Methods and compositions for modification of a HLA locus
First Claim
Patent Images
1. A genetically modified mammalian cell comprising an endogenous human leukocyte antigen (HLA) class I gene comprising a sequence selected from the group consisting of any one of the nucleotides of SEQ ID NOs:
- 97 to 111 and an endogenous HLA class II gene comprising a sequence selected from the group consisting of any one of the nucleotides of SEQ ID NOs;
112 to 115, the genetically modified cell comprising;
(i) a first genomic modification comprising an integrated exogenous nucleotide sequence encoding a chimeric antigen receptor (CAR) or T-cell receptor gene, and(ii) a second genomic modification comprising an inactivated HLA gene following zinc finger nuclease-mediated cleavage of the active HLA class I gene and/or HLA class II gene with a pair of zinc finger nucleases, each zinc finger nuclease comprising a cleavage domain and the recognition helix regions of the zinc finger proteins designated 18889, which binds to a target site within SEQ ID NO;
97;
11881, which binds to a target site within SEQ ID NO;
98;
24859, which binds to a target site within SEQ ID NO;
99;
25191, which binds to a target site within SEQ ID NO;
100;
25190, which binds to a target site within SEQ ID NO;
101;
25316, which binds to a target site within SEQ ID NO;
102;
25317, which binds to a target site within SEQ ID NO;
103;
15267, which binds to a target site within SEQ ID NO;
104;
15265, which binds to a target site within SEQ ID NO;
105;
17454, which binds to a target site within SEQ ID NO;
106;
17456, which binds to a target site within SEQ ID NO;
107;
15296, which binds to a target site within SEQ ID NO;
108;
15298, which binds to a target site within SEQ ID NO;
109;
25588, which binds to a target site within SEQ ID NO;
110;
25589, which binds to a target site within SEQ ID NO;
111;
15872, which binds to a target site within SEQ ID NO;
112;
15873, which binds to a target site within SEQ ID NO;
113;
15909, which binds to a target site within SEQ ID NO;
114;
or 15910, which binds to a target site within SEQ ID NO;
115,wherein the pair of zinc finger nucleases includes 18889 and 18881;
18889 and 24859;
25191 and 25190;
25316 and 25317;
15267 and 15265;
17454 and 17456;
15296 and 15298;
25588 and 25589;
15872 and 15873;
or 15909 and 15910;
and wherein the HLA gene is inactivated by the second genomic modification.
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Abstract
Disclosed herein are methods and compositions for modulating the expression of a HLA locus or for selectively deleting or manipulating a HLA locus or HLA regulator.
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Citations
11 Claims
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1. A genetically modified mammalian cell comprising an endogenous human leukocyte antigen (HLA) class I gene comprising a sequence selected from the group consisting of any one of the nucleotides of SEQ ID NOs:
- 97 to 111 and an endogenous HLA class II gene comprising a sequence selected from the group consisting of any one of the nucleotides of SEQ ID NOs;
112 to 115, the genetically modified cell comprising;(i) a first genomic modification comprising an integrated exogenous nucleotide sequence encoding a chimeric antigen receptor (CAR) or T-cell receptor gene, and (ii) a second genomic modification comprising an inactivated HLA gene following zinc finger nuclease-mediated cleavage of the active HLA class I gene and/or HLA class II gene with a pair of zinc finger nucleases, each zinc finger nuclease comprising a cleavage domain and the recognition helix regions of the zinc finger proteins designated 18889, which binds to a target site within SEQ ID NO;
97;
11881, which binds to a target site within SEQ ID NO;
98;
24859, which binds to a target site within SEQ ID NO;
99;
25191, which binds to a target site within SEQ ID NO;
100;
25190, which binds to a target site within SEQ ID NO;
101;
25316, which binds to a target site within SEQ ID NO;
102;
25317, which binds to a target site within SEQ ID NO;
103;
15267, which binds to a target site within SEQ ID NO;
104;
15265, which binds to a target site within SEQ ID NO;
105;
17454, which binds to a target site within SEQ ID NO;
106;
17456, which binds to a target site within SEQ ID NO;
107;
15296, which binds to a target site within SEQ ID NO;
108;
15298, which binds to a target site within SEQ ID NO;
109;
25588, which binds to a target site within SEQ ID NO;
110;
25589, which binds to a target site within SEQ ID NO;
111;
15872, which binds to a target site within SEQ ID NO;
112;
15873, which binds to a target site within SEQ ID NO;
113;
15909, which binds to a target site within SEQ ID NO;
114;
or 15910, which binds to a target site within SEQ ID NO;
115,wherein the pair of zinc finger nucleases includes 18889 and 18881;
18889 and 24859;
25191 and 25190;
25316 and 25317;
15267 and 15265;
17454 and 17456;
15296 and 15298;
25588 and 25589;
15872 and 15873;
or 15909 and 15910;and wherein the HLA gene is inactivated by the second genomic modification. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
- 97 to 111 and an endogenous HLA class II gene comprising a sequence selected from the group consisting of any one of the nucleotides of SEQ ID NOs;
Specification