntingtin Disease Protein and Ataxin-3 using double-stranded RNAs and nucleic acid analogs. Chemically-modified RNAs having at least one mismatch as compared to the target CAG repeat sequence are specifically contemplated.

Selective inhibition of polyglutamine protein expression

The present invention relates to the selective inhibition of protein expression of CAG repeat-related disease proteins such as Huntington using nucleic acid analogs. Peptide nucleic acids and locked nucleic acids are particularly useful analogs.

Transcription of a gene in a mammalian cell is methylase-independently inhibited by contacting the cell with a nucleic acid oligomer of 12-28 bases complementary for a partially single-stranded target genomic sequence of the gene.

Antigene oligomers inhibit transcription

The present invention relates to the selective inhibition of protein expression of CAG repeat-related disease proteins such as Huntingtin using nucleic acid analogs. Peptide nucleic acids and locked nucleic acids are particularly useful analogs.

Gene expression can be selectively modulated by contacting a cell with an oligomer that targets a gene region downstream of a '3-UTR, thereby increasing or decreasing the expression of the target gene.

Modulation of gene expression using oligomers that target gene regions downstream of 3' untranslated regions

Synthesis of a target transcript of a gene is selectively increased in a mammalian cell by contacting the cell with a polynucleotide oligomer of 12-28 bases complementary to a region within a target promoter of the gene under conditions whereby the oligomer selectively increases synthesis of the target transcript.

Modulation of gene expression by oligomers targeted to chromosomal DNA

Gene expression can be selectively regulated by endogenous miRNAs that target promoters of genes. Altering of the activity of these promoter-targeting miRNAs with single-stranded complementary oligonucleotides that bind the miRNA causes modulation of expression of the target gene. Endogenous miRNAs that modulate expression of target genes can be identified by (a) evaluating an endogenous miRNA for complementarity to a target gene promoter; and (b) determining that the complementary miRNA modulates expression of the target gene.

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Dallas, TX, United States of America

David R Corey