Leland Stanford Junior University

National Yang Ming Chiao Tung University

Harvard College

Cetus Corporation

Other

Functional Genetics, Inc.

Stanley N Cohen

Tzu-Hao Cheng

Limin Li

Quan Lu

Tzu-Han Wang

Chia-Rung Liu

Qiyu Wang

Annie C Chang

Herbert W Boyer

Alan S Michaels

Channing R Robertson

Joseph F Nabhan

Yun-Yun Wu

Ning Deng

Chia-Rung Lu

Jack H Nunberg

Carol Carter

Robert T Schimke

Tse-I Lin

Ronen Mosseri

Arthur Goff

Yanan Feng

Lorna Ehrlich

Wen-Chieh Hsieh

Martin Vogtli

C Richard Savage, Jr

Chih Jian Lih

Chun-Ming Huang

Christine A Miller

John J Sninsky

William J Smith

Douglas S Inloes

Wensheng Wei

Hermann G Bujard

The present invention provides a method of modulating the expression of a gene containing expanded nucleotide repeats in a cell, comprising: inhibiting the biological activity of SPT4 or SUPT4H; and regulating the formation of R-loops. The inhibition step can effectively reduce the expression of the gene containing the expanded nucleotide repeats and the regulatory step can further enhance the inhibition step. The inhibition step and the regulation step are for the purpose of regulating gene expression by interfering the capacity of RNA polymerase II transcribing over a DNA template with lengthy nucleotide repeats.

Method to enhance the transcription regulation of SUPT4H on genes containing repetitive nucleotide sequences

Methods, systems, compositions and strategies for the delivery of WW domain-containing fusion proteins into cells in vivo, ex vivo, or in vitro via ARMMs are provided. Methods, systems, compositions and strategies for the delivery of Cas9 proteins and/or Cas9 variants into cells in vivo, ex vivo, or in vitro via fusion to ARMM associated proteins (e.g., ARRDC1 or TSG101) are also provided.

Delivery of CAS9 via ARRDC1-mediated microvesicles (ARMMs)

Methods, systems, compositions and strategies for the delivery of WW domain-containing fusion proteins into cells in vivo, ex vivo, or in vitro via ARMMs are provided. Methods, systems, compositions and strategies for the delivery of cargo proteins into cells in vivo, ex vivo, or in vitro via fusion to ARMM associated proteins (e.g., ARRDC1 or TSG101) are also provided.

Delivery of cargo proteins via ARRDC1-mediated microvesicles (ARMMs)

The invention provide isolated arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs). Methods for generating and for isolating ARMMs are also provided herein. ARMMs can be used to deliver agents, for example, nucleic acids (e.g., siRNAs, microRNAs, lincRNAs), proteins (e.g., transcription factors, chromatin modulators, kinases, phosphorylases, or recombinases), or small molecules to target cells in vitro and in vivo, and methods for such ARMM-mediated delivery are provided herein. Diagnostic and therapeutic methods using ARMMs are also described herein.

ARRDC1-mediated microvesicles (ARMMS) and uses thereof

Aspects of the present disclosure include methods of reducing the deleterious impact of a target gene in a cell, such as the deleterious activity of a mutant extended nucleotide repeat (NR) containing target gene in a cell, by contacting the cell with an effective amount of an enantiomeric tetrahydrocarbazolamine compound. The deleterious activity (e.g., toxicity and/or dis-functionality of products encoded thereby) of a mutant extended NR containing target gene may be reduced, e.g., by reducing (and in some instances differentially, including selectively, reducing) the production or activity of toxic expression products (e.g., RNA or protein) encoded by the target gene. Kits and compositions for practicing the subject methods are also provided.

Enantiomeric compound for the reduction of the deleterious activity of extended nucleotide repeat containing genes

Aspects of the invention include methods of selectively reducing the deleterious activity of mutant extended trinucleotide repeat containing genes in a cell, as well as compositions used in such methods. The deleterious activity (e.g., toxicity and/or dis-functionality of products encoded thereby) of a mutant extended trinucleotide repeat containing gene may be selectively reduced in a variety of different ways, e.g., by selectively decreasing SPT4 mediated transcriptional activity, by enhancing functionality of proteins encoded thereby, etc. Aspects of the invention further include assays for identifying agents that find use in methods of the invention, e.g. as summarized above. Methods and compositions of the invention find use in a variety of different applications, including the prevention or treatment of disease conditions associated with the presence of genes containing mutant extended trinucleotide repeats, such as Huntington's Disease (HD).

Selective reduction of the deleterious activity of extended tri-nucleotide repeat containing genes

Aspects of the invention include methods of reducing the deleterious activity of a mutant extended nucleotide repeat (NR) containing target gene in a cell by contacting the cell with an effective amount of a nucleoside agent, as well as compositions used in such methods. The deleterious activity (e.g., toxicity and/or dis-functionality of products encoded thereby) of a mutant extended NR containing target gene may be reduced in a variety of different ways, e.g., by reducing (and in some instances differentially, including selectively, reducing) the production or activity of toxic expression products (e.g., RNA or protein) encoded by the target gene. Kits and compositions for practicing the subject methods are also provided.

Nucleoside agents for the reduction of the deleterious activity of extended nucleotide repeat containing genes

Methods, systems, compositions and strategies for the delivery of WW domain-containing fusion proteins into cells in vivo, ex vivo, or in vitro via ARMMs are provided. Methods, systems, compositions and strategies for the delivery of cargo proteins, such as transcription factors, tumor suppressors, developmental regulators, growth factors, metastasis suppressors, pro-apoptotic proteins, nucleases, recombinases, and reprogramming factors into cells in vivo, ex vivo, or in vitro via fusion to ARMM associated proteins (e.g., ARRDC1 or TSG101) are also provided.

The invention provide isolated arrestin domain-containing protein 1 (ARRDC1)-mediated micro vesicles (ARMMs). Methods for generating and for isolating ARMMs are also provided herein. ARMMs can be used to deliver agents, for example, nucleic acids (e.g., siRNAs, microRNAs, lincRNAs), proteins (e.g., transcription factors, chromatin modulators, kinases, phosphorylases, or recombinases), or small molecules to target cells in vitro and in vivo, and methods for such ARMM-mediated delivery are provided herein. Diagnostic and therapeutic methods using ARMMs are also described herein.

ARRDC1-mediated microvesicles (ARMMs) and uses thereof

This invention provides a method for modulating the expression of a first gene in a cell wherein the first gene is one containing more than 36 CAG trinucleotide repeats and encoding a protein that form polyglutamine-mediated protein aggregation. Suppression of the first gene is achieved by reducing the expression of SPT4 gene or SUPT4H gene. It can also be achieved by inhibiting the formation of a Spt4/Spt5 complex or a Supt4h/Supt5h complex. Also provided is a method for identifying an agent useful for modulating the expression and aggregation of CAG-expanded gene product, or treating a polyglutamine disease such as Huntington's disease.

Methods for identifying agents useful for modulating the expression and aggregation of CAG-expanded gene product in cells

Methods for modulating the expression and aggregation of a CAG-expanded gene product in cells and methods for identifying agents useful for doing the same

Methods and compositions for enhancing taxane sensitivity are provided. Aspects of the subject methods include administering to a subject a txr1 pathway modulatory agent in conjunction with a taxane. Also provided are txr1 polypeptides and nucleic acids encoding the same. The subject methods and compositions find use in a variety of different applications.

Txr1 and enhanced taxane sensitivity based on the modulation of a pathway mediated thereby

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Stanford, CA, United States of America

Stanley N Cohen