The invention provides compositions and methods useful for the treatment and prevention of conditions associated with short telomere length.

Relapsing remitting multiple sclerosis (RRMS) is the most common form of multiple sclerosis, affecting more than 80% of MS patients. RRMS is comprised of two phases: the auto-inflammatory episodes, in which the immune system is actively destroying myelin, alternate with remission phases. Currently there is no cure for this devastating disease. The present disclosure provides compositions and methods useful for inducing remyelination. The methods are useful for promoting remyelination to treat diseases and disorders such as MS. The present disclosure describes compositions and methods useful for inhibiting LRP1 activity. In one aspect, a siRNA against LRP1 can be used. It is disclosed that myelination can be regulated by inhibiting the interaction of LRP1 and p75NTR and that it inhibits activation of Rho-A.

Methods and compositions are provided for assessing CRISPR/Cas-mediated non-homologous end joining (NHEJ) activity and/or CRISPR/Cas-induced recombination of a target genomic locus with an exogenous donor nucleic acid in vivo or ex vivo. The methods and compositions employ non-human animals comprising a CRISPR reporter such as a genomically integrated CRISPR reporter for detecting and measuring targeted excision of a sequence between two CRISPR/Cas nuclease cleavage sites or disruption of a sequence near a CRISPR/Cas nuclease cleavage site and/or measuring CRISPR/Cas-induced recombination of the CRISPR reporter with an exogenous donor nucleic acid to convert the coding sequence for a first reporter protein to the coding sequence for a different second reporter protein. Methods and compositions are also provided for making and using these non-human animals.

Methods and compositions are provided herein for assessing CRISPR/Cas-mediated non-homologous end joining (NHEJ) activity and/or CRISPR/Cas-induced recombination of a target genomic locus with an exogenous donor nucleic acid in vivo and ex vivo. The methods and compositions employ cells and non-human animals comprising a Cas expression cassette such as a genomically integrated Cas expression cassette so that the Cas protein can be constitutively available or available in a tissue-specific or temporal-specific manner. Methods and compositions are also provided for making and using these non-human animals, including use of these non-human animals to assess CRISPR/Cas activity in vivo via adeno-associated virus (AAV)-mediated delivery of guide RNAs to the non-human animals.

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, three DMD mouse models are provided that can be used to test a variety of DMD exon skipping and refraining strategies. Among these are, CRISPR/Cas9 oligonucleotides, small molecules or other therapeutic modalities that promote exon skipping or exon refraining or micro dystrophin mini genes or cell based therapies. Methods for restoring the reading frame of exon 43, exon 45, and exon 52 deletion via CRISPR-mediated exon skipping and refraining in the humanized DMD mouse model, in patient-derived iPSCs 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.

The present invention provides a mouse with liver damage, having a high degree of damage against the mouse's original hepatocytes while having a uPA gene in a heterozygous form, and a method for efficiently preparing the mouse. Specifically, the method for preparing a mouse with liver damage having the uPA gene in a heterozygous form comprises the following steps of: (i) transforming mouse ES cells with a DNA fragment containing a liver-specific promoter/enhancer and cDNA that encodes a urokinase-type plasminogen activator operably linked under the control thereof; (ii) injecting the transformed mouse ES cells obtained in step (i) into a host embryo; (iii) transplanting the host embryo obtained in step (ii) via the injection of the ES cells into the uterus of a surrogate mother mouse, so as to obtain a chimeric mouse; and (iv) crossing the chimeric mice obtained in step (iii), so as to obtain a transgenic mouse in which the DNA fragment is introduced in a heterozygous form.

The present disclosure is directed, in some embodiments, to compositions and methods for inducible modification of a cell genome.

Provided herein are compositions and methods for treating or preventing metabolic disorders. In particular, provided herein are compositions, methods, and uses of Cyclin-dependent Kinase 6 (CDK6) inhibitors for treating and preventing metabolic diseases (e.g., type II diabetes, obesity, metabolic syndrome, elevated blood pressure, cardiovascular diseases, elevated fasting plasma glucose, and high serum triglycerides).

Non-human animals and methods and compositions for making and using them are provided, which non-human animals have a genome comprising an engineered or recombinant diversity cluster within an immunoglobulin heavy chain variable region, which engineered or recombinant diversity cluster comprises an insertion of one or more D.sub.H segments that are each operably linked to a 23-mer recombination signal sequence. Methods for producing antibodies from non-human animals are also provided, which antibodies optionally contain human variable regions and rodent, e.g., constant regions.

An ensemble of neurons in the basolateral amygdala (BLA) has been identified that encodes nociceptive information across pain modalities, including pain evoked by noxious thermal and mechanical stimuli. Methods are provided for screening candidate agents for inhibition of neural activity of the BLA nociceptive ensemble. Screening assays further include determining the effectiveness of candidate agents in alleviating pain and reducing aversive pain avoidance behavior.