The present disclosure provides transgenic non-human animal (e.g., nematode) systems for assessing heterologous polygenic or monogenic phenotypes, their variants and drug discovery. The transgenic non-human animals (e.g., nematodes) contain a first heterologous polypeptide coding sequence and a second heterologous polypeptide coding sequence (a plurality of heterologous polypeptide coding sequences), wherein the first and second heterologous polypeptide coding sequences are integrated into the host animal genome, and wherein expression of the first and second heterologous polypeptide coding sequence contribute to the heterologous phenotype. The plurality of heterologous polypeptide coding sequences are interrelated wherein their expression products, directly or indirectly, contribute or lead to an observable phenotype.

Provided is a genetically modified non-human mammal that comprises an anchor DNA sequence inserted at an endogenous locus of a secretory milk protein gene, wherein the anchor DNA sequence comprises a site-specific recombinase recognition site. Also provided is a genetically modified non-human mammal that comprises a transgene inserted at an endogenous locus of a secretory milk protein gene, wherein the transgene encodes a secretory protein and is operably linked to the endogenous promoter of said secretory milk protein gene, and wherein the transgene is flanked by a pair of site-specific recombinase resulting sites. The genetically modified non-human mammals provided can be used for producing the secreted recombinant protein encoded by the transgene from the milk produced by the genetically modified non-human mammals.

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits expression or activity of a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.

Provided herein are engineered TSC2 polypeptides, and nucleic acid sequences encoding them, in which the ability of a serine residue to be phosphorylated is altered. In some aspects, the TSC2 serine residue cannot be phosphorylated (e.g., by substituting the serine residue with an alanine residue). In some aspects, the TSC2 serine acts as if it is constitutively phosphorylated (e.g., by substituting the serine residue with a glutamic acid residue). Also provided herein are engineered immune cells comprising altered TSC2 polypeptides or nucleic acid sequences encoding them, and methods of making and using such engineered immune cells.

The invention relates to nucleic acid constructs for expression in mice for the reproduction of heavy chain only antibodies and V.sub.H domains, transgenic mice, related methods and uses.

The invention provides genetically modified non-human animals that express chimeric human/non-human T cell co-receptor polypeptides (e.g., CD4, CD8α, CD8β), as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified animals and methods of making the same.

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).

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 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.

The present subject matter provides, inter alia compositions, formulations, and methods for inhibiting, treating, and preventing small vessel diseases.