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Publication Number
US-10383317-B2
Publication Date
2019-08-20
Expiration Date
Abstract
The present invention provides certain animals, and in particular porcine animals, tissue and cells derived from these, which lack any expression of functional alpha 1,3 galactosyltransferase (aGT) and express one or more additional transgenes which make them suitable donors for pancreatic islet xenotransplantation. Methods of treatment and prevention of diabetes using cells derived from such animals are also provided.
Core Innovation
The invention relates to a genetically modified transgenic porcine animal for xenotransplantation in which the genetic modifications result in the lack of any expression of functional alpha 1,3 galactosyltransferase (GTKO). This addresses hyperacute rejection and related xenograft rejection mechanisms by reducing the alpha-Gal epitope-mediated responses described in the background.
The transgenic porcine animal further incorporates and expresses at least one complement inhibitor transgene in at least pancreatic islet cells and tissues. The complement inhibitor transgene is selected from CD46, CD55 (DAF), CD59, CR1, and combinations thereof, with pancreatic/islet-local expression intended to mitigate complement-mediated rejection pathways described in the background.
In addition, the transgenic porcine animal incorporates and expresses immunosuppressive and anticoagulant transgenes in pancreatic islet cells and tissues under the control of an islet-specific promoter. The transgenic porcine islet cells isolated from the animal produce insulin and reduce the instant blood mediated inflammatory reaction (IBMIR), in comparison to non-transgenic porcine islet cells, after transplantation into a host.
Claims Coverage
The document provides at least one independent claim: clm-00001. This claim is structured around five major inventive requirements, including GTKO, islet/tissue-local complement inhibition, islet-specific immunosuppressive expression, islet-specific anticoagulant expression, and functional outcomes including insulin production and reduced IBMIR after transplantation.
Genome engineering for GTKO
A genetically modified transgenic porcine animal in which the genetic modifications result in the lack of any expression of functional alpha 1,3 galactosyltransferase (GTKO).
Pancreatic islet complement inhibition
Incorporation of at least one complement inhibitor transgene and expression of at least one complement inhibitor transgene in at least pancreatic islet cells and tissues, wherein the complement inhibitor transgene is selected from CD46, CD55 (DAF), CD59, CR1, and combinations thereof.
Islet-specific immunosuppressive transgene expression
Incorporation and expression of at least one immunosuppressive transgene under the control of an islet-specific promoter in the genome of pancreatic islet cells and tissues.
Islet-specific anticoagulant transgene expression
Incorporation and expression of at least one anticoagulant transgene under the control of an islet-specific promoter in the genome of pancreatic islet cells and tissues.
Insulin production with reduced IBMIR after transplantation
Transgenic porcine islet cells isolated from the porcine animal produce insulin and reduce the instant blood mediated inflammatory reaction (IBMIR), in comparison to non-transgenic porcine islet cells, after transplantation of the transplanted porcine pancreatic cells into a host.
Independent claim clm-00001 combines GTKO with pancreatic islet/tissue-local complement inhibitor expression, islet-specific immunosuppressive transgene control, islet-specific anticoagulant transgene control, and functional requirements that transplanted porcine islet cells produce insulin while reducing IBMIR compared with non-transgenic porcine islet cells.
Stated Advantages
Reduce the instant blood mediated inflammatory reaction (IBMIR) after transplantation compared to non-transgenic porcine islet cells.
Transgenic porcine islet cells produce insulin.
Documented Applications
Xenotransplantation of transplanted porcine pancreatic cells into a host for diabetes treatment/prevention, using transgenic porcine islet cells that produce insulin and reduce IBMIR [procedural detail omitted for safety].
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