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ES2525707T3 - Uso de microRNAs para el control de ácidos nucleicos colaboradores de virus - Google Patents

Uso de microRNAs para el control de ácidos nucleicos colaboradores de virus Download PDF

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ES2525707T3
ES2525707T3 ES09764663.2T ES09764663T ES2525707T3 ES 2525707 T3 ES2525707 T3 ES 2525707T3 ES 09764663 T ES09764663 T ES 09764663T ES 2525707 T3 ES2525707 T3 ES 2525707T3
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mirna
seq
sequence
mir
capsid
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Vernon Mcneil Coffield Iii
Kurt I. Kamrud
Jonathan F. Smith
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Alphavax Inc
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    • A61K48/0041—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being polymeric
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • A—HUMAN NECESSITIES
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    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
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    • C12N2770/00011—Details
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    • C12N2770/36111—Alphavirus, e.g. Sindbis virus, VEE, EEE, WEE, Semliki
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    • C12N2820/00—Vectors comprising a special origin of replication system
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Abstract

Un ácido nucleico colaborador que comprende: (a) una secuencia de reconocimiento de la replicación en 5' de un alfavirus; (b) una secuencia de ácido nucleico que codifica para una proteína estructural de un alfavirus; (c) una secuencia de reconocimiento de la replicación en 3' de un alfavirus; y (d) al menos una secuencia de microARN objetivo de un microARN endógeno celular.

Description

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E09764663
09-12-2014
miARN objetivo
Cebador directo Cebador inverso Molde para la PCR del miARN
2 -3
lin-4 RC (SphI) F (5’-TTT GCATGCACACAGTCGA AGGTCTCAGGGA-3 ’ (ID. SEC. Nº: 3)) 3-1.1 pr1 (ID. SEC. Nº: 8) Colaborador del miARN de la cápside o de la gp 1 -3
2
T7 (ID. SEC. Nº: 1) lin-4 RC (PmeI) R (ID. SEC. Nº: 7) Colaborador del miARN de la cápside o de la gp 2 -3
4
T7 (ID. SEC. Nº: 1) miR-155 RC (PmeI) R (5’-GGGTTTAA ACTTAATGCTAATCGTGATAGGG G-3’ (ID. SEC. Nº: 9)) Colaborador del miARN de la cápside o de la gp 4 -6
4 -5
T7 (ID. SEC. Nº: 1) miR-17 RC (PmeI) R (5’-GGGTTTAA ACCAAAGTGCTTACAGTGCAGGT AGT-3’ (ID. SEC. Nº: 10)) Colaborador del miARN de la cápside o de la gp 4 -6
5
T7 (ID. SEC. Nº: 1) miR-17 RC (PmeI) R (ID. SEC. Nº: 10) Colaborador del miARN de la cápside o de la gp 5 -6
5 -6
miR-17 RC (SphI) F (5’-CA TGCATGCACTACCTGCA CTGTAAGCACTTTG-3 ’ (ID. SEC. Nº: 4)) 3-1.1pr1 (ID. SEC. Nº: 8) Colaborador del miARN de la cápside o de la gp 4 -6
6
miR-19 RC (Sphl) F (5’-CA TGCATGCTCAGTTTTGC ATAGATTTGCACA-3 ’ (ID. SEC. Nº: 5)) 3-1.1 pr1 (ID. SEC. Nº: 8) Colaborador del miARN de la cápside o de la gp 4 -6
[0069] También se construyeron colaboradores que codifican para el miARN objetivo individual repetido seis veces, en el ARN mensajero de hebra positiva producido durante la replicación del colaborador. Se eligieron seis copias de cada miARN objetivo individual porque es el número total de miARN objetivo ensayado en los constructos 5 RC1-6, y la longitud de la secuencia insertada en la NCR en 3’ también se mantendría en los nuevos constructos con respecto a los constructos RC1-6. Se sintetizaron de novo fragmentos de ADN (BlueHeron Biotechnology, Inc.; Bothell, WA) que codifican para la secuencia RC de las seis copias de cada miARN individual alineadas en tándem. Los identificadores para los respectivos fragmentos de miARN 6mero eran: RC1x6, RC2x6, RC3x6, RC4x6, RC5x6 y RC6x6. Se diseñó un sitio de restricción SphI único antes de la primera secuencia del miARN objetivo, se diseñó un 10 sitio de restricción EcoRV único entre la tercera y la cuarta copia de la secuencia del miARN objetivo y se diseñó un sitio de restricción PmeI único después de la última copia de la secuencia del miARN objetivo. Los respectivos fragmentos de secuencia de los miARNx6 se digirieron con las enzimas de restricción SphI y PmeI y después se ligaron individualmente en lugar del fragmento de secuencia del miARN1-6 encontrado en dHcap6-mut1(W-stop)RC1-6 o dHgp6-mut1-RC1-6, mediante la digestión de los colaboradores con las enzimas de restricción SphI y
15 PmeI. Los colaboradores de la cápside resultantes se denominaron dHcap6-mut1(W-stop)RC1x6, dHcap6-mutl (W-stop)RC2x6, dHcap6-mutl(W-stop)RC3x6, dHcap6-mutl(W-stop)RC4x6, dHcap6-mut1(W-stop)RC5x6 y dHcap6-mutl(W-stop)RC6x6. Los colaboradores de la GP resultantes se denominaron dHgp6-mut1-RC1x6, dHgp6-mutl-RC2x6, dHgp6-mutl-RC3x6, dHgp6-mutl-RC4x6, dHgp6-mutl-RC5x6 y dHgp6-mutl-RC6x6.
20 [0070] También se construyeron colaboradores que codifican para tres copias de una secuencia del miARN objetivo (por ejemplo, RC1x3). Esto se llevó a cabo de dos formas. Para los miARN objetivo RC1 -RC6, los colaboradores que contenían las tres copias fueron producidos mediante la digestión de los colaboradores de la cápside y de la gp que contenían las seis copias de un miARN objetivo individual (por ejemplo, RC1x6) con las enzimas de restricción EcoRV y PmeI. Esta digestión libera un fragmento de 75 pb eliminando 3 de las 6 copias del
25 miARN objetivo de cada colaborador. Los ADNs digeridos con EcoRV / PmeI se volvieron a ligar sobre sí mismos generando los colaboradores de la cápside y de la gp con 3 miARN objetivo en sus UTR en 3’. Se identificaron seis secuencias de miARN objetivo adicionales (RC7 -RC12) que se sabía que tenían una actividad específica del tipo de célula o de tejido que los objetivos más ampliamente activos representados por RC1 -RC6. Los miARN objetivo para RC7 -RC12 son como sigue: RC7 = miR-143 (5’-gagctacagtgcttcatctca-3’ (ID. SEC. Nº: 20)); RC8 = miR-30b
30 (5’-agctgagtgtaggatgtttaca-3’ (ID. SEC. Nº: 21)); RC9 = miR-181 (5’-actcaccgacagcgttgaatgtt-3’ (ID. SEC. Nº: 22)); RC10 = miR-124 (5’-ggcattcaccgcgtgcctta-3’ (ID. SEC. Nº: 23)); RC11 = miR-1 (5’-atacatacttctttacattcca-3’ (ID. SEC. Nº: 24)); y RC12 = miR-133a (5’-cagctggttgaaggggaccaaa-3’ (ID. SEC. Nº: 25)). Se produjeron colaboradores de la cápside que contenían secuencias objetivo que consisten en tres copias de cada secuencia específica de miARN objetivo de la siguiente forma. Se diseñaron cebadores inversos de la PCR que codificaban para cada secuencia de
35 miARN objetivo por triplicado (por ejemplo, RC7x3 R (5’-GCGTTTAAACTGAGATGAAGCACTGTAGCTCTGAGAT GAAGCACTGTAGC TCTGAGATGAAGCACTGTAGCTCGCATGCTTACCATTGCTCGCAGTTCTCC
GGAGTATACTTCACGGTAACTCCC-3’
(ID. SEC. Nº: 26)); RC8x3 R (5’-
GCGTTTAAACTGTAAACATCCTACACTCAGCTTGTAAACATCCTACACTCA
GCTTGTAAACATCCTACACTCAGCTGCATGCTTACCATTGCTCGCAGTTCT
40
CCGGAGTATACTTCACGGTAACTCCC-3’ (ID. SEC. Nº: 27)); RC9x3 R (5’
20
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Claims (1)

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    imagen2
ES09764663.2T 2008-12-01 2009-11-25 Uso de microRNAs para el control de ácidos nucleicos colaboradores de virus Active ES2525707T3 (es)

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US118954P 1999-02-05
US11895408P 2008-12-01 2008-12-01
PCT/US2009/065900 WO2010065414A1 (en) 2008-12-01 2009-11-25 Use of micrornas to control virus helper nucleic acids

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PE20191842A1 (es) 2017-05-08 2019-12-31 Gritstone Oncology Inc Vectores de neoantigeno de alfavirus
SG11202005792RA (en) 2017-12-20 2020-07-29 Vlp Therapeutics Llc Alphavirus replicon particle
CA3140019A1 (en) 2019-05-30 2020-12-03 Gritstone Bio, Inc. Modified adenoviruses
CN115552009A (zh) 2020-04-30 2022-12-30 Vlp治疗公司 细胞因子免疫疗法
JP2023541108A (ja) 2020-08-06 2023-09-28 グリットストーン バイオ インコーポレイテッド マルチエピトープワクチンカセット

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US5185440A (en) 1989-06-20 1993-02-09 North Carolina State University cDNA clone coding for Venezuelan equine encephalitis virus and attenuating mutations thereof
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EP2370584A1 (en) 2011-10-05
US20120100179A1 (en) 2012-04-26
US20140308312A1 (en) 2014-10-16
US10434187B2 (en) 2019-10-08
EP2370584B1 (en) 2014-11-05
US8680258B2 (en) 2014-03-25
US9597414B2 (en) 2017-03-21
US20180050118A1 (en) 2018-02-22
WO2010065414A1 (en) 2010-06-10

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