Genetically modified pigs for xenotransplantation of vascularized xenografts and derivatives thereof
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Publication Number
US-11179496-B2
Publication Date
2021-11-23
Expiration Date
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 (aGT) 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.
Core Innovation
The disclosure describes genetically modified pigs for vascularized xenograft applications in which the genetic modifications result in the lack of expression of functional alpha 1,3 galactosyltransferase. This is presented as alpha-Gal epitope removal (GTKO). The genetically modified porcine animals further incorporate into the genome and express immune-modulating and anticoagulant transgenes with specified promoter controls, including endothelial-specific expression.
A complement inhibitor transgene is incorporated and expressed, wherein the complement inhibitor transgene is CD46 ubiquitously expressed and under the control of a constitutive promoter. In addition, an immunosuppressant transgene is expressed under the control of a constitutive promoter, selected from CTLA4, CD47, and CIITA-DN. The disclosure also includes anticoagulant transgenes incorporated under an endothelial-specific promoter, where the endothelial protein C receptor (EPCR) and thrombomodulin are expressed.
The disclosure states that endothelial targeting aims to reduce HAR/AHXR/AVXR/DXR and coagulation/thrombotic microangiopathy, including consumptive coagulopathy/DIC. The combination of complement regulators, immunosuppressants, and anticoagulants is presented as enabling clinically relevant immunosuppression regimens for vascularized xenografts. The document further indicates expression evidence for relevant endothelial markers and discusses downstream donor-derived organs, tissues, and cells.
Claims Coverage
The document contains two independent claims. Across these independent claims, the coverage centers on eliminating functional alpha 1,3 galactosyltransferase expression and incorporating specific immune-related transgenes together with two endothelial anticoagulant transgenes controlled by an endothelial-specific promoter, with additional narrowing via dependent claims.
Elimination of functional alpha 1,3 galactosyltransferase expression
A transgenic porcine animal comprising genetic modifications that result in the lack of expression of functional alpha 1,3 galactosyltransferase.
Constitutive ubiquitous CD46 complement inhibitor expression
Incorporation into the genome and expression of a complement inhibitor transgene wherein the complement inhibitor transgene is CD46, wherein the complement inhibitor transgene is ubiquitously expressed and is under the control of a constitutive promoter.
Constitutive immunosuppressant transgene selection (CTLA4, CD47, or CIITA-DN)
One immunosuppressant transgene under the control of a constitutive promoter, wherein the one immunosuppressant transgene is selected from the group consisting of Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4), cluster of differentiation 47 (CD47) and Class II transactivator-DN (CIITA-DN).
Endothelial-specific EPCR and thrombomodulin anticoagulant expression
Two anticoagulant transgenes under the control of an endothelial-specific promoter, wherein the two anticoagulant transgenes are endothelial protein C receptor (EPCR) and thrombomodulin.
Constitutive immunosuppressant transgene selection (CD47 or CIITA-DN)
At least one immunosuppressant transgene expressed under the control of a constitutive promoter, wherein the at least one immunosuppressant transgene is CD47 or CIITA-DN.
Overall, the independent claim coverage requires a transgenic porcine animal lacking functional alpha 1,3 galactosyltransferase expression and expressing CD46 ubiquitously from a constitutive promoter, plus an additional immunosuppressant transgene from a constitutive promoter. Both independent claims further require endothelial-specific expression of EPCR and thrombomodulin under an endothelial-specific promoter, with dependent claims narrowing promoter options and claiming derived cells, organs, tissue, and xenotransplantation use to primates.
Stated Advantages
Reduced xenorejection/thrombosis is described as a goal of the disclosed xenotransplantation approach.
The document includes bridge/functional duration claims for whole-organ xenografts.
Endothelial targeting is stated to reduce HAR/AHXR/AVXR/DXR and coagulation/thrombotic microangiopathy, including consumptive coagulopathy/DIC.
The combination of complement regulators, immunosuppressants, and anticoagulants is stated to enable clinically relevant immunosuppression regimens.
Documented Applications
Xenotransplantation in which transgenic-animal-derived porcine organs, tissue, or cells are administered to a primate in need.
Whole-organ xenograft applications for heart, kidney, lung, liver, and pancreas, with goals of reduced xenorejection/thrombosis and bridge/functional duration claims.
Vascular grafts.
Endothelial keratoplasty (EK) and deep lamellar endothelial keratoplasty (DLEK).
Retinal endothelial cell grafts and vascular reconstructive surgery use cases, including coronary bypass and stenting.
Vascularized xenografts using donor-derived porcine organs, tissue, and cells administered to a primate in need.
Use of non-human primates as recipients in xenotransplantation contexts stated in the dependent claim set.
Post-xenotransplant administration of a clinically relevant immunosuppressant regimen to a primate after xenotransplantation of organs, tissues or cells.
Donor-derived endothelial cell uses including cornea/retina endothelial cell grafting.
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