Regeneron Pharmaceuticals, Inc.

Regeneran Pharmaceuticals, Inc.

Harvard College

Ka-Man Venus Lai

David M Valenzuela

David Frendewey

Andrew J Murphy

Wojtek Auerbach

George D Yancopoulos

Guochun Gong

Jose F Rojas

David Heslin

Lynn Macdonald

Alexander O Mujica

Jeffrey D Lee

John R McWhirter

Elena Burova

Gregg S Warshaw

Corey Momont

Chris Schoenherr

Gavin Thurston

Gustavo Droguett

Cagan Gurer

Vera Voronina

Kara Olson

Yajun Tang

Charleen Hunt

Dayong Guo

Caitlin Montagna

Eric L Smith

Aris N Economides

Jesper Gromada

Brian Zambrowicz

Michael L LaCroix-Fralish

Chia-Jen Siao

Anthony Gagliardi

Jason Mastaitis

John L Rinn

Burcin Ikiz

Amanda Atanasio

Eric B Smith

Susan D Croll

Junko Kuno

Nicole M Alessandri-Haber

Marine Prissette

Meghan Drummond Samuelson

Claudia Gonzaga-Jauregui

Chunguang Guo

Caitlin L Goshert

Susannah Brydges

Sokol Haxhinasto

Daisuke Kajimura

John Mcwhirter

Aarti Sharma-Kanning

Roxanne Ally

Hoi-Ching Lee

Zhe Li

Robert Breese

Ashok Badithe

Eric Smith

Kara L Olson

Michael L Lacroix-Fralish

Jeffrey Lee

O Mujica Alexander

Michael Lacroix-Fralish

Hovhannisyan Zaruhi

Non-human animals, expressing humanized CD3 proteins are provided. Non-human animals, e.g., rodents, genetically modified to comprise in their genome humanized CD3 proteins are also provided. Additionally, provided are methods and compositions of making such non-human animals, as well as methods of using said non-human animals.

Non-human animals expressing humanized CD3 complex

Genetically modified non-human animals comprising a humanized interleukin-15 (IL-15) gene. Cells, embryos, and non-human animals comprising a human IL-15 gene. Rodents that express humanized or human IL-15 protein.

Humanized IL-15 animals

Methods and compositions are provided for generating antigen-binding proteins against a foreign antigen of interest.

Methods for producing antigen-binding proteins against foreign antigens

Non-human animals, methods and compositions for making and using the same, are provided, wherein said non-human animals comprise a humanization of a Cluster of Differentiation 274 (CD274) gene. Such non-human animals may be described, in some embodiments, as having a genetic modification to an endogenous CD274 gene so that said non-human animals express a Programmed cell death ligand 1 (PD-L) polypeptide that includes a human portion and an endogenous portion (e.g., a non-human portion).

Genetically modified mouse that expresses humanized PD1 and PD-L1 proteins

Compositions and methods are provided for making rat pluripotent and totipotent cells, including rat embryonic stem (ES) cells. Compositions and methods for improving efficiency or frequency of germline transmission of genetic modifications in rats are provided. Such methods and compositions comprise an in vitro culture comprising a feeder cell layer and a population of rat ES cells or a rat ES cell line, wherein the in vitro culture conditions maintain pluripotency of the ES cell and comprises a media having mouse leukemia inhibitory factor (LIF) or an active variant or fragment thereof. Various methods of establishing such rat ES cell lines are further provided. Methods of selecting genetically modified rat ES cells are also provided, along with various methods to generate a transgenic rat from the genetically modified rat ES cells provided herein. Various kits and articles of manufacture are further provided.

Genetic modification of rats

Compositions and methods are provided for modifying a rat genomic locus of interest using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Compositions and methods for generating a genetically modified rat comprising one or more targeted genetic modifications in their germline are also provided. Compositions and methods are provided which comprise a genetically modified rat or rat cell comprising a targeted genetic modification in the rat interleukin-2 receptor gamma locus, the rat ApoE locus, the rat Rag2 locus, the rat Rag1 locus and/or the rat Rag2/Rag1 locus. The various methods and compositions provided herein allows for these modified loci to be transmitted through the germline.

Targeted modification of rat genome

Methods are provided herein for assembling at least two nucleic acids using a sequence specific nuclease agent (e.g., a gRNA-Cas complex) to create end sequences having complementarity and subsequently assembling the overlapping complementary sequences. The nuclease agent (e.g., a gRNA-Cas complex) can create double strand breaks in dsDNA in order to create overlapping end sequences or can create nicks on each strand to produce complementary overhanging end sequences. Assembly using the method described herein can assemble any nucleic acids having overlapping sequences or can use a joiner oligo to assemble sequences without complementary ends.

Nuclease-mediated DNA assembly

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided.

Methods and compositions for the targeted modification of a genome

Provided are non-human animals comprising a mutation in the Fbn1 gene to model neonatal progeroid syndrome with congenital lipodystrophy (NPSCL). Also provided are methods of making such non-human animal models. The non-human animal models can be used for screening compounds for activity in inhibiting or reducing NPSCL or ameliorating NPSCL-like symptoms or screening compounds for activity potentially harmful in promoting or exacerbating NPSCL as well as to provide insights in to the mechanism of NPSCL and potentially new therapeutic and diagnostic targets.

Fibrillin-1 mutations for modeling neonatal progeroid syndrome with congenital lipodystrophy

Compositions and methods are provided for creating and promoting biallelic targeted modifications to genomes within cells and for producing non-human animals comprising the modified genomes. Also provided are compositions and methods for modifying a genome within a cell that is heterozygous for an allele to become homozygous for that allele. The methods make use of Cas proteins and two or more guide RNAs that target different locations within the same genomic target locus. Also provided are methods of identifying cells with modified genomes.

Methods and compositions for targeted genetic modification using paired guide RNAs

Non-human animals, and methods and compositions for making and using the same, are provided, wherein the non-human animals comprise a humanization of a Programmed cell death 1 (Pdcd1) gene. The non-human animals, in some embodiments, comprise a genetic modification to an endogenous Pdcd1 gene so that the non-human animals express a PD-1 polypeptide that includes a human portion and an endogenous portion (e.g., a non-human portion).

Non-human animals having a humanized programmed cell death 1 gene

This disclosure relates to genetically modified rodent animals and rodent models of human diseases. More specifically, this disclosure relates to genetically modified rodents whose genome comprises a humanized Il1rl2 gene (coding for the IL1rl2 subunit of the IL-36R protein) and human IL-36&#x3b1;, &#x3b2; and &#x3b3; ligand genes. The genetically modified rodents disclosed herein display enhanced skin and intestinal inflammation as a preclinical model of psoriasis and IBD, respectively, and serve as a rodent model of human DITRA disease.

Mouse model of DITRA disease and uses thereof

Genetically modified non-human animals are provided that exhibit a functional lack of one or more lncRNAs. Methods and compositions for disrupting, deleting, and/or replacing lncRNA-encoding sequences are provided. Genetically modified mice that age prematurely are provided. Also provided are cells, tissues and embryos that are genetically modified to comprise a loss-of-function of one or more lncRNAs.

Method for screening gene expression in lincRNA-deficient mice or rats

A non-human animal model for neurodegenerative and/or inflammatory diseases is provided, which non-human animal comprises a disruption in a C9ORF72 locus. In particular, non-human animals described herein comprise a deletion of an entire coding sequence of a C9ORF72 locus. Methods of identifying therapeutic candidates that may be used to prevent, delay or treat one or more neurodegenerative (e.g., amyotrophic lateral sclerosis (ALS, also referred to as Lou Gehrig's disease) and frontotemporal dementia (FTD)), autoimmune and/or inflammatory diseases (e.g., SLE, glomerulonephritis) are also provided.

Non-human animals having a disruption in a C9ORF72 locus

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Tarrytown, NY, United States of America

Ka-Man Venus Lai