Described herein are compositions and methods for tissue-targeted expression of therapeutic genes, using AAV expression vectors that reduce the risk of toxicity associated with AAV gene therapy in the CNS by de-targeting the vulnerable neurons cells including the DRG cells on gene expression, and de-targeting the liver, a major suspect for over-expression in the periphery.

This invention relates to the use of an adenovirus to treat cancer, for example. The adenovirus may be replication deficient in cells that lack Y box binding protein. The adenovirus may encode an oncogene or an oncogene product, which may transactivate at least one viral gene.

The present invention provides methods and compositions comprising an adeno-associated vims (AAV) synthetic inverted terminal repeat (ITR), wherein the ITR may have modified promoter transcriptional function. Additionally provided are vectors and virus particles comprising the same, as well as methods of their use.

The invention relates to an artificial nucleic acid molecule comprising at least one open reading frame and at least one 3′-untranslated region element (3′-UTR element) comprising a nucleic acid sequence which is derived from the 3′-UTR of a FIG4 gene or from a variant of the 3′-UTR of a FIG4 gene. The invention further relates to the use of such an artificial nucleic acid molecule in gene therapy and/or genetic vaccination. Furthermore, the invention relates to the use of a 3′-UTR element comprising a nucleic acid sequence which is derived from the 3′-UTR of a FIG4 gene or from a variant of the 3′-UTR of a FIG4 gene for the stabilization and/or prolongation of protein expression from a nucleic acid sequence comprising such 3′-UTR element.

The present invention relates to a small activating nucleic acid molecules and uses thereof for treating diseases and conditions, such as thrombocytopenia, related to THPO protein deficiency or insufficiency. As described herein, small activating nucleic acid molecules can be double-stranded or single-stranded RNA molecules targeting the promoter region of the Thpo/THPO gene through an RNA activation mechanism and comprise a first nucleic acid strand and a second nucleic acid strand. The double-stranded RNA molecule targeting the promoter region of the Thpo/THPO gene comprises two nucleic acid strands of 16 to 35 nucleotides in length, wherein one nucleic acid strand has at least 75% homology or complementarity to a target selected from the promoter region of the Thpo/THPO gene. The present invention also relates to pharmaceutical compositions and formulations comprising the small activating nucleic acid molecules and methods for up-regulating the expression of the Thpo/THPO gene in a cell and treating diseases and conditions, related to THPO protein deficiency or insufficiency, by administering small activating nucleic acid molecules, pharmaceutical compositions, and formulations thereof.

Provision of a modified promoter derived from a xylanase promoter. A modified promoter comprising a polynucleotide of Xyn3 promoter comprising a polynucleotide that comprises at least one polynucleotide of Xyn1 promoter cis-element or a complementary strand thereof in a region corresponding to the nucleotides at position 374 to 401 of SEQ ID NO:1. The polynucleotide of Xyn3 promoter consist of the following nucleotide sequences: the nucleotide sequence represented by SEQ ID NO:1; the nucleotide sequence represented by the nucleotides at position 350 to 1084 of SEQ ID NO:1; or a nucleotide sequence that has an identity of at least 90% therewith and that comprises the sequence represented by SEQ ID NO:2 in a region corresponding to the nucleotides at position 374 to 401 of SEQ ID NO:1. The polynucleotide of Xyn1 promoter cis-element consists of the nucleotide sequence represented by SEQ ID NO:4.

The present disclosure provides expression constructs designed to provide for stable and/or inducible, tightly controlled production of genetically encoded payloads from engineered cells. These cassettes allow cells to be engineered to express genetically encoded payloads despite epigenetic silencing. As such, provided herein are expression systems for use in methods to engineer cells using CRISPR dCas9-activator systems such that expression of genetically encoded payloads (e.g., therapeutic proteins) can be optimized to overcome epigenetic silencing. In addition, provided herein are engineered cells comprising the expression systems.

Provided herein are methods and compositions for dynamically controlling and targeting multiple immunosuppressive mechanisms in cancer. Some aspects provide cells engineered to produce multiple effector molecules, each of which modulates a different immunosuppressive mechanisms of a tumor, as well as methods of using the cells to treat cancer, such as ovarian, breast, or colon cancer.

The present invention relates to nucleic acid regulatory elements that are able to enhance endothelial cell-specific expression of genes, methods employing these regulatory elements and uses of these elements. Expression cassettes and vectors containing these nucleic acid regulatory elements are also disclosed. The present invention is particularly useful for applications using gene therapy, more particularly endothelial cell-directed gene therapy, and for vaccination purposes.

A triple expression vector is disclosed for expressing an antibody molecule comprising an Fc domain in prokaryotic cells and in eukaryotic cells. The triple expression vector comprises a polynucleotide encoding an Fc domain; a polynucleotide encoding a phage coat protein; a cloning site for cloning genes encoding an antibody molecule or a part thereof wherein the antibody molecule or part thereof does not comprise an Fc domain; a prokaryotic secretion signal sequence and a eukaryotic secretion signal sequence, or a secretion signal sequence that drives efficient secretion in both prokaryotic and eukaryotic cells; a promoter for mediating expression in eukaryotic cells; and a stop codon for preventing expression of the phage coat protein in eukaryotic cells. The triple expression vector can be used for expressing an antibody molecule in a phage display format; for producing the antibody molecule in a prokaryotic cell, for example in the periplasm of a prokaryotic cell; and for producing the antibody molecule in a eukaryotic cell, for example a mammalian cell, more particularly a human cell. The antibody molecule contains an Fc domain, and may be for example a VHH-Fc molecule or an scFv-Fc molecule or a VH-Fc or a VL-Fc. Phage display libraries produced with the vector present the antibody molecule in its therapeutic format. Use of the vector avoids the need for repeated cloning when moving from one expression medium to another.