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AR101440A1 - MULTIPLE ARNi DIRECTED FOR CANCER TREATMENT - Google Patents

MULTIPLE ARNi DIRECTED FOR CANCER TREATMENT

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Publication number
AR101440A1
AR101440A1 ARP150101261A ARP150101261A AR101440A1 AR 101440 A1 AR101440 A1 AR 101440A1 AR P150101261 A ARP150101261 A AR P150101261A AR P150101261 A ARP150101261 A AR P150101261A AR 101440 A1 AR101440 A1 AR 101440A1
Authority
AR
Argentina
Prior art keywords
expression
gene
cleavage
rna molecule
reduces
Prior art date
Application number
ARP150101261A
Other languages
Spanish (es)
Inventor
Lonard David
W Omalley Bert
Nemunaitis John
Rao Donald
Original Assignee
Baylor College Medicine
Strike Bio Inc
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Filing date
Publication date
Application filed by Baylor College Medicine, Strike Bio Inc filed Critical Baylor College Medicine
Publication of AR101440A1 publication Critical patent/AR101440A1/en

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    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
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    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
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Abstract

Reivindicación 1: Una composición de ARNhp bifuncional capaz de reducir la expresión de tres o más genes, caracterizada porque comprende: una primera molécula de ARN bifuncional que reduce la expresión de un primer gen blanco; una segunda molécula de ARN bifuncional que reduce la expresión de un segundo gen blanco; y una tercera molécula de ARN bifuncional que reduce la expresión de un tercer gen blanco, en donde cada una de las moléculas de ARN bifuncional pueden activar un complejo de silenciamiento inducido por ARN dependiente de clivaje e independiente de clivaje para reducir el nivel de expresión de dichos primer, segundo y tercer genes blanco. Reivindicación 6: Los ARNhp bifuncionales de la reivindicación 1, caracterizados porque por lo menos la primera, la segunda o la tercera molécula de ARN bifuncional se selecciona entre las SEQ ID Nº 5 - 22, las SEQ ID Nº 23 - 32, las SEQ ID Nº 33 - 34, las SEQ ID Nº 36 - 37, las SEQ ID Nº 38 - 39 o las SEQ ID Nº 44 - 45. Reivindicación 9: Un vector de expresión, caracterizado porque comprende: un promotor; y un inserto de ácido nucleico ligado operativamente al promotor, en donde el inserto comprende: una primera molécula de ARN bifuncional que reduce la expresión de un primer gen blanco; una segunda molécula de ARN bifuncional que reduce la expresión de un segundo gen blanco; y una tercera molécula de ARN bifuncional que reduce la expresión de un tercer gen blanco, en donde la molécula de ARN bifuncional puede activar un complejo de silenciamiento inducido por ARN dependiente de clivaje e independiente de clivaje para reducir el nivel de expresión del primer, segundo y tercer genes blanco, en donde dichos uno o más ARNhp comprenden una molécula de ARN bifuncional que activa un complejo de silenciamiento inducido por ARN dependiente de clivaje e independiente de clivaje para reducir el nivel de expresión del primer, segundo y tercer genes blanco. Reivindicación 15: Un sistema de administración terapéutico, caracterizado porque comprende: un vehículo del agente terapéutico; y un vector de expresión que comprende un promotor y un inserto de ácido nucleico ligado operativamente al promotor, donde el inserto de ácido nucleico codifica: una primera molécula de ARN bifuncional que reduce la expresión de un primer gen blanco; una segunda molécula de ARN bifuncional que reduce la expresión de un segundo gen blanco; y una tercera molécula de ARN bifuncional que reduce la expresión de un tercer gen blanco, en donde cada una de las moléculas de ARN bifuncional puede activar un complejo de silenciamiento inducido por ARN dependiente de clivaje e independiente de clivaje para reducir el nivel de expresión de dichos primer, segundo y tercer genes blanco. Reivindicación 27: Un método para suprimir un crecimiento de células tumorales en un sujeto humano, caracterizado porque comprende los pasos de: identificar al sujeto humano que necesita dicha supresión del crecimiento de células tumorales; y administrar un vector de expresión en un complejo transportador del agente terapéutico al sujeto humano en una cantidad suficiente como para suprimir el crecimiento de células tumorales, en donde el vector de expresión comprende un inserto de ácido nucleico ligado operativamente al promotor, en donde el inserto comprende: una primera molécula de ARN bifuncional que reduce la expresión de un gen KRAS mutado; una segunda molécula de ARN bifuncional que reduce la expresión de un gen SRC-3; y una tercera molécula de ARN bifuncional que reduce la expresión de un gen del receptor del factor de crecimiento epidérmico (EGFR), en donde la molécula de ARN bifuncional puede activar un complejo de silenciamiento inducido por ARN dependiente de clivaje e independiente de clivaje para reducir el nivel de expresión de los genes KRAS, SRC-3 y EGFR mutados, y en donde la inhibición da como resultado la apoptosis, el arresto de la proliferación o una menor capacidad de invasión de las células tumorales. Reivindicación 36: Un método para evaluar un fármaco candidato considerado de utilidad en el tratamiento de un cáncer, caracterizado porque dicho método comprende: (a) medir uno o más entre: el nivel de expresión de por lo menos un gen KRAS de tipo salvaje y uno o más genes KRAS mutados, y dos o más genes blanco en las células o los tejidos del cáncer; el nivel de expresión de un gen candidato o de un grupo de genes candidato en un entorno celular con expresión disminuida de uno o más genes KRAS mutados, y de dos o más genes blanco en las células o los tejidos del cáncer; el efecto de un fármaco candidato sobre el fenotipo de dichas células compuesta por una expresión disminuida de uno o más genes KRAS mutados y los dos o más genes blanco en las células o los tejidos del cáncer; (b) administrar un fármaco candidato a un primer subconjunto de dichas células o tejidos de cáncer, y un placebo a un segundo subconjunto de dichas células o tejidos de cáncer; (c) repetir el paso (a) después de la administración de la fármaco candidato o del placebo; y (d) determinar si el fármaco candidato es efectivo en la producción de un determinado fenotipo en un entorno celular con expresión reducida del gen KRAS mutado y los dos o más genes blanco en comparación con un entorno celular que expresa un gen KRAS normal de manera estadísticamente significativa en comparación con cualquier reducción que tuviera lugar en el segundo subconjunto de células o tejidos de cáncer de pulmón, en donde una reducción estadísticamente significativa indica que el fármaco candidato es de utilidad en el tratamiento de cáncer. Reivindicación 39: Un método para suprimir el crecimiento de células tumorales en un sujeto humano, caracterizado porque comprende los pasos de: obtener una muestra de células tumorales del sujeto humano; identificar uno o más genes blanco en el sujeto humano que necesita dicha supresión para impedir el crecimiento de células tumorales; construir un vector de expresión que comprenda un inserto que expresa dos o más segmentos de ácidos nucleicos de ARNi dirigidos específicamente contra el o los genes identificados en la muestra de células tumorales; en donde dicho inserto comprende: un primer y un segundo ácido nucleico de ARNi que reduce la expresión del mismo gen blanco o de genes blanco diferentes identificados en las células tumorales; administrar el vector de expresión en un complejo transportador del agente terapéutico al sujeto humano en una cantidad suficiente como para expresar dichos dos o más segmentos de ácidos nucleicos de ARNi; y determinar si el o los genes fueron noqueados por el vector de expresión en las células tumorales de interés, en donde la inhibición da como resultado la apoptosis, el arresto de la proliferación o una menor capacidad de invasión de las células tumorales.Claim 1: A bifunctional mRNA composition capable of reducing the expression of three or more genes, characterized in that it comprises: a first bifunctional RNA molecule that reduces the expression of a first white gene; a second bifunctional RNA molecule that reduces the expression of a second white gene; and a third bifunctional RNA molecule that reduces the expression of a third white gene, where each of the bifunctional RNA molecules can activate a cleavage complex induced by cleavage-independent and cleavage-independent RNA to reduce the level of expression of said first, second and third target genes. Claim 6: The bifunctional hRNAs of claim 1, characterized in that at least the first, second or third bifunctional RNA molecule is selected from SEQ ID No. 5-22, SEQ ID No. 23-32, SEQ ID No. 33-34, SEQ ID No. 36-37, SEQ ID No. 38-39 or SEQ ID No. 44-45. Claim 9: An expression vector, characterized in that it comprises: a promoter; and a nucleic acid insert operatively linked to the promoter, wherein the insert comprises: a first bifunctional RNA molecule that reduces the expression of a first white gene; a second bifunctional RNA molecule that reduces the expression of a second white gene; and a third bifunctional RNA molecule that reduces the expression of a third white gene, where the bifunctional RNA molecule can activate a cleavage complex induced by cleavage-independent and cleavage-independent RNA to reduce the level of expression of the first, second and third target genes, wherein said one or more hRNA comprise a bifunctional RNA molecule that activates a cleavage complex induced by cleavage-independent and cleavage-independent RNA to reduce the level of expression of the first, second and third target genes. Claim 15: A therapeutic administration system, characterized in that it comprises: a vehicle of the therapeutic agent; and an expression vector comprising a promoter and a nucleic acid insert operatively linked to the promoter, wherein the nucleic acid insert encodes: a first bifunctional RNA molecule that reduces the expression of a first white gene; a second bifunctional RNA molecule that reduces the expression of a second white gene; and a third bifunctional RNA molecule that reduces the expression of a third white gene, where each of the bifunctional RNA molecules can activate a cleavage complex induced by cleavage-dependent and cleavage-independent RNA to reduce the level of expression of said first, second and third target genes. Claim 27: A method for suppressing a growth of tumor cells in a human subject, characterized in that it comprises the steps of: identifying the human subject that needs said suppression of tumor cell growth; and administering an expression vector in a therapeutic agent transport complex to the human subject in an amount sufficient to suppress the growth of tumor cells, wherein the expression vector comprises a nucleic acid insert operatively linked to the promoter, wherein the insert it comprises: a first bifunctional RNA molecule that reduces the expression of a mutated KRAS gene; a second bifunctional RNA molecule that reduces the expression of an SRC-3 gene; and a third bifunctional RNA molecule that reduces the expression of an epidermal growth factor receptor (EGFR) gene, where the bifunctional RNA molecule can activate a cleavage complex induced by cleavage-independent and cleavage-independent RNA to reduce the level of expression of the mutated KRAS, SRC-3 and EGFR genes, and where the inhibition results in apoptosis, arrest of proliferation or reduced invasion capacity of tumor cells. Claim 36: A method for evaluating a candidate drug considered useful in the treatment of a cancer, characterized in that said method comprises: (a) measuring one or more between: the level of expression of at least one wild-type KRAS gene and one or more mutated KRAS genes, and two or more target genes in cancer cells or tissues; the level of expression of a candidate gene or a group of candidate genes in a cellular environment with decreased expression of one or more mutated KRAS genes, and of two or more white genes in cancer cells or tissues; the effect of a candidate drug on the phenotype of said cells composed of a decreased expression of one or more mutated KRAS genes and the two or more target genes in cancer cells or tissues; (b) administering a candidate drug to a first subset of said cancer cells or tissues, and a placebo to a second subset of said cancer cells or tissues; (c) repeat step (a) after administration of the candidate drug or placebo; and (d) determine if the candidate drug is effective in producing a certain phenotype in a cellular environment with reduced expression of the mutated KRAS gene and the two or more white genes compared to a cellular environment that expresses a normal KRAS gene in a manner Statistically significant compared to any reduction that took place in the second subset of lung cancer cells or tissues, where a statistically significant reduction indicates that the candidate drug is useful in the treatment of cancer. Claim 39: A method for suppressing the growth of tumor cells in a human subject, characterized in that it comprises the steps of: obtaining a sample of tumor cells from the human subject; identify one or more white genes in the human subject that needs such suppression to prevent the growth of tumor cells; construct an expression vector comprising an insert that expresses two or more segments of RNAi nucleic acids specifically directed against the gene (s) identified in the tumor cell sample; wherein said insert comprises: a first and a second RNAi nucleic acid that reduces the expression of the same white gene or of different white genes identified in the tumor cells; administering the expression vector in a carrier complex of the therapeutic agent to the human subject in an amount sufficient to express said two or more segments of RNAi nucleic acids; and determine whether the gene (s) were knocked out by the expression vector in the tumor cells of interest, where inhibition results in apoptosis, arrest of proliferation or reduced invasion capacity of tumor cells.

ARP150101261A 2014-04-25 2015-04-27 MULTIPLE ARNi DIRECTED FOR CANCER TREATMENT AR101440A1 (en)

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CN112980840A (en) * 2019-12-17 2021-06-18 南京大学 Multi-targeted siRNA for cancer therapy
CN112011573A (en) * 2020-07-21 2020-12-01 山西医科大学 A lentiviral vector for transfecting mouse primary neurons and its construction method
CN111996193B (en) 2020-09-11 2024-02-20 北京键凯科技股份有限公司 siRNA sequence for effectively inhibiting expression of epidermal growth factor receptor
MX2023004899A (en) 2020-10-28 2023-07-18 Baylor College Medicine TARGETING OF SRC-3 IN IMMUNE CELLS AS A THERAPEUTIC IMMUNOMODULATOR FOR THE TREATMENT OF CANCER.
CN117327703B (en) * 2023-11-22 2024-04-23 青岛大学附属医院 Agrin-shRNA of targeted smooth muscle cells and application of Agrin-shRNA in preparation of anti-atherosclerosis drugs

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