ES2494940T3 - Moduladores de factores de coagulación mejorados - Google Patents

Moduladores de factores de coagulación mejorados Download PDF

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ES2494940T3
ES2494940T3 ES05740895.7T ES05740895T ES2494940T3 ES 2494940 T3 ES2494940 T3 ES 2494940T3 ES 05740895 T ES05740895 T ES 05740895T ES 2494940 T3 ES2494940 T3 ES 2494940T3
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cuauaccgcguaaugcugcc
uccucac
gugagga
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Christopher Rusconi
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Abstract

Un aptámero que comprende la secuencia de ácidos nucleicos de la SEC ID N.º: 19.

Description

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nucleótidos de longitud, incluidos siete, seis, cinco, cuatro, tres o dos nucleótidos de longitud. La longitud del bucle 1 también puede variarse y en un modo de realización incluye diez o nueve nucleótidos en sentido 5'-3' y un nucleótido en sentido 3'-5'.
5 Los aptámeros para un producto del gen del factor IX pueden comprender ribonucleótidos o desoxirribonucleótidos,
o una combinación de los mismos. En general, los aptámeros mejorados tienen al menos 25 nucleótidos de longitud y típicamente no tienen más de 35-40 nucleótidos de longitud. En un modo de realización, los aptámeros tienen al menos 25, 30, 35 o 40 nucleótidos de longitud. En modos de realización específicos, la secuencia del tallo 1 incluye 5 nucleótidos en sentido 5'-3'. En un submodo de realización, el tallo 1 incluye tres residuos de guanina (G) en
10 sentido 5'-3'.
Los aptámeros mejorados pueden incluir una "posición suicida". En un modo de realización, esta posición se convierte en monocatenaria y lábil tras la unión del antídoto frente al aptámero mejorado y permite la escisión del aptámero mejorado tras la unión del antídoto por enzimas en circulación, tales como endonucleasas sanguíneas o
15 hepáticas, de modo que se elimina eficazmente el aptámero activo de la circulación. La posición suicida puede estar en una guanina del tallo 2 que está hidroxilada. En un modo de realización, este nucleótido se encuentra en configuración bicatenaria hasta que se une con un antídoto y se convierte en monocatenaria y queda disponible para la escisión tras la unión del antídoto.
20 Se describe que los aptámeros incluyen la secuencia de nucleótidos gugg y la secuencia complementaria ccac. En un modo de realización, el aptámero para el factor IX comprende la secuencia de nucleótidos: gugga cuauacc gcg uaaugc ugc c uccac T (SEC ID N.º: 19).
Otro modo de realización de la invención incluye un oligonucleótido antídoto apareado con el aptámero de la
25 invención. El oligonucleótido antídoto puede ser complementario a al menos una parte del aptámero. Por ejemplo, el antídoto puede comprender las siguientes secuencias: (5'-3') secuencia: cgcgguauaguccccau (Apt/AD; SEC ID N.º: 1); (5'-3') secuencia: cgcgguauaguccc (Apt6/AD; SEC ID N.º: 2); (5'-3') secuencia: cgcgguauaguccac (Apt7/AD; SEC ID N.º: 3); (5'-3') secuencia: cgcgguauaguccauc (Apt8/AD; SEC ID N.º: 4); (5'-3') secuencia: cgcgguauagucag (Apt9/AD; SEC ID N.º: 5); (5'-3') secuencia: cgcgguauagucagg (Apt10/AD; SEC ID N.º: 6); (5'-3') secuencia:
30 cgcgguanagucagag (Apt11/AD; SEC ID N.º: 7); (5'-3') secuencia: cgcgguauaguccucac (Apt14/AD; SEC ID N.º: 8) o cualquier modificación o derivado de las mismas. En determinados modos de realización, el antídoto consiste esencialmente en una de las secuencias anteriores o consiste por completo en una de las secuencias anteriores.
No es necesario que la secuencia del antídoto sea totalmente complementaria al aptámero anticoagulante mejorado 35 siempre que el antídoto se una o hibride lo suficiente al aptámero para neutralizar su actividad.
Los pares de aptámeros incluyen las siguientes secuencias:
Aptámero
Antídoto
augggga cuauacc gcg uaaugc ugc c uccccau t (SEC ID N.º: 9)
cgcgguauaguccccau (SEC ID N.º: 1)
augggga cuauaccgcguaaugcugcc uccccau t (SEC ID N.º: 10)
cgcgguauaguccccau (SEC ID N.º: 1)
ggga cuauaccgcguaaugcugcc uccc t (SEC ID N.º: 11)
cgcgguauaguccc (SEC ID N.º: 2)
gugga cuauaccgcguaaugcugcc uccac t (SEC ID N.º: 12)
cgcgguauaguccac (SEC ID N.º: 3)
gaugga cuauaccgcguaaugcugcc uccauc t (SEC ID N.º: 13)
cgcgguauaguccauc (SEC ID N.º: 4)
cuga cuauaccgcguaaugcugcc ucag t (SEC ID N.º: 14)
cgcgguauagucag (SEC ID N.º: 5)
ccuga cuauaccgcguaaugcugcc ucagg t (SEC ID N.º: 15)
cgcgguauagucagg (SEC ID N.º: 6)
cucuga cuauaccgcguaaugcugcc ucagag t (SEC ID N.º: 16)
cgcgguauagucagag (SEC ID N.º: 7)
gugagga cuauaccgcguaaugcugcc uccucac t (SEC ID N.º: 17)
cgcgguauaguccucac (SEC ID N.º: 8)
gugagga cuauacc gcg uaaugc ugc c uccucac t (SEC ID N.º: 18)
cgcgguauaguccucac (SEC ID N.º: 8)
gugga cuauacc gcg uaaugc ugc c uccac t (SEC ID N.º: 19)
cgcgguauaguccac (SEC ID N.º: 3)
40 Se desarrollan pares de aptámero mejorado-antídoto que son más estables y bioactivos por la inclusión de modificaciones secundarias en el aptámero o en el antídoto o en ambos. En un modo de realización, el aptámero mejorado para el factor IX incluye uno o más nucleótidos 2'-O-metil modificados. En otro modo de realización, el
7
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nucleótidos en particular. Por ejemplo, una secuencia consenso podría consistir en una serie de cuatro posiciones en la que la primera posición es A en todos los miembros de la mezcla, la segunda posición es A en el 25 %, T en el 35 % y C en el 40 %, la tercera posición es T en todos los oligonucleótidos y la cuarta posición es G en el 50 % de los oligonucleótidos y C en el 50 % de los oligonucleótidos.
En modos de realización específicos, los aptámeros incluyen las secuencias de nucleótidos de las siguientes SEC ID N.ºs:
SEC ID
Código Tamaño Secuencia
9
AptA 35mero (5'-3') secuencia: augggga cuauacc gcg uaaugc ugc c uccccau t
10
Apt1 35mero (5'-3') secuencia; augggga cuauaccgcguaaugcugcc uccccau t
9
Apt2 35mero (5'-3') secuencia: augggga cuauacc gcg uaaugc ugc c uccccau t
9
Apt3 35mero (5'-3') secuencia: augggga cuauacc gcg uaaugc ugc c uccccau t
9
Apt4 35mero (5'-3') secuencia: augggga cuauacc gcg uaaugc ugc c uccccau t
9
Apt5 35mero (5'-3') secuencia: augggga cuauacc gcg uaaugc ugc c uccccau t
11
Apt6 29mer (5'-3') secuencia: ggga cuauaccgcguaaugcugcc uccc t
12
Apt7 31mero (5'-3') secuencia: gugga cuauaccgcguaaugcugcc uccac t
13
Apt8 33mero (5'-3') secuencia: gaugga cuauaccgcguaaugcugcc uccauc t
14
Apt9 29mero (5'-3') secuencia: cuga cuauaccgcguaaugcugcc ucag t
15
Apt10 31mero (5'-3') secuencia: ccuga cuauaccgcguaaugcugcc ucaggt
16
Apt11 33mero (5'-3') secuencia: cucuga cuauaccgcguaaugcugcc ucagag t
10
Apt12 35mero (5'-3') secuencia: augggga cuauaccgcguaaugcugcc uccccau t
10
Apt13 35mero (5'-3') secuencia: augggga cuauaccgcguaaugcugcc uccccau t
17
Apt14 35mero (5'-3') secuencia: gugagga cuauaccgcguaaugcugcc uccucac t
17
Apt15 35mero (5'-3') secuencia: gugagga cuauaccgcguaaugcugcc uccucac t
17
Apt16 35mero (5'-3') secuencia: gugagga cuauaccgcguaaugcugcc uccucac t
17
Apt17 35mero (5'-3') secuencia: gugagga cuauaccgcguaaugcugcc uccucac t
11
Apt18 29mero (5'-3') secuencia: ggga cuauaccgcguaaugcugcc uccc t
12
Apt19 31mero (5'-3') secuencia: gugga cuauaccgcguaaugcugcc uccac t
13
Apt20 33mero (5'-3') secuencia: gaugga cuauaccgcguaaugcugcc uccauc t
18
Apt21 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
18
Apt22 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
18
Apt23 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
18
Apt24 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
18
Apt25 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
27
Apt26 33mero (5'-3') secuencia: gugagga cuauacc gca aucg ugc c uccucac t
28
Apt27 33mero (5'-3') secuencia: gugagga cuauacc gca aucg ugc c uccucac t
29
Apt28 33mero (5'-3') secuencia: gugagga cuauacc gca aucg ugc c uccucac t
30
Apt29 33mero (5'-3') secuencia: gugagga cuauacc gca aucg ugc c uccucac t
18
Apt30 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
18
Apt31 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
18
Apt32 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
18
Apt33 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
18
Apt34 35mero (5'-3') secuencia: gugagga cuauacc gcg uaaugc ugc c uccucac t
19
Apt35 31mero (5'-3') secuencia: gugga cuauacc gcg uaaugc ugc c uccac t
19
Apt36 31mero (5'-3') secuencia: gugga cuauacc gcg uaaugc ugc c uccac t
19
Apt37 31mero (5'-3') secuencia: gugga cuauacc gcg uaaugc ugc c uccac t
19
Apt38 31mero (5'-3') secuencia: gugga cuauacc gcg uaaugc ugc c uccac t
19
Apt39 31mero (5'-3') secuencia: gugga cuauacc gcg uaaugc ugc c uccac t
12
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E05740895
22-08-2014
que mejoran la biodisponibilidad de los oligómeros, potencian la resistencia de los oligómeros a la degradación y/o fortalecen la hibridación específica de secuencia con el ARN.
Los aptámeros incluyen secuencias de nucleótidos de cualquiera de las siguientes secuencias. ("A" es 2'OH A; "a" es 2'-O-metil A; "G" es 2'-OH G; "g" es 2'-O-metil G; "C" es 2'-fluoro C; "c" es 2-O-metil C; "U" es 2'fluoro U; "u" es 2'O-metil U; y "T" es 2'H T invertida.)
SEC ID N.º:
Código Secuencia
20
AptA AUGGGGA CUAUACC GCG UAAUGC UGC C UCCCCAU T
21
Apt1 aUgggga CUAUACCGCGUAAUGCUGCC UCCCCaU T
22
Apt2 AUGGGGA CUaUaCC GCG UAAUGC UGC C UCCCCAU T
23
Apt3 AUGGGGA CUAUACC gCg UAAUGC UgC C UCCCCAU T
24
Apt4 AUGGGGA CUAUACC GCG UaaUgC UGC C UCCCCAU T
25
Apt5 aUgggga CUaUaCC gCg UaaUgC UgC C UCCCCaU T
26
Apt6 ggga CUaUaCCGCGUAAUGCUGCC uccc T
27
Apt7 gugga CUaUaCCGCGUAAUGCUGCC uccac T
28
Apt8 gaugga CUaUaCCGCGUAAUGCUGCC uccauc T
29
Apt9 cuga CUaUaCCGCGUAAUGCUGCC ucag T
30
Apt10 ccuga CUaUaCCGCGUAAUGCUGCC ucagg T
31
Apt11 cucuga CUaUaCCGCGUAAUGCUGCC ucagag T
32
Apt12 aUgggga CUaUaCCGCGUAAUGCUGCC UCCCCaU T
33
Apt13 augggga CUaUaCCGCGUAAUGCUGCC uccocau T
34
Apt14 gUga&ga CUaUaCCGCGUAAUGCUGCC UCCUCaC T
35
Apt15 gUgaggA CUaUaCCGCGUAAUGCUGCC UCCUCaC T
36
Apt16 gugaggA CUaUaCCGCGUAAUGCUGCC Uccucac T
37
Apt17 gugagga CUaUaCCGCGUAAUGCUGCC uccucac T
38
Apt18 gggA CUaUaCCGCGUAAUGCUGCC Uccc T
39
Apt19 guggA CUaUaCCGCGUAAUGCUGCC Uccac T
40
Apt20 gauggA CUaUaCCGCGUAAUGCUGCC Uccauc T
41
Apt21 gugagga CUaUaCC GCG UAAUGC UGC C Uccucac T
42
Apt22 gugaggA CUaUaCC gCg UAAUGC UgC C Uccucac T
43
Apt23 gugaggA CUaUaCC GCG UaaUgC UGC C Uccucac T
44
Apt24 gugaggA CUaUaCC gCg UaaUgC UgC C Uccucac T
45
Apt25 gugaggA CUaUaCC GCg UaaUgC UgC C Uccucac T
46
Apt26 gugaggA CUaUaCC gCa AUCG UgC C Uccucac T
47
Apt27 gugaggA CUaUaCC GCA aUCg UGC C Uccucac T
48
Apt28 gugaggA CUaUaCC gCaaUCg UgC C Uccucac T
49
Apt29 gugaggA CUaUaCC GCa aUCg UgC C Uccucac T
50
Apt30 CUaUaCC gCG UaaUgC UGC C Uccucac T
51
Apt31 gugagga CUaUaCC. gcg UaaUgC ugc C Uccucac T
52
Apt32 gugagga CUaUaCC gcg UaaUgC UgC C Uccucac T
53
Apt33 gugagga CUaUaCC gCg UaaUgC UGC C Uccucac T
54
Apt34 gugagga CUaUaCC gCg UaaUgC uGc C Uccucac T
55
Apt35 gugga CUaUaCC gCG UaaUgC UGC C Uccac T
56
Apt36 gugga CUaUaCC gCG UaaUgC ugc C Uccac T
57
Apt37 gugga CUaUaCC gCG UaaUgC UgC C Uccac T
58
Apt38 gugga CUaUaCC gCg UaaUgC UGC C Uccac T
59
Apt39 gugga CUaUaCC gCg UaaUgC uGc C Uccac T
En un modo de realización específico, el aptámero para el factor IX comprende, consiste en, o consiste 10 esencialmente en, la secuencia de nucleótidos: gugga CUaUaCC gCg UaaUgC uGc C Uccac T (Apt39; SEC ID N.º:
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