Cells, tissues, organs, and animals having one or more modified genes for enhanced xenograft survival and tolerance

A nucleic acid for expression of a protein in a porcine xenograft, wherein the nucleic acid comprises:

• (a) a first polycistronic cassette, comprising:
• (i) a first cistron encoding a thrombomodulin (THBD) protein, and (ii) a second cistron encoding an EPCR protein, wherein the first polycistronic cassette is configured to reduce a coagulation response of a host to the porcine xenograft;
• (b) a second polycistronic cassette, comprising:
• (i) a third cistron encoding an A20 protein, and (ii) a fourth cistron encoding a HO1 protein, wherein the second polycistronic cassette is configured to reduce an inflammation response of the host to the porcine xenograft;
• and
• (c) a third polycistronic cassette, comprising (i) a fifth cistron encoding a CD46 protein, (ii) a sixth cistron encoding a CD47 protein, and a (iii) a seventh cistron encoding a CD55 protein, wherein the third polycistronic cassette is configured to reduce an innate immune response and regulate a complement response of the host to the porcine xenograft.

A nucleic acid sequence for expression of a protein in a porcine xenograft, wherein the nucleic acid comprises:

• (a) a first polycistronic cassette, comprising:
• (i) a first cistron encoding a thrombomodulin (THBD) protein, (ii) a second cistron encoding an EPCR protein, and (iii) a third cistron encoding a TFPI protein, wherein the first polycistronic cassette is configured to reduce a coagulation response of a host to the porcine xenograft;
• (b) a second polycistronic cassette, comprising:
• (i) a fourth cistron encoding a B2M HLA-E fusion protein, and (ii) a fifth cistron encoding a CD47 protein, wherein the second polycistronic cassette is configured to reduce an innate immune response of the host to the porcine xenograft;
• and
• (c) a third polycistronic cassette, comprising (i) a sixth cistron encoding a CD46 protein, and (ii) a seventh cistron encoding a CD55 protein, wherein the third polycistronic cassette is configured to regulate a complement response of the host to the porcine xenograft.