Granted Patent
B2
US 12,427,170 · App. 17/818,669 · Granted Sep 30, 2025
Universal donor cells
Assignee:
CRISPR THERAPEUTICS AG
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Abstract
Genetically modified cells that are compatible with multiple subjects, e.g., universal donor cells, and methods of generating said genetic modified cells are provided herein. The universal donor cells comprise at least one genetic modification within or near at least one gene that encodes a survival factor, wherein the genetic modification comprises an insertion of a polynucleotide encoding a tolerogenic factor. The universal donor cells may further comprise at least one genetic modification within or near a gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or a component or a transcriptional regulator of a MHC-I or MHC-II complex, wherein said genetic modification comprises an insertion of a polynucleotide encoding a second tolerogenic factor.
Claims (29)
1. A genetically modified cell comprising (a) a nucleotide sequence encoding programmed death-ligand 1 (PD-L1) inserted within a gene encoding beta-2 microglobulin (B2M) and (b) a nucleotide sequence encoding HLA class I histocompatibility antigen, alpha chain E (HLA-E) inserted within a gene encoding thioredoxin interacting protein (TXNIP), wherein the genetically modified cell expresses PD-L1 and HLA-E and does not express B2M and TXNIP.
2. The genetically modified cell of claim 1 , wherein the nucleotide sequence encoding PD-L1 consists essentially of SEQ ID NO: 11.
3. The genetically modified cell of claim 1 , wherein the nucleotide sequence encoding PD-L1 is operably linked to an exogenous promoter.
4. The genetically modified cell of claim 3 , wherein the exogenous promoter is a CAG promoter comprising a CMV enhancer, a β-actin promoter, and a chimeric intron.
5. The genetically modified cell of claim 4 , wherein the CMV enhancer consists essentially of SEQ ID NO: 8, the β-actin promoter consists essentially of SEQ ID NO: 9, and the chimeric intron consists essentially of SEQ ID NO: 10.
6. The genetically modified cell of claim 1 , wherein the nucleotide sequence encoding PD-L1 is operably linked to a poly(A) signal.
7. The genetically modified cell of claim 6 , wherein the poly(A) signal consists essentially of SEQ ID NO: 12.
8. The genetically modified cell of claim 1 , wherein the nucleotide sequence encoding HLA-E consists essentially of SEQ ID NO: 55.
9. The genetically modified cell of claim 8 , wherein SEQ ID NO: 55 comprises a sequence encoding a B2M signal peptide, a sequence encoding an HLA-G presentation peptide, a sequence encoding a B2M membrane protein, and a sequence encoding HLA-E without its signal peptide.
10. The genetically modified cell of claim 9 , wherein the sequence encoding the B2M signal peptide consists essentially of SEQ ID NO: 26, the sequence encoding the HLA-G presentation peptide consists essentially of SEQ ID NO: 27, the sequence encoding the B2M membrane protein consists essentially of SEQ ID NO: 29, and the sequence encoding HLA-E without its signal peptide consists essentially of SEQ ID NO: 31.
11. The genetically modified cell of claim 1 , wherein the nucleotide sequence encoding HLA-E is operably linked to an exogenous promoter.
12. The genetically modified cell of claim 11 , wherein the exogenous promoter is a CAG promoter comprising a CMV enhancer, a β-actin promoter, and a chimeric intron.
13. The genetically modified cell of claim 12 , wherein the CMV enhancer consists essentially of SEQ ID NO: 8, the β-actin promoter consists essentially of SEQ ID NO: 9, and the chimeric intron consists essentially of SEQ ID NO: 10 or SEQ ID NO: 57.
14. The genetically modified cell of claim 1 , wherein the nucleotide sequence encoding HLA-E is operably linked to a poly(A) signal.
15. The genetically modified cell of claim 14 , wherein the poly(A) signal consists essentially of SEQ ID NO: 12.
16. The genetically modified cell of claim 1 , wherein the cell is a stem cell.
17. The genetically modified cell of claim 16 , wherein the stem cell is an embryonic stem cell, an adult stem cell, an induced pluripotent stem cell, or a hematopoietic stem cell.
18. The genetically modified cell of claim 1 , wherein the cell is a differentiated cell or a somatic cell.
19. The genetically modified cell of claim 1 , wherein the cell is capable of being differentiated into lineage-restricted progenitor cells or fully differentiated somatic cells.
20. The genetically modified cell of claim 19 , wherein the lineage-restricted progenitor cells are definitive endoderm cells, primitive gut tube cells, posterior foregut cells, pancreatic endoderm progenitors, or pancreatic endocrine progenitors, and the fully differentiated somatic cells are immature beta cells or mature beta cells.
21. A plurality of the genetically modified cells according to claim 1 .
22. The plurality of genetically modified cells of claim 21 , wherein at least about 50% of the cells express PD-L1 and/or at least about 50% of the cells express HLA-E.
23. The plurality of genetically modified cells of claim 21 , wherein at least about 70% of the cells express PD-L1 and/or at least about 70% of the cells express HLA-E.
24. The plurality of genetically modified cells of claim 21 , wherein at least about 90% of the cells express PD-L1 and/or at least about 90% of the cells express HLA-E.
25. A population of lineage-restricted progenitor cells or fully differentiated somatic cells derived from the plurality of genetically modified cells of claim 21 .
26. The population of cells of claim 25 , wherein the lineage-restricted progenitor cells are definitive endoderm cells, primitive gut tube cells, posterior foregut cells, pancreatic endoderm progenitors, or pancreatic endocrine progenitors, and the fully differentiated somatic cells are immature beta cells or mature beta cells.
27. The population of cells of claim 25 , wherein at least about 50% of the cells express PD-L1 and/or at least about 50% of the cells express HLA-E.
28. The population of cells of claim 25 , wherein at least about 70% of the cells express PD-L1 and/or at least about 70% of the cells express HLA-E.
29. The population of cells of claim 25 , wherein at least about 90% of the cells express PD-L1 and/or at least about 90% of the cells express HLA-E.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 21, 2025
From: REZANIA, ALIREZA
To: CRISPR THERAPEUTICS AG
Reel/Frame 071187/0711 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 21, 2025
From: RAMOS-ZAYAS, REBECA
To: CRISPR THERAPEUTICS AG
Reel/Frame 071187/0716 →
Continuity (5)
Provisional Application
62979756
· Feb 21, 2020
Provisional Application
62896477
· Sep 5, 2019
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