The present invention relates to a nucleic acid molecule encoding (I) a polypeptide having the activity of an endonuclease, which is (a) a nucleic acid molecule encoding a polypeptide comprising or consisting of the amino acid sequence of SEQ ID NO: 1; (b) a nucleic acid molecule comprising or consisting of the nucleotide sequence of SEQ ID NO: 2; (c) a nucleic acid molecule encoding an endonuclease, the amino acid sequence of which is at least 70% identical to the amino acid sequence of SEQ ID NO: 1; (d) a nucleic acid molecule comprising or consisting of a nucleotide sequence which is at least 50% identical to the nucleotide sequence of SEQ ID NO: 2; (e) a nucleic acid molecule which is degenerate with respect to the nucleic acid molecule of (d); or (f) a nucleic acid molecule corresponding to the nucleic acid molecule of any one of (a) to (e) wherein T is replaced by U; (II) a fragment of the polypeptide of (I) having the activity of an endonuclease. Also, the present invention relates to a vector comprising the nucleic acid molecule and a protein encoded by said nucleic acid molecule. Further, the invention relates to a method of modifying the genome of a eukaryotic cell and a method of producing a non-human vertebrate or mammal.

Provided herein are transgenic non-human animals whose genomes comprise two or more human genes selected from CD33, Siglec-5, Siglec-7, Siglec-9, Siglec-11, Siglec-14, and Siglec-16, to methods of screening candidate agents that bind to and/or modulate the function and/or activity of at least one of the human genes in the transgenic non-human animals, and to methods of screening candidate agents to determine their effect on one or more activities and/or functions associated with expression of at least one of the human genes in the transgenic non-human animals. Further provided herein are methods of recapitulating a human Siglec immune system in a non-human animal, and methods of generating a non-human animal disease model comprising a human Siglec repertoire.

The present invention provides: a composition for reconstituting human skin tissue having hair follicles, the composition characterized by containing human epidermal cells and human dermal cells, the human dermal cells containing cell groups of human hair papilla derived from non-embryos via spheroid formation; and a human skin tissue model animal to which said composition is applied. The invention also provides a method for producing said composition and animal.

An atopic dermatitis model non-human animal, containing a gene mutation in which a complex containing dedicator of cytokinesis 8 (DOCK8) protein, mammalian STE20-like kinase 1 (MST1) protein, and endothelial PAS domain protein 1 (EPAS1) protein is not formed in CD4.sup.+ T cells.

An atopic dermatitis model non-human animal, containing a gene mutation in which a complex containing dedicator of cytokinesis 8 (DOCK8) protein, mammalian STE20-like kinase 1 (MST1) protein, and endothelial PAS domain protein 1 (EPAS1) protein is not formed in CD4.sup.+ T cells.

Provided herein are compositions that include at least two different nucleic acid vectors, where each of the at least two different vectors includes a coding sequence that encodes a different portion of an otoferlin protein, and the use of these compositions to treat hearing loss in a subject.

A NOD.Cg-Prkdc.sup.scidH2rg.sup.tm1 Wjl/SzJ.(NOD-scid-IL2rγ.sup.null, NSG) mouse which is genetically modified such that the en NSG mouse lacks functional major histocompatibility complex I (MHC I) and lacks functional major histocompatibility complex II (MHC II) is provided according to aspects of the present, invention. According to specific aspects the genetically modified NSG mouse, is a NOD.Cg-Prkdc.sup.scidH2-K1.sup.tml Bpe H2-Ab1.sup.eml Mvw H2-D1.sup.tml Bpe H2rg.sup.tm Wjl/SzJ (NSG-K.sup.b D.sup.b).sup.null(IA.sup.null)) mouse, NSG-RIP-DTR (K.sup.b D.sup.b).sup.null(IA.sup.null) mouse, or a NOD.Cg-B2m.sup.tmlUnePrKdc.sup.scidH2.sup.dlAb1-E.sup.αH2rg.sup.tm1 Wjl/SzJ (NSG-B2M.sup.null(IA IE.sup.null)) mouse. Human, immune cells and/or human: tumor cells are administered to a genetically modified immunodeficient mouse according to aspects described herein and assays of one or more test substances can be performed using the provided mice.

The invention is directed to nucleic acid therapy for modulating host microflora, useful in the management of dysbiosis. The invention in embodiments thereof provides compositions and methods for alleviating dysbiosis and conditions associated therewith. According to additional embodiments, compositions and methods of the invention may be used for treating or preventing gut barrier dysfunction in a subject in need thereof, and for reducing the risk of developing adverse events related to expansion of gastrointestinal bacteria in patients at risk for developing dysbiosis, for example in hospitalized patients and immune suppressed subjects.

Provided are genetically modified non-human animals that express a human or chimeric (e.g., humanized) CCR8, and methods of use thereof.

The present disclosure relates to a pharmaceutical composition for the treatment of Leber congenital amaurosis, and a method for treating Leber congenital amaurosis using the pharmaceutical composition.