Methods and compounds for conferring site-specific or local immune privilege.

Provided herein are compositions and methods for preventing calcification of replacement heart valves. In particular, provided herein are compositions and methods for increasing local production of adenosine on or in the valve.

Genetically modified cells that are compatible with multiple subjects, e.g., universal donor cells, and methods of generating said genetic modified cells are provided herein. The universal donor cells comprise at least one genetic modification within or near a gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or a component or a transcriptional regulator of a MHC-I or MHC-II complex, wherein genetic modification comprises an insertion of a polynucleotide encoding a tolerogenic factor and/or survival factor. The universal donor cells may further comprise at least one genetic modification within or near a gene that encodes a survival factor, wherein said genetic modification comprises an insertion of a polynucleotide encoding a second tolerogenic factor and/or a different survival factor.

Polynucleotide constructs and engineered natural killer (NK) cells expressing such constructs are provided for the treatment of cancer and other adenosine-overexpressing disease states. The constructs are a fusion of at least an antigen binding domain specific to an adenosine producing (or adenosine-intermediary producing) cell surface protein and a receptor for promoting cytotoxic or cytolytic activity of the NK cell upon activation, where activation occurs upon the antigen binding domain binding its target cell. Pharmaceutical compositions of the engineered NK cells are also provided, as well as methods of treating an adenosine overexpressing cancer using such pharmaceutical compositions.

The present invention provides a recombinant microorganism for producing citicoline and a method for producing citicoline by using the recombinant microorganism, wherein genes for degradation and utilization of citicoline, choline, and phosphocholine are knocked out, In addition, a pyrimidine nucleoside synthesis pathway is genetically engineered to remove feedback inhibition to the synthesis pathway. A yield of more than 20 g/L of citicoline can be obtained with recombinant strains in a 5-liter fermenter by means of a biological fermentation method, achieving industrial mass production with low citicoline production costs and less pollution; therefore, the method is a simple, environmentally friendly and has a relatively high promotion and application value.

Genetically modified cells that are compatible with multiple subjects, e.g., universal donor cells, and methods of generating said genetic modified cells are provided herein. The universal donor cells comprise at least one genetic modification within or near a gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or a component or a transcriptional regulator of a MHC-I or MHC-II complex, wherein genetic modification comprises an insertion of a polynucleotide encoding a tolerogenic factor and/or survival factor. The universal donor cells may further comprise at least one genetic modification within or near a gene that encodes a survival factor, wherein said genetic modification comprises an insertion of a polynucleotide encoding a second tolerogenic factor and/or a different survival factor.

The present invention features bifunctional, soluble ecto-enzymes that are engineered to hydrolyze extracellular nucleotide triphosphates (e.g., ATP) to a nucleoside (e.g., adenosine), through the fusion of the ectodomains (ECD) of an ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and a nucleotide monophosphatase (NMPAse), such as an ecto-5′ nucleotidase (eN), alkaline phosphatase (ALP), or an acid phosphatase (AP). Also described are methods of use thereof, e.g. for limiting and decreasing inflammation and sequelae.

Genetically modified cells that are compatible with multiple subjects, e.g., universal donor cells, and methods of generating said genetic modified cells are provided herein. The universal donor cells comprise at least one genetic modification within or near a gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or a component or a transcriptional regulator of a MHC-I or MHC-II complex, wherein genetic modification comprises an insertion of a polynucleotide encoding a tolerogenic factor and/or survival factor. The universal donor cells may further comprise at least one genetic modification within or near a gene that encodes a survival factor, wherein said genetic modification comprises an insertion of a polynucleotide encoding a second tolerogenic factor and/or a different survival factor.

Genetically modified cells that are compatible with multiple subjects, e.g., universal donor cells, and methods of generating the genetically modified cells are provided herein. The universal donor cells comprise at least one genetic modification within or near a gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or a component or a transcriptional regulator of a MHC-I or MHC-II complex, wherein genetic modification comprises an insertion of a polynucleotide encoding a tolerogenic factor and/or survival factor. The universal donor cells may further comprise at least one genetic modification within or near a gene that encodes a survival factor, wherein the genetic modification comprises an insertion of a polynucleotide encoding a second tolerogenic factor and/or a different survival factor.

The present invention is inserted in the fields of nanotechnology, pharmacy and genetics and refers to specific sequences of interference RNA (siRNA), capable of silencing the gene responsible for the expression of an adhesion protein, which produces overexpressed extracellular adenosine in tumors, the enzyme ecto-5′-nucleotidase/CD73 (CD73). The specific siRNA sequences for CD73 are proposed in a nanometer scale composition in the form of liposomes or nanoemulsions in order to promote a site-directed release complex capable of being incorporated into several types of formulation, such as intratumor, intravenous injection or administration nasal. The siRNA sequences to silence CD73 can also be applied in the manufacture of kits and/or in silencing tests of CD73 for scientific research using liposomes, nanoemulsions or other transfection reagents.