The present invention relates to compositions and methods for treating autoimmune, microbial, metabolic, neoplastic, and posttraumatic diseases mediated by inflammation in a subject. Compositions and methods including at least one importin beta-selective nuclear transport modifier (NTM) and/or at least one importin alpha-selective NTM, and/or at least one importin alpha-specific NTM, and/or at least one inhibitor of importin alpha and importin beta complex formation may be administered to a subject to modulate the transport of transcription factors, mediated by nuclear import adaptors, into the nucleus of a cell resulting in a decrease or abrogation of inflammation.

The present disclosure generally relates to, inter alia, a new class of chimeric Notch receptors containing a synthetic zinc finger transcriptional effector (synZTE) module, engineered to modulate gene expression and cellular activities in a ligand-dependent manner. The new Notch receptors surprisingly retain the ability to transduce signals in response to ligand binding despite that the Notch extracellular subunit, which includes the negative regulatory region previously believed to be essential for the functioning of Notch receptors, is partly or completely deleted. In addition, the synZTE is designed to bind orthogonal DNA target sequences in target organisms which in turn facilitates precise regulation of therapeutic gene expression with minimal off-target activity. Also provided are compositions and methods useful for producing such receptors, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating an activity of a cell and/or for treatment of various health conditions.

The invention relates to methods of modifying DNA methylation by contacting a cell with a catalytically inactive site specific nuclease fused to an effector domain having methylation or demethylation activity and one or more guide sequences.

Disclosed are compositions and methods for treating inflammation including its end-stage sepsis and conditions mediated by inflammation such as liver apoptosis and cirrhosis, thrombocytopenia, hypoglycogenemia, hyperglycemia, and hypertriglyceridemia. In one aspect, the compositions and methods disclosed herein can also be used to enhance clearance of microbes from infected tissues, organs, or systems in a subject. Also disclosed herein are compositions and methods for reducing levels of stress responsible transcription factors and metabolic transcription factors in a cell in a subject with microbial, allergic, autoimmune, metabolic, and posttraumatic inflammation.

Provided herein are Class 2 Type V CRISPR:gNA systems comprising Class 2 Type V CRISPR polypeptides (e.g. CasX), guide nucleic acids (gNA), and optionally donor template nucleic acids useful in the modification of a RHO gene. The systems are also useful for introduction into cells, for example eukaryotic cells having mutations in the rhodopsin protein. Also provided are methods of using such systems to modify cells having such mutations and utility in methods of treatment of a subject with a RHO-related disease, such as retinitis pigmentosa.

Provided are compositions, including products of manufacture and kits, and methods, for remotely-controlled and non-invasive manipulation of intracellular nucleic acid expression, genetic processes, function and activity in live cells such as a T cell, a primary T cell, a B cell, a monocyte, a macrophage, a dendritic cell or a natural killercell in vivo, for example, including activating, adding functions or changing or adding specificities for an immune cell, for monitoring physiologic processes, for the correction of pathological processes and for the control of therapeutic outcomes. Provided are tamoxifen-gated photoactivatable split-Cre recombinase optogenetic systems, called TamPA-Cre, that feature high spatiotemporal control to control or alter cell activities in vivo, for example, to limit the activity of a Chimeric Antigen Receptor (CAR)-expressing cell such as an immune cell and its activity at a tumor site for immunotherapy applications.

The present invention provides methods and compositions for detecting genomic sequences of interest in living cells. In particular, the present disclosure provides a split-enzyme system that works with guide RNAs and RNA-guided nucleases to produce detectable luminescent signals exclusively in the presence of targeted genomic sequences.

The present invention relates to a chimeric enzyme comprising a CRISPR class 2 type II enzyme backbone, wherein the HNH domain in the backbone has been replaced, essentially, by a peptide or protein domain having catalytic activity on a single stranded polynucleotide.

The present disclosure provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides novel class 1, Type IV and novel class I, Type I Cas proteins and their use in modifying target sequences.

The present disclosure provides recombineering-editing systems using CRISPR and recombination enzymes as well as methods, vectors, nucleic acid compositions, and kits thereof. The methods and systems provide means for altering target DNA, including genomic DNA in a host cell.