IP Library › Granted Patent US 12,630,838
Granted Patent B2
US 12,630,838 · App. 18/327,565 · Granted May 19, 2026

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

Inventors: Jacob Layer (Cambridge, MA); Wenning Qin (Cambridge, MA); Yinan Kan (Cambridge, MA); Juliet Crabtree (Cambridge, MA); Michele Youd (Cambridge, MA); David Heja (Cambridge, MA); David Angeles Albores (Cambridge, MA); Ranjith Anand (Cambridge, MA); Paola Perrat (Cambridge, MA); Russell Ernst (Cambridge, MA); Violette Paragas (Cambridge, MA)
Assignee: eGenesis, Inc.
C12N15/85A01K67/0276C07K14/4747C07K14/70503C07K14/70596C07K14/7455C12N9/0083C12Y114/99003A01K2207/12A01K2227/108A01K2267/025C12N2830/20C12N2830/50
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Quick Facts
Patent No.
US 12,630,838
App. No.
18/327,565
Granted
May 19, 2026
Kind
B2
Abstract

The present disclosure relates to cells, tissues, organs, and/or animals having one or more modified genes for enhanced xenograft survival and/or tolerance. In addition, the present disclosure relates to methods of making and using the cells, tissues, organs, and/or animals having one or more of the modified genes.

Claims (115)

1 . A genetically modified porcine cell comprising a nucleic acid molecule, wherein the nucleic acid molecule comprises:

(a) a first polycistronic cassette comprising: (i) an endothelial protein C receptor (EPCR) transgene and (ii) a thrombomodulin (THBD) transgene;

(b) a second polycistronic cassette comprising: (i) a tumor necrosis factor a-induced protein 3 (A20) transgene and (ii) a heme oxygenase-1 (HO1) transgene; and

(c) a third polycistronic cassette comprising: (i) a cluster of differentiation 46 (CD46) transgene, (ii) a CD55 transgene, and (iii) a CD47 transgene,

wherein the nucleic acid molecule is integrated at a single genomic locus.

2 . The genetically modified porcine cell of claim 1 , wherein:

(a) the EPCR transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 92, 93, or 181;

(b) the THBD transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 97-102, 166, or 265-266;

(c) the A20 transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 64-65, 104, 182, or 188;

(d) the HO1 transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 63, 109, 165, 183, or 189;

(e) the CD46 transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 71-76, 185, 200, or 253-258;

(f) the CD55 transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 84, 85, 107, or 184; and

(g) the CD47 transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 77-83, 180, or 259.

3 . The genetically modified porcine cell of claim 2 , wherein:

(a) the EPCR transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 92, 93, or 181;

(b) the THBD transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 97-102, 166, or 265-266;

(c) the A20 transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 64-65, 104, 182, or 188;

(d) the HO1 transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 63, 109, 165, 183, or 189;

(e) the CD46 transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 71-76, 185, 200, or 253-258;

(f) the CD55 transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 84, 85, 107, or 184; and

(g) the CD47 transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 77-83, 180, or 259.

4 . The genetically modified porcine cell of claim 3 , wherein:

(a) the EPCR transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 92, 93, or 181;

(b) the THBD transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 97-102, 166, or 265-266;

(c) the A20 transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 64-65, 104, 182, or 188;

(d) the HO1 transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 63, 109, 165, 183, or 189;

(e) the CD46 transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 71-76, 185, 200, or 253-258;

(f) the CD55 transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 84, 85, 107, or 184; and

(g) the CD47 transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 77-83, 180, or 259.

5 . The genetically modified porcine cell of claim 4 , wherein:

(a) the EPCR transgene comprises any one of SEQ ID NOS: 92, 93, or 181;

(b) the THBD transgene comprises any one of SEQ ID NOS: 97-102, 166, or 265-266;

(c) the A20 transgene comprises any one of SEQ ID NOS: 64-65, 104, 182, or 188;

(d) the HO1 transgene comprises any one of SEQ ID NOS: 63, 109, 165, 183, or 189;

(e) the CD46 transgene comprises any one of SEQ ID NOS: 71-76, 185, 200, or 253-258;

(f) the CD55 transgene comprises any one of SEQ ID NOS: 84, 85, 107, or 184; and

(g) the CD47 transgene comprises any one of SEQ ID NOS: 77-83, 180, or 259.

6 . The genetically modified porcine cell of claim 1 , wherein the nucleic acid molecule comprises a sequence having at least 80% identity to SEQ ID NO: 30.

7 . The genetically modified porcine cell of claim 6 , wherein the nucleic acid molecule comprises a sequence having at least 90% identity to SEQ ID NO: 30.

8 . The genetically modified porcine cell of claim 7 , wherein the nucleic acid molecule comprises a sequence having at least 95% identity to SEQ ID NO: 30.

9 . The genetically modified porcine cell of claim 8 , wherein the nucleic acid molecule comprises a sequence having at least 98% identity to SEQ ID NO: 30.

10 . The genetically modified porcine cell of claim 9 , wherein the nucleic acid molecule comprises a sequence having at least 99% identity to SEQ ID NO: 30.

11 . The genetically modified porcine cell of claim 10 , wherein the nucleic acid molecule comprises SEQ ID NO: 30.

12 . A genetically modified porcine cell comprising a nucleic acid molecule, wherein the nucleic acid molecule comprises:

(a) a first polycistronic cassette comprising: (i) a tissue factor pathway inhibitor (TFPI) transgene, (ii) an endothelial protein C receptor (EPCR) transgene, and (iii) a thrombomodulin (THBD) transgene;

(b) a second polycistronic cassette comprising: (i) (A) a beta 2 microglobulin (B2M) transgene and a human leukocyte antigen E (HLA-E) transgene, or (B) a transgene encoding a B2M-HLA-E fusion; and (ii) a cluster of differentiation 47 (CD47) transgene; and

(c) a third polycistronic cassette comprising: (i) a CD46 transgene and (ii) a CD55 transgene,

wherein the nucleic acid molecule is integrated at a single genomic locus.

13 . The genetically modified porcine cell of claim 12 , wherein the second polycistronic cassette comprises the transgene encoding the B2M-HLA-E fusion, and wherein:

(a) the TFPI transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 94-96, 103, or 187;

(b) the EPCR transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 92, 93, or 181;

(c) the THBD transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 97-102, 166, or 265-266;

(d) the transgene encoding the B2M-HLA-E fusion comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 62, 66, or 105;

(e) the CD47 transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOs: SEQ ID NOS: 77-83, 180, or 259;

(f) the CD46 transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 71-76, 185, 200, or 253-258; and

(g) the CD55 transgene comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOS: 84, 85, 107, or 184.

14 . The genetically modified porcine cell of claim 13 , wherein:

(a) the TFPI transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 94-96, 103, or 187;

(b) the EPCR transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 92, 93, or 181;

(c) the THBD transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 97-102, 166, or 265-266;

(d) the transgene encoding the B2M-HLA-E fusion comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 62, 66, or 105;

(e) the CD47 transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: SEQ ID NOs: 77-83, 180, or 259;

(f) the CD46 transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 71-76, 185, 200, or 253-258; and

(g) the CD55 transgene comprises a nucleic acid sequence having at least 90% identity to any one of SEQ ID NOS: 84, 85, 107, or 184.

15 . The genetically modified porcine cell of claim 14 , wherein:

(a) the TFPI transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 94-96, 103, or 187;

(b) the EPCR transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 92, 93, or 181;

(c) the THBD transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 97-102, 166, or 265-266;

(d) the transgene encoding the B2M-HLA-E fusion comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 62, 66, or 105;

(e) the CD47 transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: SEQ ID NOs: 77-83, 180, or 259;

(f) the CD46 transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 71-76, 185, 200, or 253-258; and

(g) the CD55 transgene comprises a nucleic acid sequence having at least 95% identity to any one of SEQ ID NOS: 84, 85, 107, or 184.

16 . The genetically modified porcine cell of claim 15 , wherein:

(a) the TFPI transgene comprises any one of SEQ ID NOS: 94-96, 103, or 187;

(b) the EPCR transgene comprises any one of SEQ ID NOS: 92, 93, or 181;

(c) the THBD transgene comprises any one of SEQ ID NOS: 97-102, 166, or 265-266;

(d) the transgene encoding the B2M-HLA-E fusion comprises any one of SEQ ID NOS: 62, 66, or 105;

(e) the CD47 transgene comprises any one of SEQ ID NOS: SEQ ID NOs: 77-83, 180, or 259;

(f) the CD46 transgene comprises any one of SEQ ID NOS: 71-76, 185, 200, or 253-258; and

(g) the CD55 transgene comprises any one of SEQ ID NOS: 84, 85, 107, or 184.

17 . The genetically modified porcine cell of claim 12 , wherein the nucleic acid molecule comprises a sequence having at least 80% identity to SEQ ID NO: 31.

18 . The genetically modified porcine cell of claim 17 , wherein the nucleic acid molecule comprises a sequence having at least 90% identity to SEQ ID NO: 31.

19 . The genetically modified porcine cell of claim 18 , wherein the nucleic acid molecule comprises a sequence having at least 95% identity to SEQ ID NO: 31.

20 . The genetically modified porcine cell of claim 19 , wherein the nucleic acid molecule comprises a sequence having at least 98% identity to SEQ ID NO: 31.

21 . The genetically modified porcine cell of claim 20 , wherein the nucleic acid molecule comprises a sequence having at least 99% identity to SEQ ID NO: 31.

22 . The genetically modified porcine cell of claim 21 , wherein the nucleic acid molecule comprises SEQ ID NO: 31.

23 . The genetically modified porcine cell of claim 2 or 13 , wherein:

(a) the first polycistronic cassette comprises a first promoter, wherein the first promoter comprises a sequence having at least 80% identity to any one of SEQ ID NOS: 126-145, 167-168, 178-179, 231-238, or 250;

(b) the second polycistronic cassette comprises a second promoter, wherein the second promoter comprises a sequence having at least 80% identity to any one of SEQ ID NOS: 126-145, 167-168, 178-179, 231-238, or 250; and

(c) the third polycistronic cassette comprises a third promoter, wherein the third promoter comprises a sequence having at least 80% identity to any one of SEQ ID NOS: 126-145, 167-168, 178-179, 231-238, or 250.

24 . The genetically modified porcine cell of claim 23 , wherein:

(a) the first promoter comprises any one of SEQ ID NOS: 126-145, 167-168, 178-179, 231-238, or 250;

(b) the second promoter comprises any one of SEQ ID NOS: 126-145, 167-168, 178-179, 231-238, or 250; and

(c) the third promoter comprises any one of SEQ ID NOS: 126-145, 167-168, 178-179, 231-238, or 250.

25 . The genetically modified porcine cell of claim 2 or 13 , wherein:

(a) the first polycistronic cassette comprises a first poly A sequence having at least 80% identity to any one of SEQ ID NOS: 112-125, 154-156, 159-162, 190-192, or 239-240;

(b) the second polycistronic cassette comprises a second poly A sequence having at least 80% identity to any one of SEQ ID NOS: 112-125, 154-156, 159-162, 190-192, or 239-240; and

(c) the third polycistronic cassette comprises a third poly A sequence having at least 80% identity to any one of SEQ ID NOS: 112-125, 154-156, 159-162, 190-192, or 239-240.

26 . The genetically modified porcine cell of claim 25 , wherein:

(a) the first poly A sequence comprises any one of SEQ ID NOS: 112-125, 154-156, 159-162, 190-192, or 239-240;

(b) the second poly A sequence comprises any one of SEQ ID NOS: 112-125, 154-156, 159-162, 190-192, or 239-240; and

(c) the third poly A sequence comprises any one of SEQ ID NOS: 112-125, 154-156, 159-162, 190-192, or 239-240.

27 . The genetically modified porcine cell of claim 2 or 13 , wherein the CD46 transgene or the THBD transgene comprises a splice site mutation.

28 . The genetically modified porcine cell of claim 2 or 13 , wherein the nucleic acid molecule further comprises a nucleic acid sequence encoding a 2A peptide.

29 . The genetically modified porcine cell of claim 28 , wherein the 2A peptide is selected from the group consisting of E2A, T2A, F2A, and P2A.

30 . The genetically modified porcine cell of claim 2 or 13 , wherein the nucleic acid molecule further comprises an IRES sequence.

31 . The genetically modified porcine cell of claim 1 or 12 , wherein the nucleic acid molecule is integrated into a genomic safe harbor locus in a genome of the genetically modified porcine cell.

32 . The genetically modified porcine cell of claim 31 , wherein the genomic safe harbor locus is Adeno-Associated Virus Integration Site 1 (AAVS1), CCR5, or Fos5.

33 . The genetically modified porcine cell of claim 1 or 12 , wherein at least one polycistronic cassette of the nucleic acid molecule is a bicistronic cassette.

34 . The genetically modified porcine cell of claim 1 or 12 , wherein the genetically modified porcine cell lacks expression of an endogenous glycoprotein alpha-1,3-galactosyltransferase (GGTA1) gene, an endogenous β-1,4-N-acetyl-galactosaminyltransferase 2 (β4GALNT2) gene, and an endogenous cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) gene.

35 . The genetically modified porcine cell of claim 1 or 12 , wherein each transgene is a human transgene.

36 . A genetically modified organ comprising the genetically modified porcine cell of claim 1 or 12 .

37 . The genetically modified organ of claim 36 , wherein the genetically modified organ is a liver, a heart, or a kidney.

38 . A genetically modified pig comprising the genetically modified porcine cell of claim 1 or 12 .

39 . The genetically modified pig of claim 38 , wherein the genetically modified pig is a genetically modified Yucatan pig or a genetically modified Yorkshire pig.

Assignments (3)
SECURITY INTEREST Recorded Sep 8, 2025
From: EGENESIS, INC.; HUCKLEBERRY FARMS, LLC
To: JPMORGAN CHASE BANK, N.A.
Reel/Frame 072182/0562 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 5, 2023
From: QIN, WENNING; KAN, YINAN; CRABTREE, JULIET; YOUD, MICHELE; HEJA, DAVID; ANAND, RANJITH; PERRAT, PAOLA; ERNST, RUSSELL; LAYER, JACOB; PARAGAS, VIOLETTE
To: EGENESIS, INC.
Reel/Frame 063853/0001 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 5, 2023
From: ANGELES ALBORES, DAVID
To: EGENESIS, INC.
Reel/Frame 063858/0275 →
Continuity (5)
Continuation PCTUS2021059265 · Nov 12, 2021
Provisional Application 63247544 · Sep 23, 2021
Provisional Application 63218080 · Jul 2, 2021
Provisional Application 63113650 · Nov 13, 2020
Related Publication 20240084322A1 · Mar 14, 2024
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