Sirna Therapeutics, Inc.

Wave Life Sciences Ltd.

Novartis Ag

Gilead Sciences, Inc.

Nexstar Pharmaceuticals, Inc.

Other

Merck Sharp + Dohme Corp.

Arrowhead Pharmaceuticals, Inc.

Merck Sharpe & Dohme Corp.

Chandra Vargeese

Weimin Wang

Leonid Beigelman

James A McSwiggen

Naoki Iwamoto

David Charles Donnell Butler

Genliang Lu

Subramanian Marappan

Tongqian Chen

Keith A Bowman

Jason Jingxin Zhang

Sethumadhavan Divakaramenon

Pachamuthu Kandasamy

Christopher J Francis

Nebojsa Janjic

Jeremy Lee Baryza

Kurt Vagle

Junping Zhao

Gopal Reddy Bommineni

Larry M Gold

Paul J Schmidt

Rohan Eric John Beckwith

Thomas Zabawa

Gabriel Grant Gamber

Peter Haeberli

Tanzina Fazal

Cameron Chuck-munn Lee

Gregory Lawrence Verdine

Maria Frank-Kamenetsky

Meena

Andrew John Geall

Vasant R Jadhav

Nassim Usman

Jasenka Matulic-Adamic

Alexander Karpeisky

Laura Ellen West

Ye Zhang

Ritesh Bhanudasji Tichkule

Shuangxi Wang

Crystal Byers

Christopher Shaffer

David Morrissey

Hailin Yang

Mamoru Shimizu

Christopher P Hencken

Nenad Svrzikapa

Ilia Korboukh

Michael Willis

Vinod Vathipadiekal

Luciano Henrique Apponi

Young Jin Cho

Susovan Mohapatra

Snehlata Tripathi

Anna Sokolovska

Vincent Aduda

Stephany Michelle Standley

Mohammed Rowshon Alam

Keith Andrew Bowman

Chikdu Shakti Shivalila

Alvaro Andres Lanao

Andrew Geall

Jeremy Baryza

Sumedha D Jayasena

James D Thompson

James Mcswiggen

Jan Weiler

Shawn Patrick Zinnen

Wenlai Zhou

Pamela Pavco

Dieter Huesken

Bharat Chowrira

Kathy L Fosnaugh

Zhong Zhong

Frank Peter Stegmeier

Aaron Jay Morris

Dennis G Macejak

Cameron Lee

Xiayun Cheng

Jinyun Chen

Narendra K Vaish

Hanna Maria Wisniewska

Noah Gardner

Travis Jeannotte

Yuanjing Liu

Kalyani Gampa

Jean-Cosme Dodart

Mark Stump

Prashant Monian

Jayakanthan Kumarasamy

Ann Fiegen Durbin

Selvi Ramasamy

Nayantara Kothari

Tanzina Labonte

Sharon F Jamison

Roberto Guerciolini

Cameron Chuck-Munn Lee

Rohan Eric Beckwith

Among other things, the present disclosure provides technologies for oligonucleotide preparation, particularly chirally controlled oligonucleotide preparation, which technologies provide greatly improved crude purity and yield, and significantly reduce manufacturing costs.

Technologies for oligonucleotide preparation

The present disclosure, among other things, provides technologies for synthesis, including reagents and methods for stereoselective synthesis. In some embodiments, the present disclosure provides compounds useful as chiral auxiliaries. In some embodiments, the present disclosure provides reagents and methods for oligonucleotide synthesis. In some embodiments, the present disclosure provides reagents and methods for chirally controlled preparation of oligonucleotides. In some embodiments, technologies of the present disclosure are particularly useful for constructing challenging internucleotidic linkages, providing high yields and stereoselectivity.

Compounds, compositions and methods for synthesis

The present disclosure pertains to the recognition that immune responses mediated by CpG oligonucleotides can be affected by the stereochemistry of modified internucleotidic linkages such as phosphorothioates. In some embodiments, the present disclosure relates to chirally controlled CpG oligonucleotide compositions comprising CpG oligonucleotides comprising multiple modified internucleotidic linkages such as phosphorothioate linkages, wherein the oligonucleotides comprise one or more CpG region motifs having defined stereochemistry patterns of chiral internucleotidic linkages. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are capable of agonizing an immune response. In some embodiments, CpG oligonucleotides comprising one or more CpG region motifs are antagonistic. Methods for making and using chirally controlled CpG oligonucleotide compositions are also described. In some embodiments, no immune modulation is desired, and the present disclosure provides methods of identifying chirally controlled oligonucleotide compositions which have decreased immune modulation.

Oligonucleotides, compositions and methods thereof

Among other things, the present disclosure provides designed DMD oligonucleotides, compositions, and methods of use thereof. In some embodiments, the present disclosure provides technologies useful for repairing mutant DMD transcripts by skipping exon 51 or exon 53, so that the transcript can be translated into an internally truncated but at least partially functional Dystrophin protein variant. In some embodiments, the present disclosure provides technologies useful for modulating DMD transcript splicing. In some embodiments, provided technologies can alter splicing of a dystrophin (DMD) DMD transcript. In some embodiments, the present disclosure provides methods for treating diseases, such as muscular dystrophy, including but not limited to Duchenne muscular dystrophy, Becker's muscular dystrophy, etc.

Oligonucleotide compositions and methods of use thereof

Among other things, the present disclosure provides oligonucleotides, compositions, and methods thereof. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., knockdown ability, stability, delivery, etc. In some embodiments, the oligonucleotides decrease the expression, activity and/or level of a C9orf72 gene, including but not limited to, one comprising a repeat expansion, or a gene product thereof. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in treatment of C9orf72-related disorders.

Oligonucleotide compositions and methods thereof

Among other things, the present disclosure relates to designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide altered splicing of a transcript. In some embodiments, provided oligonucleotide compositions have low toxicity. In some embodiments, provided oligonucleotide compositions provide improved protein binding profiles. In some embodiments, provided oligonucleotide compositions have improved delivery. In some embodiments, provided oligonucleotide compositions have improved uptake. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions.

Among other things, the present disclosure provides designed oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide improved single-stranded RNA interference and/or RNase H-mediated knockdown. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., RNA interference (RNAi) activity, stability, delivery, etc. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in RNA interference and/or RNase H-mediated knockdown.

Among other things, the present disclosure provides designed PNPLA3 oligonucleotides, compositions, and methods thereof. In some embodiments, provided oligonucleotide compositions provide improved single-stranded RNA interference and/or RNase H-mediated knockdown. Among other things, the present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages) or N patterns thereof, conjugation with additional chemical moieties, and/or stereochemistry [e.g., stereochemistry of backbone chiral centers (chiral internucleotidic linkages)], and/or patterns thereof, can have significant impact on oligonucleotide properties and activities, e.g., RNA interference (RNAi) activity, stability, delivery, etc. In some embodiments, the present disclosure provides methods for treatment of diseases using provided oligonucleotide compositions, for example, in RNA interference and/or RNase H-mediated knockdown.

Among other things, the present disclosure provides technologies for altering splicing, particularly for increasing inclusion of exons in splicing products. In some embodiments, the present disclosure provides SMN2 oligonucleotides, compositions, and methods thereof. In some embodiments, the present disclosure provides chirally controlled SMN2 oligonucleotide compositions. In some embodiments, provided oligonucleotides and compositions can increase level of an exon 7-containing SMN2 splicing product and/or a gene product thereof. In some embodiments, the present disclosure provides methods for treatment of splicing-related conditions, disorders and diseases. In some embodiments, the present disclosure provides methods for treating SMN2-related conditions, disorders and diseases such as SMA (spinal muscular atrophy) and ALS (amyotrophic lateral sclerosis).

The present invention concerns methods and reagents useful in modulating gene expression in a variety of applications, including use in therapeutic, diagnostic, target validation, and genomic discovery applications. Specifically, the invention relates to synthetic chemically modified small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi) against target nucleic acid sequences. The small nucleic acid molecules are useful in the treatment of any disease or condition that responds to modulation of gene expression or activity in a cell, tissue, or organism.

RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)

This invention provides for a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R1-R4, L and X are defined herein. The compounds of formula (I) and pharmaceutically acceptable salts thereof are cationic lipids useful in the delivery of biologically active agents to cells and tissues.

Lipids and lipid compositions for the delivery of active agents

This invention provides for a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R-R, L and X are defined herein. The compounds of formula (I) and pharmaceutically acceptable salts thereof are cationic lipids useful in the delivery of biologically active agents to cells and tissues.

Growing community of inventors

Schwenksville, PA, United States of America

Chandra Vargeese