Models and methods related to targeting binding immunoglobulin protein (BiP) are described, where the models and methods allow identification and analysis of protein folding and misfolding.

Non-human animals comprising a human or humanized IL-4 and/or IL-4Rα nucleic acid sequence are provided. Non-human animals that comprise a replacement of the endogenous IL-4 gene and/or IL-4Rα gene with a human IL-4 gene and/or IL-4Rα gene in whole or in part, and methods for making and using the non-human animals, are described. Non-human animals comprising a human or humanized IL-4 gene under control of non-human IL-4 regulatory elements is also provided, including non-human animals that have a replacement of non-human IL-4-encoding sequence with human IL-4-encoding sequence at an endogenous non-human IL-4 locus. Non-human animals comprising a human or humanized IL-4Rα gene under control of non-human IL-4Rα regulatory elements is also provided, including non-human animals that have a replacement of non-human IL-4Rα-encoding sequence with human or humanized IL-4Rα-encoding sequence at an endogenous non-human C IL-4Rα locus. Non-human animals comprising human or humanized IL-4 gene and/or IL-4Rα sequences, wherein the non-human animals are rodents, e.g., mice or rats, are provided.

Disclosed herein are methods and compositions for inactivating mutant genes associated with LCA, using engineered nucleases comprising a DNA binding domain and a cleavage domain or cleavage half-domain in conditions promoting the cleavage of the mutant genes. Polynucleotides encoding nucleases, vectors comprising polynucleotides encoding nucleases, and cells comprising polynucleotides encoding nucleases and/or cells comprising nucleases are also provided.

The present invention is related to short-term renal injury models and methods for creating these models. The models and methods can be used for identifying, testing or characterizing candidate molecules with respect to their suitability to treat renal injury. The methods comprise a step of inducing, in a test subject, renal injury by administering subcutaneously a bolus of a renal injury inducer, in a dosage sufficiently high to induce renal injury. Different types of readout for renal injury are provided such as albumin creatinine ratio (ACR) determined in a urine sample taken from the subject, or the development of transcutaneous fluorescence after injection of a fluorescent molecule. Based on the readout the degree of renal injury and/or alteration of GFR can be determined.

The present invention relates to compositions comprising a delivery vehicle conjugated to a targeting domain, wherein the delivery vehicle comprises at least one agent, and wherein the targeting domain specifically binds to an CD4.sup.+ T cell antigen. The invention also relates to methods of treating or preventing diseases and disorders, including cancers, infectious diseases, and immunological disorders, using the described compositions.

An object of the present invention is to provide an evaluation system capable of detecting an extracellular purinergic receptor ligand minimally invasively, chronologically and systemically, and the present invention provides a genetically modified non-human animal expressing a first fusion protein and a second fusion protein for detecting an extracellular purinergic receptor ligand, in which the first fusion protein comprises a membrane protein that binds to a purinergic receptor ligand, and a first reporter protein, and the second fusion protein comprises a protein that binds to the membrane protein bound to the ligand, and a second reporter protein; and a cell thereof.

Non-human animals comprising a human or humanized IL-4 and/or IL-4Rα nucleic acid sequence are provided. Non-human animals that comprise a replacement of the endogenous IL-4 gene and/or IL-4Rα gene with a human IL-4 gene and/or IL-4Rα gene in whole or in part, and methods for making and using the non-human animals, are described. Non-human animals comprising a human or humanized IL-4 gene under control of non-human IL-4 regulatory elements is also provided, including non-human animals that have a replacement of non-human IL-4-encoding sequence with human IL-4-encoding sequence at an endogenous non-human IL-4 locus. Non-human animals comprising a human or humanized IL-4Rα gene under control of non-human IL-4Rα regulatory elements is also provided, including non-human animals that have a replacement of non-human IL-4Rα-encoding sequence with human or humanized IL-4Rα-encoding sequence at an endogenous non-human C IL-4Rα locus. Non-human animals comprising human or humanized IL-4 gene and/or IL-4Rα sequences, wherein the non-human animals are rodents, e.g., mice or rats, are provided.

The present disclosure provides multispecific antigen-binding molecules capable of binding to CD3 and CD137 (4-1BB) but not binding to CD3 and CD137 at the same time, and capable of binding to CLDN6. The multispecific antigen-binding molecules of the present disclosure exhibit enhanced T-cell dependent cytotoxicity activity in a CLDN6-dependent manner through binding to the CD3/CD37 and CLDN6. The present invention provides multi-specific antigen-binding molecules and pharmaceutical compositions thereof that can be used for targeting cells expressing CLDN6, for use in immunotherapy for treating various cancers, especially those associated with CLDN6 such as CLDN6-positive cancers.

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.

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.