The current Alzheimer's disease model mouse, developed by manipulating the expression of a gene directly related to distinctive pathology that is specific to the disease, such as acceleration of amyloid plaque deposition, is a model of a preclinical state, or of a pathology that is fundamentally different from human Alzheimer's disease. In view of the current state described above, the present invention addresses the problem of developing a non-human transgenic animal in which Alzheimer's pathology is more accurately reflected, and thereby elucidating a disease mechanism or contributing to drug discovery. In the present invention, by heterozygous knockout of the drebrin gene of a non-human Alzheimer's disease model animal used as a base, senescence risk can be imparted to the conventional non-human Alzheimer's disease model animal. Alzheimer's pathology is more accurately reflected in this non-human Alzheimer's disease model animal.

Application of a fragment of an isolated nucleotide sequence in the construction of zebrafish without intermuscular bones. The nucleotide sequence is shown in SEQ ID NO:1. Gene mutation is performed by taking SEQ ID NO:1 as a target gene; the mutant F0 embryos are selected and cultured to adult fish; F0 mutant is hybridized with wild type zebrafish to generate an F1 embryos; sense mutant heterozygotes F1 is screened out and cultured to adult fish; and then F1 heterozygote self-crosses to generate F2 generation of three gene types, including homozygote, heterozygote, and wild type. Zebrafish without intermuscular bones is obtained by using a gene mutation method, which provided a basis for subsequent research on a molecular formation mechanism of fish intermuscular bones and the cultivation of economic fishes without intermuscular bone and possessed a basic research value and an application value in other economic aquaculture fish species.

Methods for treatment and diagnosis of neurological disorders such as autism and autism spectrum disorder are disclosed. Also disclosed are modulators of alternative splicing regulators SRRM4 and/or SRRM3 for treating neurological disorders. Further disclosed are agents that modulate the expression of at least one splice variant for treating neurological disorders. Mouse models of neurological disorders having increased or decreased expression of SRRM4 and/or SRRM3 are also disclosed.

Genetically modified non-human animals are provided that exhibit a functional lack of one or more IncRNAs. Methods and compositions for disrupting, deleting, and/or replacing IncRNA-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 IncRNAs.

Provided herein are mice that are heterozygous knock outs for Ctla4 and homozygous knockouts for Pdcd1 (Ctla4.sup.+/− Pdcd1.sup.−/− mice), which may suffer from autoimmunity, including myocarditis and insulin-dependent diabetes mellitus. Also provided are methods of using such mice to screen for therapeutic agents that mitigate immune-related adverse events.

Provided herein are phosphorylated Dicer 1 (pDicer1) antibodies, including those that selectively bind Serine 1728 and/or Serine 1852. Further provided herein are methods of treating cancer by administering the pDicer1 antibodies alone or in combination with other therapies.

An animal model for motor neuron dysfunction in disease, e.g., amyotrophic lateral sclerosis (ALS), comprising a genetically modified non-human animal that comprises a genetically modified DR6 allele and exhibits normal phenotypes at birth and for a few weeks or months after birth. However, as the non-human animal ages, it develops motor neuron dysfunction that presents as one or more ALS-like symptoms, which may progress rapidly after onset. Methods of identifying candidate agents that may be used to prevent, delay or treat ALS are also provided.

The invention involves a method for modulating leukocyte activity, comprising delivering to a leukocyte a vector containing nucleic acid molecule(s), whereby the leukocyte contains Cas9 and the vector expresses one or more RNAs to guide the Cas9 to introduce mutations in one or more target genetic loci in the leukocyte, thereby modulating expression of one or more genes expressed in the leukocyte. The invention also involves identifying genes associated with leukocyte responses and experimental modeling of aberrant leukocyte activation and diseases associated with leukocytes by introducing mutations into leukocytes. The invention comprehends testing putative treatments with such models, e.g., testing putative chemical compounds that may be pharmaceutically relevant for treatment or gene therapy that may be relevant for treatment, or combinations thereof. The invention allows for the study of genetic diseases and putative treatments to better understand and alleviate leukocyte associated diseases.

The present disclosure provides compositions and methods for treating, preventing, or inhibiting laminopathies. In one aspect, the disclosure provides nucleic acid constructs and/or vectors comprising a nucleotide sequence encoding lamin A and/or lamin C.

Provided herein is a gene therapy for GLUT1 Deficiency Syndrome and related disorders using a recombinant adeno-associated virus (rAAV) virion as a vector to express an GLUT1 protein or functional variant thereof. The rAAV virion may use an endothelial-specific promoter, e.g., a FLT-1 or Tie-1 promoter. The capsid may be an AAV6, AAV8, AAV9, AAVrh.74, or AAVrh.10 capsid or a functional variant thereof. Other promoters or capsids may be used. Further provided are methods of treatment, such as by intracerebrally and/or intravenously of the rAAV virion, and other compositions and methods.