A method for preparing a CKO/KI animal model by using Cas9 technology includes a Cas9 protein expressed and purified in vitro, high-efficiency sgRNA(s) screened by sgRNA cleavage efficiency test on embryos in advance, and single-stranded DNA as targeting vector(s) are mixed with Cas9 protein and sgRNA(s) and then subjected to embryo injection and transplantation; mice born after transplantation are marked as F0 and the genotype identification of F0 is carried out; sexually mature F0 with the correct genotype are bred, and the offspring mice thereof are marked as F1; and the F1 mice are analyzed and verified, and the F1 mice with the correct genotype are the prepared CKO/KI animal model.

Artificial expression constructs for selectively modulating gene expression in selected central nervous system cell types are described. The artificial expression constructs can be used to selectively express synthetic genes or modify gene expression in GABAergic neurons generally; and/or GABAergic neuron cell types such as lysosomal associated membrane protein 5 (Lamp5) neurons; vasoactive intestinal polypeptide-expressing (Vip) neurons; somatostatin (Sst) neurons; and/or parvalbumin (Pvalb) neuron cell types. Certain artificial expression constructs additionally drive selective gene expression in Layer 4 and/or layer 5 intratelencephalic (IT) neurons, deep cerebellar nuclear neurons or cerebellar Purkinje cells.

Provided are ionizable cationic lipids and lipid nanoparticles for the delivery of nucleic acids to cells (e.g., immune cells), and methods of making and using such lipids and targeted lipid nanoparticles.

Disclosed herein are methods and non-human mammals for in vivo functional genomic screens.

The present invention relates to a compound comprising (1) a first binding moiety that binds to an Interleukin 4 receptor; and (2) a second binding moiety that binds to a cytokine receptor (e.g., an Interleukin 10 receptor, Interleukin 13 receptor, interleukin 27 receptor, interleukin 33 receptor, or transforming growth factor beta 1/2 receptor). Compounds of the disclosure cluster or crosslink the IL4 receptor and a cytokine receptor, and surprisingly, elicit unique responses in the nervous system, including unique signaling and gene expression profiles. The signaling and gene expression profiles generated IL4-cytokine fusion proteins of the disclosure are distinct from those observed in response to the combination of IL4 and the cytokine, and contribute to the superior therapeutic effects over the combination of the component parts.

Compositions and methods are provided for modifying and treating neuroinflammatory and neurodegenerative diseases. The methods and compositions can be used to ameliorate the effects of a deficiency in the LC3-associated endocytosis (LANDO) pathway for clearing β-amyloid. Thus, methods are further provided for modulating β-amyloid clearance using an effective amount of a pharmaceutical composition that targets the LANDO pathway. Accordingly, pharmaceutical compositions that target the LANDO pathway are provided herein. The methods and compositions described herein can be used to treat neuroinflammatory and neurodegenerative diseases, such as Alzheimer's disease.

The present disclosure relates to the genetically modified non-human animals that express a human or chimeric OX40, and methods of use thereof.

The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) programmed cell death protein 1 (PD-1), and methods of use thereof. In one aspect, the animals have an insertion of a sequence encoding a human or humanized programmed cell death protein 1 (PD-1) at an endogenous PD-1 gene locus. This animal model can express a PD-1 protein containing a functional domain of the human PD-1 protein, and can be used as an animal model for developing therapeutics for human diseases and disorders, and assessing the toxicity and/or the efficacy of these human therapeutics.

Provided is the use of an ECM1 gene-knockout mouse in the screening of an anti-hepatic fibrosis drug. Specifically, provided is a method for preparing an animal model of hepatic fibrosis or related diseases thereof in non-human mammals, which method comprises the following steps: (a) providing a non-human mammalian cell and inactivating an ECM1 gene in the cell, thereby obtaining a non-human mammalian cell in which the ECM1 gene is inactivated; and (b) using the cell in which the ECM1 gene is inactivated obtained in step (a) to prepare an animal model of hepatic fibrosis or related diseases thereof in which the ECM1 gene is inactivated. The animal model is an effective animal model of hepatic fibrosis or related diseases thereof, may be used for studying hepatic fibrosis or related diseases thereof, and may be used in the screening and testing of a particular drug.

Disclosed herein are genetically modified rodent animals comprising in their genome a nucleic acid which comprises a nucleotide sequence encoding a human CR1 polypeptide, wherein the rodent animals display a human-like expression of the human CR1 polypeptide. Also disclosed herein are isolated rodent cells including rodent embryonic stem cells, and rodent tissues. Further disclosed are nucleic acid vectors and methods for making the genetically modified rodent animals, as well as methods of using such genetically modified rodent animals for screening and testing candidate compounds.