Max-Planck-Gesellschaft Zur F&#xf6;rderung Der Wissenschaften E. V.

The Rockefeller University

Massachusetts Institute of Technology

University of Massachusetts

Whitehead Institute for Biomedical Research

Memorial Sloan Kettering Cancer Center

Rutgers, the State University of New Jersey

University of Bonn

Europaisches Laboratorium Fur Molekularbiologie

Thomas Tuschl

Winfried Lendeckel

Sayda Mahgoub Elbashir

Reinhard Rauhut

Mariana Lagos-Quintana

Jutta Meyer

Phillip D Zamore

Phillip A Sharp

David P Bartel

Sebastien Pfeffer

Markus Stoffel

Markus Landthaler

Dinshaw J Patel

Matthew N Poy

Manuel Ascano, Jr

Gunter Meister

Gunther Hartmann

Roger A Jones

Winfried Barchet

Thomas Zillinger

Pu Gao

Janos Ludwig

Barbara L Gaffney

Yizhou Liu

Yang Wu

Reinhard Luehrmann

Yi Pei

Henning Urlaub

Carolina Lin

Pavol Cekan

Pablo Landgraf

Agnieszka Patkaniowska

Javier Martinez

Yasutomi Asano

Taku Kamei

Rei Okamoto

Mayako Michino

Lodoe Lama

Cherin Sohn

Tilmann Achsel

John Pena

Jutta Dammann

Toshihiro Imaeda

Liang Deng

Weiyi Wang

Jumpei Aida

Jenny Li

Matthias Wilm

J Fraser Glickman

Daisuke Tomita

Shogo Hashizume

Mathew N Poy

Marina Lagos-Quintana

Sara H Rouhanifard

Takanobu Kuroita

Reinhard Lührmann

Michael Miller

Sara Hakim

Mihaela Zavolan

Jutta Myer

Klaas Max

Karl Bertram

Kemal Akat

Neil Renwick

Markus Hafner

Mohsen Khorshid

Lukas Burger

Kimberly Bogardus

Philip D Zamore

Reinhard LÜHRMANN

Taku Kamel

JFraser Glickman

Roger Jones

Manuel Ascano

Tri-cyclyl nitrogen-containing heterocyclic compounds are disclosed. The compounds are inhibitors of human cGAS in interferon-producing cell types. They are thus useful as therapeutic agents for treating cGAS-related autoimmune diseases in humans.

Inhibitors of gas for treating autoinflammatory diseases and cancer metastasis

1-(3,4-Dihydro-1H-pyrido[4, 3-b]indol-2(5H)-yl)-2-hydroxyethanones are disclosed. The compounds are inhibitors of human cGAS in interferon-producing cell types. They are thus useful as therapeutic agents for treating cGAS-related autoimmune diseases in humans.

Substituted pyrido[4,3-b]indoles and azepino[4,5-b]indoles as inhibitors of cGAS

The present disclosure provides, among other things, compounds comprising cyclic dinucleotides containing a 2',5' linkage useful in the design of research tools, as research tools, and as therapeutic modalities such as enzyme modulators.

Compositions and methods for altering second messenger signaling

The disclosure provides methods for isolating nucleic acids from a biological fluid. In one aspect, the disclosure provides a method for isolating RNA. In another aspect, the disclosure provides a method for isolating DNA. In one aspect, the methods described herein utilize a protocol that combines a detergent-based initial denaturation, protease digestion, and organic extraction followed by column purification that maximizes RNA/DNA yield and preserves RNA/DNA integrity. In yet another aspect, the disclosure provides a kit for isolating RNA and/or DNA.

Method of RNA isolation from clinical samples

Double-stranded RNA (dsRNA) induces sequence-specific post-transcriptional gene silencing in many organisms by a process known as RNA interference (RNAi). Using ain vitro system, we demonstrate that 19-23 nt short RNA fragments are the sequence-specific mediators of RNAi. The short interfering RNAs (siRNAs) are generated by an RNase III-like processing reaction from long dsRNA. Chemically synthesized siRNA duplexes with overhanging 3' ends mediate efficient target RNA cleavage in the lysate, and the cleavage site is located near the center of the region spanned by the guiding siRNA. Furthermore, we provide evidence that the direction of dsRNA processing determines whether sense or antisense target RNA can be cleaved by the produced siRNP complex.

RNA interference mediating small RNA molecules

The present invention relates to ain vitro system which was used to demonstrate that dsRNA is processed to RNA segments 21-23 nucleotides (nt) in length. Furthermore, when these 21-23 nt fragments are purified and added back toextracts, they mediate RNA interference in the absence of long dsRNA. Thus, these 21-23 nt fragments are the sequence-specific mediators of RNA degradation. A molecular signal, which may be their specific length, must be present in these 21-23 nt fragments to recruit cellular factors involved in RNAi. This present invention encompasses these 21-23 nt fragments and their use for specifically inactivating gene function. The use of these fragments (or chemically synthesized oligonucleotides of the same or similar nature) enables the targeting of specific mRNAs for degradation in mammalian cells, where the use of long dsRNAs to elicit RNAi is usually not practical, presumably because of the deleterious effects of the interferon response. This specific targeting of a particular gene function is useful in functional genomic and therapeutic applications.

RNA sequence-specific mediators of RNA interference

The invention relates to compositions, methods, kits, and assays related to the use and/or exploitation of isomers of cGAMP as well as the structure of the enzyme cGAS.

The present invention provides STING crystals. The present invention also provides STING modulators that interact with sites present in and/or defined by such crystals. The present invention also provides methods of making and using such crystals and modulators. Other aspects and/or features of the present invention will be apparent to those skilled in the art, reading the present specification.

STING crystals and modulators

The present invention relates to sequence and structural features of single-stranded (ss)RNA molecules required to mediate target-specific nucleic acid modifications by RNA-interference (RNAi), such as target mRNA degradation and/or DNA methylation.

RNA-interference by single-stranded RNA molecules

The present disclosure provides, among other things, novel cyclic-GMP-AMP (cGAMP) analogs, mimics, mimetics and variants, and compositions and kits thereof; methods of using the compounds as described herein for treating cancer, and immune disease, disorders, or conditions; methods of using the compounds as described herein for modulating cGAS and STING; and methods of designing or characterizing a cGAS modulator.

In, lin-4 and let-7 enclode 22- and 21-nucleotide RNAs, respectively, that function as key regulators of developmental timing. Because the appearance of these short RNAs is regulated during development, they are also referred to as 'small temporal RNAs' (stRNAs). We show that many more 21- and 22-nt expressed RNAs, termed microRNAs, (miRNAs), exist in invertebrates and vertebrates, and that some of these novel RNAs, similar to let-7 stRAN, are also highly conserved. This suggests that sequence-specific post-transcriptional regulatory mechanisms mediated by small RNAs are more general than previously appreciated.

Identification of novel genes coding for small temporal RNAs

The invention relates to isolated nucleic acid molecules comprising the sequence of a human cytomegalovirus microRNA. In another embodiment, the invention relates to single stranded DNA virus microRNA molecules comprising the sequence of a human cytomegalovirus microRNA. The invention also relates to the anti-DNA virus microRNA molecules.

DNA virus MicroRNA and methods for inhibiting same

Growing community of inventors

New York, NY, United States of America

Thomas Tuschl