The present invention describes transgenic animals with human(ized) immunoglobulin loci and transgenes encoding human(ized) Ig and/or Ig sequences. Of particular interest are animals with transgenic heavy and light chain immunoglobulin loci capable of producing a diversified human(ized) antibody repertoire that have their endogenous production of Ig and/or endogenous Ig and/or Ig sequences suppressed. Simultaneous expression of human(ized) immunoglobulin and human(ized) Ig and/or Ig results in normal B-cell development, affinity maturation and efficient expression of human(ized) antibodies.

Described herein is a compound of Formula I or a pharmaceutically acceptable salt thereof: wherein Ring A R.sup.1, R.sup.2, a, b, and n are as defined herein. Also described is a method of treating a subject having a disorder in need of treatment, comprising inhibiting aminolevulinic acid synthase 2 (ALAS2) in the subject by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Disorders that are of particular interest are blood disorders, such as porphyria and anemia.

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A transgenic non-human animal model for Neurofibromatosis type 1, wherein the Nf1 gene is specifically inactivated in BC cells and derivatives thereof. Also, an in vitro method of producing cutaneous and plexiform Neurofibromas (NFBs) and/or for studying the development and composition of plexiform NFBs, including culturing in vitro Prss56-expressing cells and-derivatives thereof obtained from the transgenic non-human animal model. Further, a method for screening a candidate compound for use as a drug to treat Neurofibromatosis type 1, cutaneous NFBs and/or plexiform NFBs including contacting the candidate compound Prss56-expressing cells and-derivatives thereof obtained from the transgenic non-human animal model or administering the candidate compound to the transgenic non-human animal model.

This invention relates to the engineering of animal cells, preferably mammalian, more preferably rat, that are deficient due to the disruption of tumor suppressor gene(s) or gene product(s). In another aspect, the invention relates to genetically modified rats, as well as the descendants and ancestors of such animals, which are animal models of human cancer and methods of their use.

Described herein are compositions (e.g. cells and transgenic animals) and methods relating to engineered Ig loci that permit expression of particular antibodies or antibody segments while still permitting recombination and/or maturation process for antibody optimization.

Duchenne muscular dystrophy (DMD), which affects 1 in 5,000 male births, is one of the most common genetic disorders of children. This disease is caused by an absence or deficiency of dystrophin protein in striated muscle. The major DMD deletion hot spots are found between exon 6 to 8, and exons 45 to 53. Here, a humanized mouse model is provided that can be used to test a variety of DMD exon skipping strategies. Among these are, CRISPR/Cas9 oligonucleotides, small molecules or other therapeutic modalities that promote exon skipping or micro dystrophin mini genes or cell based therapies. Methods for restoring the reading frame of exon 44 deletion via CRISPR-mediated exon skipping in the humanized mouse model, in patient-derived iPS cells and ultimately, in patients using various delivery systems are also contemplated. The impact of CRISPR technology on DMD is that gene editing can permanently correct mutations.

Non-human animals suitable for use as animal models for Retinoschisis are provided. In some embodiments, provided non-human animals are characterized by a disruption in a Retinoschisin-1 locus. In some embodiments, provided non-human animals are characterized by a mutant Retinoschisin-1 gene. The non-human animals may be described, in some embodiments, as having a phenotype that includes the development of one or more symptoms or phenotypes associated with Retinoschisis. Methods of identifying therapeutic candidates that may be used to prevent, delay or treat Retinoschisis or eye-related diseases, disorders or conditions are also provided.

Non-human animals suitable for use as animal models for Retinoschisis are provided. In some embodiments, provided non-human animals are characterized by a disruption in a Retinoschisin-1 locus. In some embodiments, provided non-human animals are characterized by a mutant Retinoschisin-1 gene. The non-human animals may be described, in some embodiments, as having a phenotype that includes the development of one or more symptoms or phenotypes associated with Retinoschisis. Methods of identifying therapeutic candidates that may be used to prevent, delay or treat Retinoschisis or eye-related diseases, disorders or conditions are also provided.

Described herein are compositions (e.g. cells and transgenic animals) and methods relating to engineered Ig loci that permit expression of particular antibodies or antibody segments while still permitting recombination and/or maturation process for antibody optimization.

In alternative embodiments, the invention provides nucleic acid sequences that are genetic polymorphic variations of the human TMEM216 gene, and TMEM216 polypeptide encoded by these variant alleles. In alternative embodiments, the invention provides methods of determining or predicting a predisposition to, or the presence of, a ciliopathy (or any genetic disorder of a cellular cilia or cilia anchoring structure, basal body or ciliary function) in an individual, such as a Joubert Syndrome (JS), a Joubert Syndrome Related Disorder (JSRD) or a Meckel Syndrome (MKS). In alternative embodiments, the invention provides compositions and methods for the identification of genetic polymorphic variations in the human TMEM216 gene, and methods of using the identified genetic polymorphisms and the proteins they encode, e.g., to screen for compounds that can modulate the human TMEM216 gene product, and possibly treat JS, JSRD or MKS. In alternative embodiments, the invention provides cells, cell lines and/or non-human transgenic animals that can be used as screening or model systems for studying ciliopathies and testing various therapeutic approaches in treating ciliopathies, e.g., JS, JSRD or MKS.