Granted Patent
B2
US 12,577,582 · App. 18/177,693 · Granted Mar 17, 2026
Universal donor cells
Assignee:
CRISPR THERAPEUTICS AG
C12N15/85C07K14/70532C07K14/70539C12N5/0606C12N5/0607C12N5/0676C12N5/0696C12N9/22C12N15/11C12N15/907C12N2310/20C12N2506/02C12N2506/03C12N2506/45C12N2800/80
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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 one or more MHC-I or MHC-II human leukocyte antigens or component or transcriptional regulator of the MHC-I or MHC-II complex, at least one genetic modification that increases the expression of at least one polynucleotide that encodes a tolerogenic factor, and optionally at least one genetic modification that increases or decreases the expression of at least one gene that encodes a survival factor.
Claims (21)
1 . A genetically modified cell, comprising:
an insertion of a polynucleotide encoding programmed death-ligand 1 (PD-L1); and
an insertion of a polynucleotide encoding mesencephalic astrocyte derived neurotrophic factor (MANF), wherein the cell expresses PD-L1 and MANF at an increased level relative to an unmodified cell, and wherein the cell comprises increased expression of one or more safety switch proteins relative to an unmodified cell.
2 . The genetically modified cell of claim 1 , wherein the polynucleotide encoding PD-L1 comprises the sequence of SEQ ID NO: 17.
3 . The genetically modified cell of claim 1 , wherein the polynucleotide encoding PD-L1, the polynucleotide encoding MANF, or both is operably linked to an exogenous promoter.
4 . The genetically modified cell of claim 3 , wherein the exogenous promoter is a constitutive, inducible, temporal-, tissue-, or cell type-specific promoter.
5 . The genetically modified cell of claim 3 , wherein the exogenous promoter is a CMV, EF1α, PGK, CAG, or UBC promoter.
6 . The genetically modified cell of claim 1 , comprising a disrupted beta-2 microglobulin (B2M) gene, wherein the cell has reduced or eliminated expression of B2M.
7 . The genetically modified cell of claim 6 , wherein the polynucleotide encoding PD-L1 is inserted into the disrupted B2M gene.
8 . The genetically modified cell of claim 1 , comprising a disrupted B2M gene caused by a deletion in the B2M gene.
9 . The genetically modified cell of claim 8 , wherein the polynucleotide encoding PD-L1 is inserted at a site that partially overlaps, completely overlaps, or is contained within the deletion of the B2M gene.
10 . The genetically modified cell of claim 1 , wherein the polynucleotide encoding MANF is inserted at a safe harbor locus.
11 . The genetically modified cell of claim 10 , wherein the safe harbor locus is selected from the group consisting of AAVS1 (PPP1 R12C), ALB, Angptl3, ApoC3, ASGR2, CCR5, FIX (F9), G6PC, Gys2, HGD, Lp(a), Pcsk9, Serpina1, TF, and TTR.
12 . The genetically modified cell of claim 1 , wherein the one or more safety switch proteins comprises herpes simplex virus-1 thymidine kinase (HSV-tk), inducible caspase-9, or both.
13 . The genetically modified cell of claim 1 , wherein the cell is a stem cell.
14 . The genetically modified cell of claim 13 , wherein the stem cell is an embryonic stem cell, an adult stem cell, an induced pluripotent stem cell, a pluripotent stem cell, or a hematopoietic stem and progenitor cell.
15 . The genetically modified cell of claim 13 , wherein the stem cell is a human stem cell.
16 . A plurality of genetically modified stem cells of claim 13 .
17 . A plurality of lineage-restricted progenitor cells or fully differentiated somatic cells derived from the plurality of genetically modified stem cells of claim 16 .
18 . The plurality of lineage-restricted progenitor cells or fully differentiated somatic cells of claim 17 , comprising definitive endoderm cells, primitive gut tube cells, posterior foregut cells, pancreatic endoderm cells, pancreatic endocrine precursor cells, immature beta cells, pancreatic beta cells, or combinations thereof.
19 . A composition, comprising the plurality of lineage-restricted progenitor cells or fully differentiated somatic cells of claim 17 and at least one pharmaceutically acceptable excipient.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 8, 2025
From: REZANIA, ALIREZA
To: CRISPR THERAPEUTICS AG
Reel/Frame 070776/0328 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Apr 8, 2025
From: RAMOS-ZAYAS, REBECA
To: CRISPR THERAPEUTICS AG
Reel/Frame 070776/0338 →
Continuity (6)
Provisional Application
62728529
· Sep 7, 2018
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