DK3020727T3 - Mutant calreticulin til diagnose af myeloide maligniteter - Google Patents
Mutant calreticulin til diagnose af myeloide maligniteter Download PDFInfo
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Claims (27)
1. Fremgangsmåde til vurdering af, om en patient lider af en myeloid malignitet eller er tilbøjelig til at lide af en myeloid malignitet, hvilken fremgangsmåde omfatter - at bestemme tilstedeværelsen af et genprodukt af et eller flere mutante alleler af calreticulin-genet i en prøve fra patienten; og - at vurdere, at patienten lider af en myeloid malignitet eller er tilbøjelig til at lide afen myeloid malignitet, når genproduktet er til stede, hvor det ene eller de flere mutante alleler omfatter nukleinsyre, der koder for et mutant calreticulin-protein, hvor det mutante calreticulin-protein er udvalgt fra gruppen bestående af (a) et protein, der er kodet af et nukleinsyremolekyle med nukleinsyresekven-sen som gengivet i SEQ ID NO: 1,2 eller 3; (b) et protein omfattende aminosyresekvensen som vist i SEQ ID NO: 4, (c) et protein som defineret i (a) eller (b), hvor en til 10 aminosyrer er deleteret, insereret, tilsat eller substitueret (d) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, der hybridiserer under stringente forhold til den komplementære streng af nu-kleinsyremolekyler som defineret i (a) eller (c), og hvor proteinet er en mutant af calreticulin-genet; (e) et protein med mindst 70 % identitet med proteinet i et hvilket som helst af (a) til (d); og (f) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, som er degenereret som som følge af den genetiske kode til nukleotidsekven-sen af en nukleinsyre som defineret i (a) eller (d), hvor genproduktet er protein, og hvor tilstedeværelsen eller mængden af proteinet bestemmes ved immunhisto-kemi (IHC), by immunoassay, gel- eller blotbaserede fremgangsmåder, mas-sespektrometri, flowcytometri eller FACS.
2. Fremgangsmåde ifølge krav 1, hvor det mutante calreticulin-protein er udvalgt fra gruppen bestående af (a) et protein, der er kodet af et nukleinsyremolekyle med nukleinsyresekven-sen som gengivet i SEQ ID NO: 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19, 21, 22, 23, 25, 26, 27, 29, 30, 31,33, 34, 35, 37, 38, 39, 41,42, 43, 45, 46, 47, 49, 50, 51,53, 54, 55, 57, 58, 59, 61,62, 63, 65, 66, 67, 69, 70, 71,73, 74, 75, 77, 78, 79, 81,82, 83, 85, 86, 87, 89, 90, 91,93, 94, 95, 97, 98, 99, 101,102, 103, 105, 106, 107, 109, 110, 111, 113, 114, 115, 117, 118, 119, 121, 122, 123, 125, 126, 127, 129, 130, 131, 133, 134, 135, 137, 138, 139, 141, 142, 143, 145, 146, 147, 149, 150, 151, 153, 154, 155, 157, 158, 159, 161, 162, 163, 165, 166, 167, 169, 170, 171, 173, 174, 175, 177, 178, 179, 181, 182, 183, 185, 186, 187, 189, 190, 191, 193, 194, 195, 197, 198, 199, 201, 202, 203, 205, 206, 207, 209, 210, 211, 213, 214, 215, 217, 218, 219, 221, 222, 223, 225, 226, 227, 229, 230, 231, 233, 234, 235, 237, 238, 239, 241, 242, 243, 245, 246, 247, 249, 250, 251, 253, 254, 255, 257, 258, 259, 261, 262, 263, 265, 266, 267, 269, 270, 271, 273, 274, 275, 277, 278, 279, 281, 282, 283, 285, 286, 287, 291, 292, 293, 295, 296, 297, 299, 300, 301, 303, 304, 305, 307, 308, 309, 311, 312, 313, 315, 316, 317, 319, 320, 321, 323, 324, 325, 327, 328, 329, 331, 332, 333, 335, 336, 337, 339, 340, 341, 343, 344, 345, 347, 348, 349, 351, 352, 353, 355, 356, 357, 359, 360, 361, 363, 364, 365, 367, 368, 369, 371, 372, 373, 375, 376, 377, 379, 380, 381, 383, 384, 385, 387, 388, 389, 391, 392, 393, 395, 396, 397, 399, 400, 401, 403, 404, 405, 407, 408, 409, 411, 412, 413, 415, 416, 417, 419, 420, 421, 423, 424, 425, 427, 428, 429, 431,432 eller 433; og (b) et protein omfattende aminosyresekvensen som vist i SEQ ID NO: 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 358, 362, 366, 370, 374, 378, 382, 386, 390, 394, 398, 402, 406, 410, 414, 418, 422, 426, 430 eller 434.
3. Fremgangsmåde ifølge krav 1 eller 2, hvor det mutante allel omfatter en nukleinsyre udvalgt fra gruppen bestående af (a) en nukleinsyre, der koder for et polypeptid omfattende en aminosyrese-kvens som gengivet i SEQ ID NO: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 358, 362, 366, 370, 374, 378, 382, 386, 390, 394, 398, 402, 406, 410, 414, 418, 422, 426, 430 eller 434; og (b) en nukleinsyre omfattende en nukleotidsekvens som gengivet i SEQ ID NO: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81,85, 89, 93, 97, 101,105,109, 113,117, 121,125,129, 133, 137,141,145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339, 343, 347, 351, 355, 359, 363, 367, 371, 375, 379, 383, 387, 391,395, 399, 403, 407, 411,415,419, 423, 427 eller 431.
4. Fremgangsmåde ifølge et hvilket som helst af kravene 1 to 3, hvor genproduktet omfatter et polypeptid udvalgt fra gruppen bestående af (a) et protein, der er kodet af et nukleinsyremolekyle med nukleinsyresekven-sen som gengivet i SEQ ID NO: 1,2 eller 3; (b) et protein omfattende aminosyresekvensen som vist i SEQ ID NO: 4; (c) et protein som defineret i (a) eller (b), hvor en til 10 aminosyrer er deleteret, insereret, tilsat eller substitueret; (d) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, der hybridiserer under stringente forhold til den komplementære streng af nu-kleinsyremolekyler som defineret i (a) eller (c), og hvor proteinet er en mutant af calreticulin-genet; (e) et protein med mindst 70 % identitet med proteinet i et hvilket som helst af (a) til (d); og (f) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, som er degenereret som som følge af den genetiske kode til nukleotidsekven-sen af en nukleinsyre som defineret i (a) eller (d).
5. Fremgangsmåde ifølge et hvilket som helst af kravene 1 to 4, hvor genproduktet omfatter et polypeptid udvalgt fra gruppen bestående af (a) et protein, der er kodet af et nukleinsyremolekyle med nukleinsyresekven-sen som gengivet i SEQ ID NO: 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19, 21,22, 23, 25, 26, 27, 29, 30, 31,33, 34, 35, 37, 38, 39, 41,42, 43, 45, 46, 47, 49, 50, 51,53, 54, 55, 57, 58, 59, 61,62, 63, 65, 66, 67, 69, 70, 71,73, 74, 75, 77, 78, 79, 81,82, 83, 85, 86, 87, 89, 90, 91, 93, 94, 95, 97, 98, 99, 101, 102, 103, 105, 106, 107, 109, 110, 111, 113, 114, 115, 117, 118, 119, 121, 122, 123, 125, 126, 127, 129, 130, 131, 133, 134, 135, 137, 138, 139, 141, 142, 143, 145, 146, 147, 149, 150, 151, 153, 154, 155, 157, 158, 159, 161, 162, 163, 165, 166, 167, 169, 170, 171, 173, 174, 175, 177, 178, 179, 181, 182, 183, 185, 186, 187, 189, 190, 191, 193, 194, 195, 197, 198, 199, 201, 202, 203, 205, 206, 207, 209, 210, 211, 213, 214, 215, 217, 218, 219, 221, 222, 223, 225, 226, 227, 229, 230, 231, 233, 234, 235, 237, 238, 239, 241, 242, 243, 245, 246, 247, 249, 250, 251, 253, 254, 255, 257, 258, 259, 261, 262, 263, 265, 266, 267, 269, 270, 271, 273, 274, 275, 277, 278, 279, 281, 282, 283, 285, 286, 287, 291, 292, 293, 295, 296, 297, 299, 300, 301, 303, 304, 305, 307, 308, 309, 311, 312, 313, 315, 316, 317, 319, 320, 321, 323, 324, 325, 327, 328, 329, 331, 332, 333, 335, 336, 337, 339, 340, 341, 343, 344, 345, 347, 348, 349, 351, 352, 353, 355, 356, 357, 359, 360, 361, 363, 364, 365, 367, 368, 369, 371, 372, 373, 375, 376, 377, 379, 380, 381, 383, 384, 385, 387, 388, 389, 391, 392, 393, 395, 396, 397, 399, 400, 401, 403, 404, 405, 407, 408, 409, 411, 412, 413, 415, 416, 417, 419, 420, 421, 423, 424, 425, 427, 428, 429, 431,432 eller 433; (b) et protein omfattende aminosyresekvensen som vist i SEQ ID NO: 4, 8,12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 358, 362, 366, 370, 374, 378, 382, 386, 390, 394, 398, 402, 406, 410, 414, 418, 422, 426, 430 eller 434; (c) et protein som defineret i (a) eller (b), hvor en til 10 aminosyrer er deleteret, insereret, tilsat eller substitueret; (d) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, der hybridiserer under stringente forhold til den komplementære streng af nu-kleinsyremolekyler som defineret i (a) eller (c), og hvor proteinet er en mutant af calreticulin-genet (e) et protein med mindst 70 % identitet med proteinet i et hvilket som helst af (a) til (d); og (f) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, som er degenereret som som følge af den genetiske kode til nukleotidsekven-sen af en nukleinsyre som defineret i (a) eller (d).
6. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 5, hvor prøven er en knoglemarvsprøve eller en blodprøve.
7. Fremgangsmåde ifølge krav 6, hvor knoglemarvsprøven opnås ved hjælp af biopsi.
8. Protein, der er udvalgt fra gruppen bestående af (a) et protein, der er kodet af et nukleinsyremolekyle med nukleinsyresekven-sen som gengivet i SEQ ID NO: 1,2 eller 3; (b) et protein omfattende aminosyresekvensen som vist i SEQ ID NO: 4; (c) et protein som defineret i (a) eller (b), hvor en til 10 aminosyrer er deleteret, insereret, tilsat eller substitueret; (d) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, der hybridiserer under stringente forhold til den komplementære streng af nu-kleinsyremolekyler som defineret i (a) eller (c), og hvor proteinet er en mutant af calreticulin-genet; (e) et protein med mindst 70 % identitet med proteinet i et hvilket som helst af (a) til (d); og (f) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, som er degenereret som som følge af den genetiske kode til nukleotidsekven-sen af en nukleinsyre som defineret i (a) eller (d).
9. Protein ifølge krav 8, hvor proteinet er udvalgt fra gruppen bestående af (a) et protein, der er kodet af et nukleinsyremolekyle med nukleinsyresekven-sen som gengivet i SEQ ID NO: 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19,21,22, 23, 25, 26, 27, 29, 30, 31,33, 34, 35, 37, 38, 39, 41,42, 43, 45, 46, 47, 49, 50, 51,53, 54, 55, 57, 58, 59, 61,62, 63, 65, 66, 67, 69, 70, 71,73, 74, 75, 77, 78, 79, 81,82, 83, 85, 86, 87, 89, 90, 91,93, 94, 95, 97, 98, 99, 101, 102, 103, 105, 106, 107, 109, 110, 111, 113, 114, 115, 117, 118, 119, 121, 122, 123, 125, 126, 127, 129, 130, 131, 133, 134, 135, 137, 138, 139, 141, 142 eller 143; (b) et protein omfattende aminosyresekvensen som vist i SEQ ID NO: 4, 8,12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140 eller 144; (c) et protein som defineret i (a) eller (b), hvor en til 10 aminosyrer er deleteret, insereret, tilsat eller substitueret; (d) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, der hybridiserer under stringente forhold til den komplementære streng af nu-kleinsyremolekyler som defineret i (a) eller (c), og hvor proteinet kodes af et eller flere mutante alleler af calreticulin-genet; (e) et protein med mindst 70 % identitet med proteinet i et hvilket som helst af (a) til (d); og (f) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, som er degenereret som som følge af den genetiske kode til nukleotidsekven-sen afen nukleinsyre som defineret i (a) eller (d).
10. Protein ifølge krav 8 eller 9, hvor proteinet er udvalgt fra gruppen bestående af (a) et protein, der er kodet af et nukleinsyremolekyle med nukleinsyresekven- sen som gengivet i SEQ ID NO: 291,292, 293, 295, 296, 297, 299, 300, 301, 303, 304, 305, 307, 308, 309, 311, 312, 313, 315, 316, 317, 319, 320, 321, 323, 324, 325, 327, 328, 329, 331, 332, 333, 335, 336, 337, 339, 340, 341, 343, 344, 345, 347, 348, 349, 351, 352, 353, 355, 356, 357, 359, 360, 361, 363, 364, 365, 367, 368, 369, 371, 372, 373, 375, 376, 377, 379, 380, 381, 383, 384, 385, 387, 388, 389, 391, 392, 393, 395, 396, 397, 399, 400, 401, 403, 404, 405, 407, 408, 409, 411, 412, 413, 415, 416, 417, 419, 420, 421, 423, 424, 425, 427, 428, 429, 431,432 eller 433; (b) et protein omfattende aminosyresekvensen som vist i SEQ ID NO: 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 358, 362, 366, 370, 374, 378, 382, 386, 390, 394, 398, 402, 406, 410, 414, 418,422,426,430 eller 434; (c) et protein som defineret i (a) eller (b), hvor en til 10 aminosyrer er deleteret, insereret, tilsat eller substitueret; (d) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, der hybridiserer under stringente forhold til den komplementære streng af nu-kleinsyremolekyler som defineret i (a) eller (c), og hvor proteinet er en mutant af calreticulin-genet; (e) et protein med mindst 70 % identitet med proteinet i et hvilket som helst af (a) til (d); og (f) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, som er degenereret som som følge af den genetiske kode til nukleotidsekven-sen afen nukleinsyre som defineret i (a) eller (d).
11. Protein ifølge et hvilket som helst af kravene 8 til 10, hvor proteinet er udvalgt fra gruppen bestående af (a) et protein, der er kodet af et nukleinsyremolekyle med nukleinsyresekven- sen som gengivet i SEQ ID NO: 145, 146, 147, 149, 150, 151, 153, 154, 155, 157, 158, 159, 161, 162, 163, 165, 166, 167, 169, 170, 171, 173, 174, 175, 177, 178, 179, 181, 182, 183, 185, 186, 187, 189, 190, 191, 193, 194, 195, 197, 198, 199, 201, 202, 203, 205, 206, 207, 209, 210, 211, 213, 214, 215, 217, 218, 219, 221, 222, 223, 225, 226, 227, 229, 230, 231, 233, 234, 235, 237, 238, 239, 241, 242, 243, 245, 246, 247, 249, 250, 251, 253, 254, 255, 257, 258, 259, 261, 262, 263, 265, 266, 267, 269, 270, 271, 273, 274, 275, 277, 278, 279, 281,282, 283, 285, 286 eller 287; (b) et protein omfattende aminosyresekvensen som vist i SEQ ID NO: 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284 eller 288; (c) et protein som defineret i (a) eller (b), hvor en til 10 aminosyrer er deleteret, insereret, tilsat eller substitueret; (d) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, der hybridiserer under stringente forhold til den komplementære streng af nu-kleinsyremolekyler som defineret i (a) eller (c), og hvor proteinet er en mutant af calreticulin-genet; (e) et protein med mindst 70 % identitet med proteinet i et hvilket som helst af (a) til (d); og (f) et protein omfattende en aminosyresekvens, der kodes af en nukleinsyre, som er degenereret som som følge af den genetiske kode til nukleotidsekven-sen afen nukleinsyre som defineret i (a) eller (d).
12. Vaccine omfattende proteinet ifølge krav 8 eller 9.
13. Protein ifølge krav 8 eller 9, såsom et protein omfattende 15 til 25 sammenhængende aminosyrer af proteinet som vist i SEQ ID NO: 4, til anvendelse som vaccine.
14. Immunogent middel, hvor det immunogene middel er et mutant calreticulin-protein ifølge et hvilket som helst af kravene 8 til 11.
15. Konjugat omfattende det immunogene middel ifølge krav 14, bundet til et bæreprotein.
16. Antistof, der binder specifikt til den C-terminale ende af mutant(e) calreti-culin-protein(er) som vist i SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140 eller 144.
17. Immunogent middel ifølge krav 14 eller antistof ifølge krav 16 til anvendelse ved behandling afen myeloid malignitet.
18. Anvendelse af et antistof, der binder specifikt til proteinet ifølge et hvilket som helst af kravene 8 til 11 til vurdering af, om en patient lider af en myeloid malignitet eller er tilbøjelig til at lide af en myeloid malignitet.
19. Antistof, der binder specifikt til den C-terminale ende af mutant(e) calreti-culin-protein(er) som vist i SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140 eller 144 til fremstilling af et diagnosekit til anvendelse i fremgangsmåden ifølge et hvilket som helst af kravene 1 til 7.
20. Anvendelse ifølge krav 18, hvor antistoffet binder specifikt til den C-terminale ende af mutant(e) calreticulin-protein(er) som vist i SEQ ID NOs: 4, 8,12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140 eller 144.
21. Antistof ifølge krav 16, eller antistof til anvendelse ifølge krav 17, eller anvendelse ifølge krav 18 eller 20, hvor antistoffet er et polyklonalt antistof, et monoklonalt antistof, et komplet antistof (immunoglobulin), et F(ab)-fragment, et F(ab)2-fragment, et enkeltkædet antistof, et kimært antistof, et CDR-podet antistof, et bivalent antistof-konstrukt, et bispecifikt enkeltkædet antistof, et syntetisk antistof eller et krydsklonet antistof.
22. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 7, anvendelse ifølge et hvilket som helst af kravene 18, 20 og 21 eller antistof til anvendelse ifølge krav 17 eller 21 eller immunogent middel til anvendelse ifølge krav 17, hvor den myeloide malignitet er en myeloproliferativ neoplasme, eller hvor den myeloide malignitet er et myelodysplastisk syndrom.
23. Fremgangsmåde ifølge krav 22, eller anvendelse ifølge krav 22, eller antistof til anvendelse ifølge krav 22 eller immunogent middel til anvendelse ifølge krav 22, hvor den myeloproliferative neoplasme er primær myelofibrose (PMF), eller hvor den myeloproliferative neoplasme er essentiel trombocytæmi (ET).
24. Fremgangsmåde ifølge krav 22 eller anvendelse ifølge krav 22 eller antistof til anvendelse ifølge krav 22 eller immunogent middel til anvendelse ifølge krav 22, hvor det myelodysplastiske syndrom er refraktær anæmi med ring-sideroblaster og trombocytæmi (RARS-T).
25. Protein ifølge krav 8 eller 9 eller antistof ifølge krav 16 eller 21 til anvendelse som et medikament.
26. Proces til fremstilling af polypeptidet ifølge et hvilket som helst af kravene 8 til 11, hvilken proces omfatter at dyrke værtsceller omfattende en nukleinsyre udvalgt fra gruppen bestående af (a) en nukleinsyre, der koder for et polypeptid omfattende en aminosyrese-kvens som gengivet i SEQ ID NO: 4; (b) en nukleinsyre omfattende en nukleotidsekvens som gengivet i SEQ ID NO: 2; (c) en nukleinsyre, der hybridiserer under stringente forhold til den komplementære streng af nukleinsyren som defineret i (a) eller (b), og hvor nukleinsyren omfatter en frameshift-mutation i exon 9 sammenlignet med vildtype-calreticulin-genet; (d) en nukleinsyre omfattende en nukleotidsekvens med mindst 70 % identitet med nukleotidsekvensen af nukleinsyrerne ifølge et hvilket som helst af (a) til (c); og (e) en nukleinsyre omfattende en nukleotidsekvens, som er degenereret som som følge af den genetiske kode til nukleotidsekvensen af en nukleinsyre ifølge et hvilket som helst af (a) til (d); eller at dyrke værtsceller omfattende en vektor omfattende nukleinsyren under betingelser, der muliggør ekspression af polypeptidet, og udvinde det fremstillede polypeptid fra kulturen.
27. Transgen celle eller transgent ikke-menneskeligt dyr, der omfatter og/eller eksprimerer en nukleinsyre eller en vektor omfattende nukleinsyren, hvor nukleinsyren omfatter mindst et eller flere mutante alleler af calreticulin-genet som defineret i et hvilket som helst af kravene 1 til 3.
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