Tandem gene pairs are described in which the GC3 Content of one gene changes its level of expression, and changes the level of expression of the tandem gene. This gene control is called Mercury and can be used to control the expression level of a gene of interest. Mercury is used herein to reduce tonic signaling from chimeric antigen receptors by reducing the expression of a chimeric antigen receptor.

The present disclosure relates to methods for increasing telomere length in one or more human cells and/or increasing genome stability of one or more human cells, for example by contacting one or more human cells with an agent that increases expression of Zscan4 in the one or more human cells. Methods of treating a subject in need of telomere lengthening, treating a disease or condition associated with a genomic and/or chromosome abnormality, of rejuvenating one or more human cells, of rejuvenating tissues or organs, and of rejuvenating a subject in need thereof, for example by contacting one or more human cells in the subject with an agent that increases expression of Zscan4, or by administering to a subject in need thereof, an agent that increases expression of Zscan4 are also provided.

This invention relates to genetic engineering, in particular to an insertion site for a transgene, cells comprising a transgene or other modification at that insertion site, vectors for targeting that insertion site, and methods for creating transgenic cells by insertion or other modification at that site. The insertion site, or “safe harbour locus”, is identified within the SPATA13 gene on human chromosome 13q12.12. Mammalian cells comprising a genetic modification within the SPATA13 gene on chromosome 13q12.12 are described, wherein the modification may be an insertion such as an integrated transgene. Nucleic acid molecules able and adapted to guide the insertion of a transgene to that insertion site are also described. These cells or nucleic acids may be useful in therapy.

Nucleic acid regulatory elements that are able to enhance muscle-specific expression of genes, in particular expression in muscle cells and/or tissues such as in diaphragm, smooth muscle, heart and/or skeletal muscle, including at least two diaphragm-specific regulatory elements and a heart- and skeletal muscle-specific regulatory element. Expression cassettes and vectors containing these nucleic acid regulatory elements, as well as uses thereof such as applications using gene therapy of muscle-related disorders, more particularly diaphragm, heart and/or skeletal muscle-directed gene therapy, and for vaccination purposes.

The disclosure provides gene therapy vectors, such as adeno-associated virus (AAV), optimized for delivering a transgene to muscles. The optimized vectors contain constitutive or a muscle-specific promoter to deliver whole body or skeletal/heart muscle-specific transgene expression, respectively, in combination with a transgene cDNA to replace the gene mutation found in a muscle disease with a normal copy of the gene, an internal ribosomal entry site (IRES) to allow for production of a second protein from the same transcript, and a muscle growth factor, to build new muscle growth and strength. For example, the invention provides The disclosure provides gene therapy vectors, such as recombinant adeno-associated vims (rAAV), designed for treatment of GNE myopathy in which the rAAV expresses UDP-GlcNAc-epimerase/ManNAc-6 alone or in combination with a muscle growth factor or muscle transdifferentation factor. The provided AAV replace the mutated GNE gene expression while expressing proteins that stimulate muscle growth.

The present disclosure includes compositions and methods for treating cancer, such as bladder cancer.

Disclosed herein are circular RNAs and transfer vehicles, along with related compositions and methods of treatment. The circular RNAs can comprise group I intron fragments, spacers, an IRES, duplex forming regions, and/or an expression sequence, thereby having the features of improved expression, functional stability, low immunogenicity, ease of manufacturing, and/or extended half-life compared to linear RNA. Pharmaceutical compositions comprising such circular RNAs and transfer vehicles are particularly suitable for efficient protein expression in immune cells in vivo. Also disclosed are precursor RNAs and materials useful in producing the precursor or circular RNAs, which have improved circularization efficiency and/or are compatible with effective circular RNA purification methods.

Compositions and methods for the treatment of muscular dystrophies are provided.

The present disclosure relates to a compound of Formula (I)

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or a pharmaceutically acceptable salt thereof, which can be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid.

Methods and compositions for tissue regeneration of the present invention include a biocompatible porous composite of a decellularized tissue and an aptamer-functionalized hydrogel, wherein the aptamers of the aptamer-functionalized hydrogel specifically and reversibly bind to an active agent.