Ionis Pharmaceuticals, Inc.

Cold Spring Harbor Laboratory

Biogen Ma Inc.

Rosalind Franklin University of Medicine and Science

University of California

The University of Texas System

Johns Hopkins University

Washington University

Isis Pharmaceuticals, Inc.

Academisch Ziekenhuis Leiden

University of Michigan

Baylor College of Medicine

Ludwig Institute for Cancer Research Limited

Fred Hutchinson Cancer Center

Academisch Ziekenhuis Leiden (h.o.d.n. Lumc)

Frank Rigo

C Frank Bennett

Susan M Freier

Adrian R Krainer

Thazha P Prakash

Gene Hung

Michelle L Hastings

Yimin Hua

Punit P Seth

Seng H Cheng

Lamya S Shihabuddin

Huynh-Hoa Bui

Chrissa A Dwyer

Marco A Passini

David R Corey

Michael Oestergaard

Don W Cleveland

Katherine W Klinger

Timothy M Miller

David L Spector

Sarah Devos

Amanda Ward

Wilhelmina Maria Clasina Van Roon-Mom

Lodewijk Julius Anton Toonen

Michael W Baughn

John M Ravits

Clotilde Lagier-Tourenne

Stephen J Tapscott

Arthur L Beaudet

Paymaan Jafar-nejad

Charlotte J Sumner

Katherine M Bishop

Rahul Sinha

Constantin Van Outryve D'Ydewalle

Zhenxun Wang

Berit Elissa Powers

Peter Todd

Caitlin Rodriguez

Felicia Heidibrecht

Kung-Chi Chang

Mark Dockrell

Linyan Meng

Amanda Whipple

Carmen Berasain

Jan Bergmann

Allen Tingjin Yu

Gayatri Arun

Sarah Daniela Diermeier

Qiang Zhu

Jie Jiang

Clotilde Lagier-Tourene

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of GFAP RNA in a cell or subject, and in certain instances reducing the amount of GFAP in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a leukodystrophy. Such symptoms and hallmarks include motor delays, cognitive delays, paroxysmal deterioration, seizures, vomiting, swallowing difficulties, ataxic gait, palatal myoclonus, autonomic dysfunction, and presence of intra-astrocytic inclusions called Rosenthal fibers. Such leukodystrophies include Alexander Disease.

Compounds and methods for modulating GFAP

The present disclosure provides half duplex compounds comprising a first oligomeric compound and a second, shorter, oligomeric compound, wherein the first oligomeric compound is complementary to a target nucleic acid and the second oligomeric compound is complementary to the first oligomeric compound. In certain embodiments, the compounds disclosed herein are useful for modulating the expression of extra-hepatic target nucleic acids.

Conjugated antisense compounds and their use

Provided herein are methods for decreasing Ataxin-2 mRNA expression. Such methods are useful to ameliorate symptoms of Ataxin-2 associated diseases. Such Ataxin-2 associated diseases include amyotrophic lateral sclerosis (ALS). Such symptoms include loss of motor function, reduced CMAP amplitude, denervation, and loss of motor neurons.

Methods for reducing Ataxin-2 expression

Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a subject. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders, including spinal muscular atrophy. Also provided are kits for detecting the amount of SMN protein in a sample of cerebrospinal fluid.

Compositions and methods for detection of SMN protein in a subject and treatment of a subject

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN2 RNA in a cell or animal, and in certain instances reducing the amount of Ataxin-2 protein in a cell or animal Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include ataxia, neuropathy, and aggregate formation. Such neurodegenerative diseases include spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), and parkinsonism.

Compounds and methods for reducing ATXN2 expression

Provided are oligomeric compounds, methods, and pharmaceutical compositions for DMPK the amount or activity of DMPK RNA in a cell or animal, and in certain instances reducing the amount of DMPK protein in a cell or animal. Such oligomeric compounds, methods, and pharmaceutical compositions are useful to treat type 1 myotonic dystrophy.

Oligomeric compounds for reducing DMPK expression

Disclosed herein are methods for reducing expression of Tau mRNA and protein in an animal with Tau antisense compounds. Also disclosed are methods for modulating splicing of Tau mRNA in an animal with Tau antisense compounds. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof. Examples of neurodegenerative diseases that can be treated, prevented, and ameliorated with the administration Tau antisense oligonucleotides include Alzheimer's Disease, Fronto-temporal Dementia (FTD), FTDP-17, Progressive Supranuclear Palsy, Chronic Traumatic Encephalopathy, Epilepsy, and Dravet's Syndrome.

Methods for treating Alzheimer's disease

Certain embodiments disclosed herein are directed to compounds and methods for modulating APP expression. In certain embodiments, modulating the splicing of amyloid precursor protein (APP) reduces amyloid &#x3b2; (A&#x3b2;) production.

Compounds and methods for the modulation of amyloid-&#x3b2; precursor protein

Provided are methods for increasing the amount or activity of FMR1 RNA, and in certain instances of increasing the amount of FMRP protein, in an animal Such methods are useful to prevent or ameliorate at least one symptom of a Fragile X-Spectrum disorder. Such Fragile X-Spectrum disorders include FXS, FXTAS, and FXPOI.

Methods for modulating FMR1 expression

Disclosed herein are compounds, compositions and methods for modulating splicing of SMN2 mRNA in a subject.

Compositions and methods for modulation of SMN2 splicing in a subject

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 compositions and methods for reducing expression of C9ORF72 mRNA and protein in an animal with C9ORF72 specific inhibitors. Also disclosed herein are compositions and methods of selectively inhibiting a C9ORF72 pathogenic associated mRNA variant by administering an antisense compound targeting the region beginning at the start site of exon 1A to the start site of exon 1B of a C9ORF72 pre-mRNA. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof. Such C9ORF72 specific inhibitors include antisense compounds.

Compositions for modulating C9ORF72 expression

Provided are compounds, methods, and pharmaceutical compositions for modulating SMN2 RNA and/or protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom of a neurodegenerative disorder. Such symptoms include reduced muscle strength; inability or reduced ability to sit upright, to stand, and/or walk; reduced neuromuscular activity; reduced electrical activity in one or more muscles; reduced respiration; inability or reduced ability to eat, drink, and/or breathe without assistance; loss of weight or reduced weight gain; and/or decreased survival.

Compounds and methods for modulating SMN2

Growing community of inventors

Carlsbad, CA, United States of America

Frank Rigo