Non-human animal genomes, non-human animal cells, and non-human animals comprising a humanized KLKB1 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 KLKB1 locus express a human plasma kallikrein protein or a chimeric plasma kallikrein protein, fragments of which are from human plasma kallikrein. Methods are provided for using such non-human animals comprising a humanized KLKB1 locus to assess in vivo efficacy of human-KLKB 1-targeting reagents such as nuclease agents designed to target human KLKB1.

The present disclosure provides transgenic nematode systems for assessing function of heterologous genes, their variants and drug discovery. The transgenic nematodes contain a heterologous gene that is inserted via homologous recombination at the native locus replacing and removing the nematode ortholog, wherein expression of the heterologous gene rescues function of the removed nematode ortholog and a transgenic control animal is provided. The heterologous gene may be further modified to provide a variant, such as a human clinical variant, whereby a transgenic test animal is provided. Those transgenic test animals are used in methods to assess function of the heterologous variant and drug screens to find therapeutic candidates reversing deviant activity back to wildtype.

The present disclosure relates to genetically modified non-human animals (e.g., genetically-modified mice or rodents) that express a hACE2 and/or hTMPRRS2 under control of the mouse promoter and the genetically modified non-human animal does not express native ACE2 and/or hTMPRRS2. The present disclosure also relates to methods of generating the genetically-modified animals (e.g., genetically modified mice or rodents), and methods of using the genetically modified non-human animals (e.g., genetically modified mice or rodents) described herein.

The present invention pertains to a non-human genetically modified animal with increased susceptibility to infection with a human virus. The invention suggests to genetically impair the expression of newly identified viral infection repression factors CD302, Cr11, Ndufc2, AW112010, Scarb2 and Zc3hav1, which markedly improves infection with human viruses in none-human hosts. Furthermore provided are methods for the generation of the animal of the invention, methods for increasing or reducing the susceptibility of a cell to viral infection, methods for screening novel modulators of viral infection as well as new therapy options for the treatment of viral diseases, in particular hepatitis C.

The invention relates to a kit of parts comprising (i) pharmacological chaperones or a pharmaceutically acceptable salt thereof and (ii) a therapeutic acid-alpha glucosidase (GAA) polypeptide or a nucleic acid molecule encoding a therapeutic GAA polypeptide, wherein said pharmacological chaperones are 1-deoxynojirimycin (DNJ) or a derivative thereof and ambroxol (ABX) or a derivative thereof.

The present invention relates to adeno-associated viral (AAV) particles encoding siRNA molecules and methods for treating amyotrophic lateral sclerosis (ALS).

The present disclosure provides, among other things, genetically modified non-human animals whose germline genome comprises an engineered endogenous immunoglobulin κ light chain locus comprising a single rearranged human immunoglobulin λ light chain variable region operably linked to a non-human Cλ gene segment, where the single rearranged human immunoglobulin λ light chain variable region comprises a human Vλ gene segment and a human Jλ gene segment. All immunoglobulin λ light chains expressed by B cells of the genetically modified non-human animal include human immunoglobulin λ light chain variable domains expressed from the single rearranged human immunoglobulin λ light chain variable region or a somatically hypermutated version thereof. Such animals, tissues from such animals, and cells from such animals represent an effective platform for producing antibodies, e.g., bispecific antibodies.

The present invention is directed to genetically-modified non-human animal models with specific mutations in exon 3 of proline-rich acidic protein 1 (PRAP1) gene. Also disclosed herein are methods of treating hyperlipidemia or a hyperlipidemia-related disease by using a PRAP1 inhibitor or a modified PRAP1 polypeptide, as well as pharmaceutical compositions comprising the modified PRAP1 polypeptide.

This disclosure relates to genetically modified animals and cells with humanized light chain immunoglobulin locus and/or humanized heavy chain immunoglobulin locus. In one aspect, the endogenous light chain immunoglobulin locus comprises a limit number of human IGKV genes and human IGKJ genes.

An object of the present invention is to provide a method of conveniently producing a genetically modified non-human mammal with high efficiency using a CRISPR-Cas9 system and particularly a production method whereby gene knock-in can be achieved with high efficiency regardless of the gene size. The method of producing a genetically modified non-human mammal comprises introducing a Cas9 protein, a crRNA fragment comprising a nucleotide sequence complementary to a target DNA region, and a tracrRNA fragment into a non-human mammalian oocyte to genetically modify the target DNA.