Described herein are donor vectors and systems for use in in vivo dual recombinase-mediated cassette exchange. Also described are animal models for consistent, rigorous, and facile investigation of transgene expression. Further described are methods of screening for therapeutic drugs using these animal models, and methods of treatment.

A primatized rodent or swine, and methods of making and using the primatized rodent or swine, are provided.

The invention provides for systems, methods, and compositions for altering expression of target gene sequences and related gene products. Provided are structural information on the Cas protein of the CRISPR-Cas system, use of this information in generating modified components of the CRISPR complex, vectors and vector systems which encode one or more components or modified components of a CRISPR complex, as well as methods for the design and use of such vectors and components. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for utilizing the CRISPR-Cas system. In particular the present invention comprehends optimized functional CRISPR-Cas enzyme systems, wherein the guide sequence is modified by secondary structure to increase the specificity of the CRISPR-Cas system and whereby the secondary structure can protect against exonuclease activity and allow for 5′ additions to the guide sequence.

Disclosed herein are rodents (such as mice and rats) genetically modified at an endogenous Scn9a locus to comprise an exogenous Scn nucleotide sequence such as the coding sequence of a human SCN2A gene. Also disclosed are methods and compositions useful for making such rodents, and methods of using such rodents for generating anti-NaV1.7 antibodies.

A non-human mammalian model for human diseases or disorders comprising a non-human neutrophil depleted mammalian host engrafted with a human skin equivalent (huSE) and human immune cells.

Provided is use of thiamine pyrophosphokinase TPK as a target in the treatment of Alzheimer's disease; and AD symptoms due to the inhibited TPK can be prevented by promoting the kinase activity and/or expression level of TPK protein in brain with TPK as a target.

A preparation method of an anti-PD-1/PD-L1 monoclonal antibody (mAb)-induced autoimmune myocarditis model is provided, including: mediating a model with adeno-associated virus 9 (AAV9) to achieve the high expression of PDL1 in a myocardial tissue, and applying an anti-PD-1/PD-L1 mAb to the model with high PDL1 expression in the myocardial tissue for modeling. The present disclosure also provides use of an animal model prepared by the preparation method. The model prepared by the present disclosure truly simulates the pathogenesis and clinical course of autoimmune myocarditis in a patient administered with an anti-PD1/PD-L1 mAb, is close to a pathophysiological status of a clinical patient, has a high modeling rate, and can be dynamically monitored.

The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) major histocompatibility complex (MHC) protein complex, and methods of use thereof.

The disclosure provides for methods and compositions for treating a premature aging disorder or neurodegenerative disorder, particularly neurodegenerative disorders associated with amyloid deposition and neuronal death, such as Alzheimer's disease. Accordingly, aspects of the disclosure relate to a method for treating a premature aging disorder in a subject in need thereof, comprising administering a TERT activating therapy to the subject. Further aspects relate to a method for treating a neurodegenerative disorder in a subject comprising administering a TERT activating therapy to the subject.

A method of restoring lysosomal function of retinal pigment epithelial (RPE) cells and a method of preventing and/or treating age-related macular degeneration (AMD), Stargardt's macular retinal degeneration, neurodegenerative disease, or diabetic retinopathy in a subject are provided. The methods comprise administering (i) a nucleic acid encoding a polypeptide comprising a constitutively active form of transcription factor EB (TFEB) or (ii) the polypeptide to a subject in need thereof. Associated polypeptides, nucleic acids, vectors, and compositions thereof also are provided.