Genetically modified pigs for xenotransplantation of vascularized xenografts and derivatives thereof
AssigneeRevivicor, Inc.
InventorDavid AYARES
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Abstract
The present invention provides certain donor animals, tissues and cells that are particularly useful for xenotransplantation therapies. In particular, the invention includes porcine animals, as well as tissue and cells derived from these, which lack any expression of functional alpha 1,3 galactosyltransferase (αGT) and express one or more additional transgenes which make these animals suitable donors for xenotransplantation of vascularized xenografts and derivatives thereof. Methods of treatment and using organs, tissues and cells derived from such animals are also provided.
Claims22
A method of treating an organ dysfunction in a subject in need thereof comprising administering to the subject an organ, a tissue, or a cell from a transgenic animal, wherein the transgenic animal comprises genetic modifications that result in:
- (a) lack of any expression of a functional alpha 1,3 galactosyltransferase (GTKO);
- and
- (b) incorporation into the genome and expression of:
- a cytoprotective transgene that is ubiquitously expressed or is under the control of a constitutive promoter, wherein the cytoprotective transgene is selected from the group consisting of HO-1, FAT-1, A20, and soluble tumor necrosis factor-alpha (TNF-alpha) receptor;
- an immunosuppressant transgene selected from the group consisting of cluster of differentiation 47 (CD47), and Class II transactivator-DN (CIITA-DN);
- and
- one anticoagulant transgene under the control of an endothelial cell-specific promoter, wherein the one anticoagulant transgene is endothelial protein C receptor (EPCR) or thrombomodulin (TBM);
- wherein the EPCR or the TBM is expressed in an aorta, a lung, a kidney, a heart, a liver, an intestine, a stomach, or a spleen;
- and
- wherein the transgenic animal is a transgenic ungulate.
A method of treating an organ dysfunction in a subject in need thereof comprising administering to the subject an organ, a tissue, or a cell from a transgenic porcine animal, wherein the transgenic porcine animal comprises genetic modifications that result in:
- (a) lack of expression of functional alpha 1,3 galactosyltransferase;
- and
- (b) incorporation into the genome and expression of
- (i) two complement inhibitor transgenes, wherein the two complement inhibitors are CD46 and DAF;
- CD46 and CD59;
- or DAF and CD59, and wherein the complement inhibitors are ubiquitously expressed and are under the control of a constitutive promoter;
- and
- (ii) two anticoagulant transgenes under the control of an endothelial cell-specific promoter, wherein the two anticoagulant transgenes are endothelial protein C receptor (EPCR), and thrombomodulin, and wherein the EPCR and the thrombomodulin are expressed in an aorta, a lung, a kidney, a heart, a liver, an intestine, a stomach, or a spleen;
- and
- (iii) a CD47 transgene under the control of a constitutive promoter.
A method of treating an organ dysfunction in a subject in need thereof comprising administering to the subject an organ, a tissue, or a cell from a transgenic porcine animal, wherein the transgenic porcine animal comprises genetic modifications that result in:
- (a) lack of expression of functional alpha 1,3 galactosyltransferase;
- and
- (b) incorporation into the genome and expression of:
- (i) one complement inhibitor transgene, wherein the complement inhibitor is selected from the group consisting of CD46 and DAF, and wherein the complement inhibitor is ubiquitously expressed and is under the control of a constitutive promoter;
- (ii) a CD47 transgene under the control of a constitutive promoter;
- (iii) a HO-1 transgene;
- and (iv) one anticoagulant transgene under the control of an endothelial cell-specific promoter, wherein the anticoagulant transgene is selected from the group consisting of endothelial protein C receptor (EPCR) and thrombomodulin, and wherein the anticoagulant transgene is expressed in an aorta, a lung, a kidney, a heart, a liver, an intestine, a stomach, or a spleen.
Dependencies are inferred from the claim text.