The invention involves inducing 3-50 or more mutations (e.g., any whole number between 3 and 50 of mutations, with it noted that in some embodiments there can be up to 16 different RNA(s), e.g., sgRNAs each having its own a promoter, in a vector, such as AAV, and that when each sgRNA does not have its own promoter, there can be twice to thrice that amount of different RNA(s), e.g., sgRNAs, e.g., 32 or even 48 different guides delivered by one vector) in transgenic Cas9 eukaryotes to model genetic disease, e.g. cancer. 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 a genetic disease or a condition, e.g., cancer.

Non-human animal genomes, non-human animal cells, and non-human animals comprising a humanized albumin (ALB) locus and methods of making and using such non-human animal genomes, non-human animal cells, and non-human animals are provided. Non-human animal cells or non-human animals comprising a humanized albumin locus express a human albumin protein or a chimeric albumin protein, fragments of which are from human albumin. Methods are provided for using such non-human animals comprising a humanized albumin locus to assess in vivo efficacy of human-albumin-targeting reagents such as nuclease agents designed to target human albumin.

The present disclosure provides, among other things, polynucleotide constructs, compositions, and methods of treating ornithine transcarbamylase deficiency, including administering to a subject in need thereof a composition comprising a polynucleotide construct comprising a 5′ UTR, a codon optimized mRNA encoding an ornithine transcarbamylase, and a 3′ UTR.

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.

Provided is an obsessive-compulsive disorder animal model and a production method thereof, in which a neuronal circuit connecting the basolateral amygdala (BLA) and the dorsomedial striatum (DMS) is activated. In the present disclosure, it was confirmed that the BLA and DMS are connected to each other, and that when the BLA-DMS neuronal circuit is activated, there is a large increase in checking, repeating, cleaning, and collecting, which are compulsive behaviors representative of obsessive-compulsive disorder, and a decrease in cognitive flexibility. Therefore, animals in which the BLA-DMS neuronal circuit is activated may be useful as animal models for studying obsessive-compulsive disorder. In particular, the obsessive-compulsive disorder animal model can reproduce all of the compulsive behaviors and thus may become the first animal model to provide an understanding of the interactions between anxiety behaviors and compulsive behaviors, which existing animal models have not been able to provide.

The invention discloses methods for the generation of chimaeric human-non-human antibodies and chimaeric antibody chains, antibodies and antibody chains so produced, and derivatives thereof including fully humanised antibodies; compositions comprising said antibodies, antibody chains and derivatives, as well as cells, non-human mammals and vectors, suitable for use in said methods.

Methods for modification of target nucleic acids. The method involves a construct in which guide RNA is covalently linked to donor RNA (fusion NA) to be introduced into the target nucleic acid by homologous recombination and is based on the introduction of a nuclease, e.g. CRISPR or TALEN, into the cell containing the target nucleic acid. The fusion NA may be introduced as a DNA vector.

The present disclosure relates to genetically modified non-human animals that express a fusion protein including B2M and FcRn, and methods of use thereof. In some embodiments, the animals can have a B-NDG background. In some embodiments, the endogenous B2M gene is knocked out in the animals.

The invention discloses methods for the generation of chimaeric human—non-human antibodies and chimaeric antibody chains, antibodies and antibody chains so produced, and derivatives thereof including fully humanised antibodies; compositions comprising said antibodies, antibody chains and derivatives, as well as cells, non-human mammals and vectors, suitable for use in said methods.

Provided are improved compositions and methods for achieving gene therapy in hematopoietic cells and hematopoietic precursor cells, including erythrocytes, erythroid progenitors, and embryonic stem cells. Also provided are improved gene therapy methods for treating hematopoietic-related disorders. Retroviral gene therapy vectors that are optimized for erythroid specific expression and treatment of hemoglobinopathic conditions are disclosed.