PT1550719E - Arn de cadeia dupla (arncd), para a inibição da expressão de um gene previamente definido - Google Patents
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Description
ΕΡ 1 550 719/ΡΤ
DESCRIÇÃO "ARN de cadeia dupla (ARNcd), para a inibição da expressão de um gene previamente definido" 0 invento refere-se a um oligorribonucleótido com estrutura de cadeia dupla, para a inibição da expressão de um gene alvo previamente definido numa célula. Refere-se além disso, a um medicamento e a uma utilização de oligorribonucleótidos de cadeia dupla.
Conhece-se um processo para a inibição da expressão de um gene alvo previamente definido de WO 99/3219, posteriormente publicado. Este processo que se conhece refere-se à inibição da expressão de genes em células de invertebrados. Para este efeito é necessário que o oligorribonucleótido de cadeia dupla apresente uma sequência idêntica à do gene alvo, com um comprimento de pelo menos 50 bases. Para se obter uma inibição eficaz é necessário que a sequência idêntica tenha um comprimento de 300 a 1000 pares de bases. A produção de um oligorribonucleótido deste tipo é complicada. A DE 196 31 919 C2 descreve um ARN antisense com
estruturas secundárias especiais, sendo que o ARN antisense existe sob a forma de um vector que o codifica. O ARN antisense é uma molécula de ARN que é complementar a regiões do ARNm. Através da ligação a estas regiões é obtida uma inibição da expressão génica. Esta inibição pode ser utilizada especialmente para o diagnóstico e/ou terapia de doenças, p.e. doenças tumorais ou infecções virais. - O ARN antisense tem de ser introduzido, com grande inconveniente, na célula, numa quantidade que seja, pelo menos, tão elevada como a quantidade do ARNm. A eficácia dos métodos antisense que se conhecem não é muito elevada.
De US 5,712,257 conhece-se um medicamento que contém ARN de cadeia dupla (ARNcd) de emparelhamento incorrecto e fracções de ARNcd de emparelhamento incorrecto biologicamente activas, sob a forma de um complexo ternário com um agente tensioactivo. O ARNcd utilizado neste caso, consiste em cadeias de ácido nucleico simples produzidas sinteticamente, 2 ΕΡ 1 550 719/ΡΤ sem sequência de bases definida. As cadeias simples emparelham-se de forma não regular, formando emparelhamentos de bases chamados "não-Watson-Crick", formando assim cadeias duplas de emparelhamento incorrecto. O ARNcd que se conhece, serve para a inibição da proliferação de retrovirus, como por exemplo HIV. A proliferação do vírus pode ser inibida no caso de se introduzir na célula ARNcd não específico da sequência. Neste caso dá-se uma indução de interferão, pelo qual se pretende inibir a proliferação do vírus. O efeito inibidor, ou seja, a eficácia deste método é reduzida.
De Fire, A. e outros, NATURE, Vol. 391, pp. 806 sabe-se que ARNcd do qual uma das cadeias é em segmentos complementar a um gene de um nematode a inibir, inibe com elevada eficácia a expressão deste gene. É defendida a opinião de que a eficácia particular do ARNcd utilizado em células do nematode não se baseia no princípio antisense mas que se deve, possivelmente, a propriedades catalíticas do ARNcd ou a enzimas induzidas por este. - Este artigo não diz nada sobre a eficácia de ARNcd específico em relação à inibição da expressão génica, especialmente em células de mamífero e células humanas. WO 99/53050 descreve meios e processos para a redução da expressão génica em células eucarióticas, especialmente células vegetais, onde se introduzem genes quiméricos que não só codificam moléculas de ARN sense como também antisense, dirigidas contra o gene alvo. WO 99/53050 não revela um oligorribonucleótido com duas cadeias de ARN simples separadas, especialmente para a inibição da expressão génica em células de mamífero. WO 00/63364 descreve processos e composições para a inibição da função de uma sequência nucleotídica alvo numa célula de mamífero. O agente previsto tem um ARN pelo menos parcialmente de cadeia dupla, com um comprimento de cerca de 200 nucleótidos. WO 99/32619 descreve ARN que apresentam uma região com estrutura de cadeia dupla, para a inibição da expressão génica de um gene alvo numa célula. O invento é exemplificado por meio da inibição da expressão génica em C. elegans. 3 ΕΡ 1 550 719/ΡΤ WO 99/32619 nao descreve uma ligação química das cadeias simples. WO 94/01550 descreve agentes terapêuticos que são utilizados na abordagem terapêutica baseada em oligonucleótidos antisense. O problema a resolver pelo presente invento é o de eliminar os inconvenientes existentes de acordo com o estado da técnica. Pretende-se especialmente indicar um processo, medicamento e utilização tão eficientes quanto possível para a fabricação de um medicamento com o/a qual se pode obter uma inibição particularmente eficaz da expressão de um gene alvo previamente definido. O invento é definido através das reivindicações. De acordo com estas, o invento disponibiliza um oligorribonucleótido com estrutura de cadeia dupla (ARNcd), para a inibição da expressão de um gene alvo previamente definido em células de mamífero, em que o ARNcd consiste em 15 a 21 pares de bases e uma cadeia do ARNcd apresenta uma região I complementar ao gene alvo que consiste em 15 a 21 pares de nucleótidos seguidos, e em que uma região complementar II dentro da estrutura de cadeia dupla é formada por duas cadeias simples de ARN separadas, sendo que a estrutura de cadeia dupla é estabilizada por ligação química das cadeias simples.
Concretizações vantajosas resultam das reivindicações 2 a 28.
Para a inibição da expressão de um gene alvo previamente definido numa célula alvo de mamífero in vitro está previsto de acordo com o invento, introduzir na célula um oligorribonucleótido com estrutura de cadeia dupla (ARNcd) apresentando 15 a 21 pares de bases, definido nas reivindicações, sendo que uma cadeia do ARNcd apresenta uma região I complementar ao gene alvo e apresentando no máximo 21 pares de nucleótidos seguidos, e uma região complementar II dentro da estrutura de cadeia dupla é formada por duas cadeias simples de ARN separadas. O oligorribonucleótido apresenta, pelo menos em segmentos, uma 4 ΕΡ 1 550 719/ΡΤ sequência nucleotídica definida. A secção definida pode estar limitada à região complementar I. No entanto, pode também acontecer que o oligorribonucleótido de cadeia dupla apresente, na sua totalidade, uma sequência nucleotídica definida. Também está descrito que o ARNcd pode ser mais comprido do que a região I complementar ao gene alvo. A região I complementar pode encontrar-se numa posição terminal ou estar integrada no interior do ARNcd. O ARNcd de acordo com o invento pode ser produzido sintética ou enzimaticamente pelos métodos habituais.
Inesperadamente verificou-se que já com um comprimento de - no máximo - 49 pares de bases da região complementar I pode ser obtida uma inibição eficaz da expressão do gene alvo. Oligorribonucleótidos correspondentes podem ser disponibilizados sem grandes investimentos na produção.
Especialmente ARNcd com um comprimento superior a 50 pares de nucleótidos induz em células de mamífero e células humanas determinados mecanismos celulares, p.e. a proteína-quinase dependente de ARNcd ou o sistema 2-5A. Isto conduz ao desaparecimento do efeito de interferência mediado pelo ARNcd que apresenta uma sequência definida. Devido a esta situação, a biossíntese de proteína na célula é bloqueada. Especialmente, este inconveniente é eliminado pelo presente invento.
Além disso fica nitidamente facilitada a integração de ARNcd de cadeia curta na célula ou no núcleo celular, em comparação com ARNcd de cadeia mais comprida.
Revelou-se ser vantajoso que o ARNcd esteja presente sob a forma embalada em estruturas micelares, de preferência em lipossomas. O ARNcd pode igualmente estar incluído em cápsides virais naturais ou em cápsides sintéticas produzidas por via química ou enzimática ou em estruturas daí derivadas.
As características mencionadas anteriormente tornam possível a introdução do ARNcd em células alvo previamente definidas. É conveniente que o gene a inibir seja expresso em células eucarióticas. O gene alvo pode ser escolhido do grupo 5 ΕΡ 1 550 719/ΡΤ seguinte: oncogene, gene de citoquina, gene de proteína Id, gene de desenvolvimento, gene de prião. Pode também ser expresso em organismos patogénicos, de preferência em plasmódios. Pode ser parte integrante de um vírus ou viróide, de preferência patogénico em humanos. - O processo proposto torna possível a produção de produtos para a terapia de doenças controladas geneticamente, p.e. cancro, doenças virais ou a doença de Alzheimer. O vírus ou viróide pode também ser um vírus ou viróide patogénico em animais ou plantas. Neste caso, o processo de acordo com o invento permite também proporcionar produtos para o tratamento de doenças animais ou vegetais.
De acordo com uma outra característica de realização, o ARNcd tem em algumas secções uma configuração de cadeia dupla. Os terminais do ARNcd podem ser modificados, para contrariar uma degradação na célula ou uma dissociação nas cadeias simples. Uma dissociação ocorre especialmente em caso de utilização de concentrações baixas ou de comprimentos de cadeia curtos. Para uma inibição particularmente eficaz da dissociação, a coesão da região complementar II originada pelos pares de nucleótidos pode ser aumentada através de pelo menos uma, de preferência duas outras ligação/ções químicas. - Um ARNcd de acordo com o invento com uma dissociação diminuída apresenta uma maior resistência contra uma degradação enzimática e química na célula ou no organismo. A ligação química é formada, de forma conveniente, por uma ligação covalente ou iónica, por uma ligação de ponte de hidrogénio, por interacções hidrófobas, de preferência por interacções de van-der-Waals ou de empilhamento, ou por coordenação de iões metálicos. De acordo com uma característica de realização particularmente vantajosa, pode ser produzida em pelo menos um, de preferência em ambos os terminais da região complementar II.
Além disso revelou-se ser vantajoso criar a ligação química mediante um ou vários grupos de ligação, sendo estes grupos de ligação de preferência cadeias de poli(oxifosfinicooxi-1,3-propanodiol) e/ou polietilenoglicol. A ligação química pode também ser formada através de análogos 6 ΕΡ 1 550 719/ΡΤ de purina utilizados nas regiões complementares II em vez de purinas. Além disso é vantajoso criar a ligação química através de unidades de azabenzeno introduzidas na região complementar. Pode ser criada além disso, através de análogos nucleotídicos utilizados nas regiões complementares II em vez de nucleótidos.
Revelou-se ser vantajoso utilizar para a criação da ligação química, pelo menos um dos grupos seguintes: azul de metileno; grupos bifuncionais, de preferência bis-(2-cloroetil) amina; IV-acetil-IV'-(p-glioxilbenzoil) cistamina; 4-tiouracilo; psoraleno. Além disso, a ligação química pode ser criada através de grupos tiofosforilo colocados nas extremidades da região de cadeia dupla. De preferência, a ligação química é criada nas extremidades da região de cadeia dupla, através de ligações de hélice tripla. É conveniente induzir a ligação química através de luz ultravioleta.
Os nucleótidos do ARNcd podem estar modificados. Isto contraria a activação de uma proteína-quinase, PKR, dependente de ARN de cadeia dupla, na célula. É vantajoso que pelo menos um grupo 2' -hidroxilo dos nucleótidos do ARNcd na região complementar II seja substituído por um grupo químico, de preferência um grupo 2'-amino ou 2'-metilo. Pelo menos um nucleótido em, pelo menos, uma cadeia da região complementar II pode também ser um denominado "locked nucleotide" com um anel de açúcar modificado quimicamente, de preferência através de uma ponte 2'-O, 4'-C-metileno. De preferência, vários nucleótidos são "locked nucleotides".
De acordo com uma outra forma de realização particularmente vantajosa prevê-se que o ARNcd seja ligado, associado ou envolvido a/por pelo menos uma proteína de invólucro virai proveniente ou derivada de um vírus, ou sintetizada. A proteína de invólucro pode ser derivada do poliomavírus. A proteína de invólucro pode conter a proteína virai 1 (VP1) e/ou a proteína virai 2 (VP2) do poliomavírus. Conhece-se a utilização de proteínas de invólucro deste género, p.e., da DE 196 18 797 Al, cujo conteúdo é incluído 7 ΕΡ 1 550 719/ΡΤ aqui. - As características mencionadas anteriormente facilitam substancialmente a introdução do ARNcd na célula.
Na formação de uma cápside ou de uma estrutura do tipo cápside, a partir da proteína de invólucro, um lado fica, de preferência, virado para o interior da cápside ou da estrutura do tipo cápside. A construção formada é particularmente estável. O ARNcd pode ser complementar ao transcrito primário ou processado de ARN do gene alvo. - A célula pode ser uma célula de vertebrado ou uma célula humana.
Podem ser introduzidos na célula, pelo menos dois ARNcd distintos um do outro, sendo que em cada um dos casos uma cadeia de cada ARNcd é, pelo menos em segmentos, complementar a um de pelo menos dois genes alvo diferentes. Desta maneira fica possível inibir simultaneamente a expressão de pelo menos dois genes alvo diferentes. Para suprimir a expressão de uma proteína-quinase dependente de ARN de cadeia dupla, PKR, na célula, convém que um dos genes alvo seja o gene da PKR. Desta maneira fica possível suprimir de maneira eficaz a actividade da PKR na célula.
Além disso, é descrito um medicamento com pelo menos um oligorribonucleótido apresentando 15 a 49 pares de bases, com estrutura de cadeia dupla (ARNcd), para a inibição da expressão de um gene alvo previamente definido em células de mamífero, sendo que uma cadeia do ARNcd apresenta uma região I pelo menos em segmentos complementar ao gene alvo e apresentando no máximo 49 pares de nucleótidos seguidos, e uma região complementar II dentro da estrutura de cadeia dupla é formada por duas cadeias simples de ARN separadas. -Inesperadamente verificou-se que um ARNcd deste género é apropriado para ser utilizado como medicamento para a inibição da expressão de um gene previamente definido, em células de mamífero. A inibição é já obtida, em comparação com a utilização de oligorribonucleótidos de cadeia simples, a concentrações que são, pelo menos, uma ordem de grandeza mais baixas. O medicamento de acordo com o invento é altamente eficaz. São de esperar efeitos secundários menos significativos. Inesperadamente verificou-se que já com um 8 ΕΡ 1 550 719/ΡΤ comprimento da região complementar I de, no máximo 49 pares de bases, pode ser obtida uma inibição eficaz da expressão do gene alvo. Os oligorribonucleótidos correspondentes podem ser disponibilizados com um investimento de fabricação mais baixo. É também descrita a utilização de um oligorribonucleótido de cadeia dupla (ARNcd) apresentando 15 a 49 pares de bases, para a fabricação de um medicamento para a inibição da expressão de um gene alvo previamente definido, em células de mamífero, sendo que uma cadeia do ARNcd apresenta uma região I pelo menos em segmentos complementar ao gene alvo e apresentando no máximo 49 pares de nucleótidos seguidos, e uma região complementar II dentro da estrutura de cadeia dupla é formada por duas cadeias simples de ARN separadas. - Inesperadamente, um ARNcd deste género é adequado para a fabricação de um medicamento para inibição da expressão de um gene previamente definido. Em caso de utilizar ARNcd, a inibição já é provocada em concentrações numa ordem de grandeza mais baixas, em comparação com a utilização de oligorribonucleótidos de cadeia simples. A utilização mencionada torna então possível a fabricação de medicamentos particularmente eficazes.
No que se refere a outras realizações do medicamento e da utilização, remetemos à descrição das características precedentes. A seguir pormenorizar-se-ão melhor exemplos de realização do invento, por meio das figuras. Mostram:
Fig. 1 representação esquemática de um plasmídeo para a transcrição in vitro com polimerase de T7 e SP6,
Fig. 2 ARN após electroforese num gel de poliacrilamida a 8% e coloração com brometo de etídio,
Fig. 3 representação de transcritos de ARN radioactivos
Fig. 4a-e após electrof orese num gel de poliacrilamida a 8% com ureia 7M, por meio de um "Instant Imager", e fluorescência de vermelho de Texas e YFP em fibroblastos murinos. 9 ΕΡ 1 550 719/ΡΤ
Exemplo de realização 1: A inibição da transcrição foi comprovada por meio de ARNcd sequencialmente homólogo num sistema de transcrição in vitro, com um extracto de núcleo de células HeLa humanas. A matriz de ADN para este ensaio foi o plasmídeo pCMV1200 linearizado por meio de BamHI.
Produção dos plasmídeos de matriz:
Para utilização na síntese enzimática do ARNcd foi construído o plasmídeo representado na fig. 1. Para este efeito realizou-se em primeiro lugar uma reacção em cadeia com polimerase (PCR) com o "positive control DNA" do kit de transcrição in vitro HeLaScribe® Nuclear Extract da firma Promega, Madison, Estados Unidos, como matriz de ADN. Um dos iniciadores utilizados continha a sequência de um local de restrição EcoRI e do promotor de ARN-polimerase de T7 de acordo com a sequência n.°l. O outro iniciador continha a sequência de um local de restrição BamHI e do promotor de ARN-polimerase de SP6 de acordo com a sequência n.°2. Além disso, ambos os iniciadores apresentavam nos seus terminais 3', regiões idênticas ou complementares à matriz de ADN. A PCR foi realizada por meio do "Taq PCR Core Kit" da firma Qiagen, Hilden, Alemanha, de acordo com as indicações do fabricante. Num volume de 100 μΐ foram utilizados MgCl2 1,5 mM, 200 μΜ de cada um dos dNTP, 0,5 μΜ de cada um dos iniciadores, 2,5 U de ADN-polimerase Taq e cerca de 100 ng de "positive control DNA" como matriz, em tampão de PCR. Após a desnaturação inicial do ADN de matriz através de um aquecimento de 5 minutos a 94°C, foi realizada a amplificação em 30 ciclos de, respectivamente, 60 segundos de desnaturação a 94°C, 60 segundos de annealing (hibridação) a 5°C abaixo da temperatura de fusão calculada dos iniciadores e 1,5-2 minutos de polimerização a 72°C. Após uma polimerização final de 5 minutos a 72°C, foram analisados 5 μΐ da preparação reaccional, através de electroforese em gel de agarose. O comprimento do fragmento de ADN assim amplificado era de 400 pares de bases, sendo que 340 pares de bases correspondiam ao "positive control DNA". O produto da PCR foi purificado, hidrolisado com EcoRI e BamHI e, após uma outra purificação, utilizado para a ligação a um vector pUC18 10 ΕΡ 1 550 719/ΡΤ também hidrolisado com EcoRI e BamHI. Realizou-se a transformação de E. coli XLl-blue. O plasmídeo obtido (pCMV5) contém um fragmento de ADN que no terminal 5' é flanqueado pelo promotor de T7 e no terminal 3', pelo promotor de SP6. Através da linearização do plasmídeo por meio de BamHI, o mesmo pode ser utilizado in vitro juntamente com a ARN-polimerase de T7, para a transcrição run-off de um ARN de cadeia simples com um comprimento de 340 nucleótidos, representado na sequência n.° 3. No caso do plasmídeo ser linearizado com EcoRI, o mesmo pode ser utilizado para a transcrição run-off com a ARN-polimerase de SP6, na qual é originada a cadeia complementar. Em analogia com o procedimento anteriormente descrito foi também sintetizado um ARN 23 nucleótidos mais comprido. Para este efeito foi ligado um ADN representado na sequência n.° 4, através dos locais de restrição de EcoRI e BamHI, ao vector pUC18.
Como matriz de ADN para a transcrição in vitro com extracto de núcleo HeLa, foi construído o plasmídeo pCMV1200. Para este efeito foi amplificado um fragmento EcoRI/BamHI de 1191 pb, do ADN de controlo positivo contido no kit de transcrição in vitro HeLaScribe® Nuclear Extract, por meio de PCR. O fragmento amplificado compreende o promotor "precoce imediato" de CMV com um comprimento de 828 pb e um fragmento de ADN com um comprimento de 363 pb apto a ser transcrito. 0 produto da PCR foi ligado ao vector pGEM-T através de "ligação de saliência T". No terminal 5' do fragmento existe um local de restrição BamHI. O plasmídeo foi linearizado através de hidrólise com BamHI e utilizado como matriz para a transcrição run-off.
Transcrição in vitro das cadeias simples complementares: ADN do plasmídeo pCMV5 foi linearizado com EcoRI ou BamHI. Foi utilizado como matriz de ADN para uma transcrição in vitro das cadeias de ARN simples complementares, com ARN-polimerase de SP6 ou T7. Para este efeito utilizou-se o sistema "Riboprobe in vitro Transcription" da firma Promega, Madison, Estados Unidos. Em conformidade com as indicações do fabricante foram incubados durante 5-6 horas a 37°C, 2 yg de ADN de plasmídeo linearizado em 100 μΐ de tampão de transcrição e 40 U de ARN-polimerase de T7 ou SP6. A seguir, a matriz de ADN foi degradada através de adição de 2,5 μΐ de 11
ΕΡ 1 550 719/PT ADNase RQ1 isenta de ARNase e incubação durante 30 minutos a 37°C. A preparação de transcrição foi completada com H20 até 300 μΐ e purificada por extracção com fenol. O ARN foi precipitado através de adição de 150 μΐ de acetato de amónio 7 M e 1125 μΐ de etanol e armazenado a -65°C até à hibridação.
Produção das cadeias duplas de ARN:
Para a hibridação foram centrifugados 500 μΐ do ARN de cadeia simples precipitado e armazenado em etanol. A pelete resultante foi seca e retomada em 30 μΐ de tampão PIPES, pH 6,4, na presença de formamida a 80%, NaCl 400 mM e EDTA 1 mM. Em cada um dos casos juntaram-se 15 μΐ das cadeias simples complementares e aqueceu-se durante 10 minutos a 85°C. A seguir, as preparações foram incubadas durante a noite a 50°C e arrefecidas até à temperatura ambiente.
Na hibridação utilizaram-se quantidades apenas aproximadamente equimolares de ambas as cadeias simples.
Devido a isto, as preparações de ARNcd continham como contaminação, ARN de cadeia simples (ARNcs). Para remover estas contaminações de ARNcs, as preparações foram tratadas a seguir à hibridação, com as ribonucleases especificas das cadeias simples, ARNase A de pâncreas bovino e ARNase de TI de Aspergillus oryzae. A ARNase A é uma endo-ribonuclease especifica de pirimidinas. A ARNase de TI é uma endo- ribonuclease que cinde de preferência do lado 3' de guanosinas. O ARNcd não é um substrato para estas ribonucleases. Para o tratamento com ARNase foram adicionados às preparações em 300 μΐ de tris, pH 7,4, NaCl 300 mM e EDTA 5 mM, 1,2 μΐ de ARNase A numa concentração de 10 mg/ml e 2 μΐ de ARNase de TI numa concentração de 290 pg/ml. As preparações foram incubadas durante 1,5 horas a 30°C. A seguir, as ARNases foram desnaturadas através de adição de 5 μΐ de proteinase K numa concentração de 20 mg/ml, assim como de 10 μΐ de SDS a 20% e incubação durante 30 minutos a 37°C. O ARNcd foi purificado através de extracção com fenol e precipitado com etanol. Para se poder verificar se a digestão com ARNase era completa, foram tratadas duas preparações de controlo com ARNcs, em analogia com as preparações de hibridação. 12 ΕΡ 1 550 719/ΡΤ A pelete seca foi retomada em 15 μΐ de tampão TE pH 6,5 e sujeita a electroforese em gel nativo de poliacrilamida a 8%. A seguir, o gel de acrilamida foi colorido numa solução de brometo de etidio e lavado num banho-maria. A fig. 2 mostra o ARN visualizado num transiluminador UV. Sob as condições escolhidas, o ARN sense aplicado na banda 1 e o ARN antisense aplicado na banda 2 mostraram um outro comportamento de passagem do que o ARNcd da preparação de hibridação aplicado na banda 3. Os ARN sense e o antisense tratados com ARNase, aplicado nas bandas 4 e 5, respectivamente, não produziram nenhuma banda visível. Isto mostra que os ARN de cadeia simples foram completamente degradados. O ARNcd da preparação de hibridação tratado com ARNase, aplicado na banda 6, é resistente em relação ao tratamento com ARNase. A banda que no gel nativo avança mais depressa em comparação ao ARNcd aplicado na banda 3, resulta de ARNcd isento de ARNcs. Após o tratamento com ARNase aparecem além da banda principal dominante, bandas mais fracas de avanço mais rápido.
Teste de transcrição in vitro com extracto de núcleo celular humano:
Utilizando o kit de transcrição in vitro HeLaScribe® Nuclear Extract da firma Promega, Madison, Estados Unidos, foi verificada a eficácia de transcrição do fragmento de ADN anteriormente indicado, contido no plasmídeo pCMV1200 e homólogo ao “positive control DNA", na presença do ARNcd sequencialmente homólogo (ARNcd-CMV5). Além disso foi analisada a influência do ARNcd não sequencialmente homólogo, correspondente ao gene da "proteína de fluorescência amarela (YFP)" (ARNcd-YFP). Este ARNcd tinha sido produzido em analogia com o ARNcd sequencialmente homólogo. A sequência de uma cadeia deste ARNcd consta da sequência n.° 5. Como matriz para a transcrição run-off serviu o plasmídeo pCMV1200. Contém o promotor "precoce imediato" do citomegalovírus, o qual é reconhecido pela ARN-polimerase II eucariótica, e um fragmento de ADN apto de ser transcrito. A transcrição foi realizada por meio do extracto nuclear HeLa, que contém todas as proteínas necessárias para uma transcrição. Através de adição de [a-32P]rGTP à preparação de transcrição foi obtido um transcrito marcado radioactivamente. A [a-32P]rGTP 13 ΕΡ 1 550 719/ΡΤ utilizada tinha uma actividade especifica de 400 Ci/mmol, 10 mCi/ml. Por cada preparação foram utilizados no tampão de transcrição MgCl2 3 mM, rATP, rCTP, rUTP, 400 μΜ respectivamente, rGTP 16 μΜ, [oc-32P]rGTP 0,4 μΜ e, conforme o ensaio, 1 fmol de ADN de plasmideo linearizado e quantidades diferentes de ARNcd. Cada preparação foi completada com H20 até se atingir um volume de 8,5 μΐ. As preparações foram misturadas cuidadosamente. Para o arranque da transcrição foram adicionados 4 U de extracto nuclear HeLa num volume de 4 μΐ e incubou-se durante 60 minutos a 30°C. A reacção foi terminada através de adição de 87,5 μΐ de mistura de paragem aquecida a 30°C. Para a remoção das proteínas foram adicionados às preparações 100 μΐ de fenol/clorofórmio/álcool isoamílico (25:24:1, v/v/v), saturados com tampão TE, pH 5,0, e agitou-se fortemente durante 1 minuto. Para a separação das fases centrifugou-se durante cerca de 1 minuto a 12000 rpm, e a fase superior foi transferida para um novo recipiente reaccional. A cada preparação foram adicionados 250 μΐ de etanol. As preparações foram bem misturadas e incubadas durante pelo menos 15 minutos sobre neve carbónica/metanol. Para a precipitação do ARN, as preparações foram centrifugadas durante 20 minutos a 12000 rpm e 4°C. O sobrenadante foi rejeitado. A pelete foi seca durante 15 minutos sob vácuo e ressuspensa em 10 μΐ de H20. A cada preparação foram adicionados 10 μΐ de tampão de amostra desnaturante. A separação do GTP livre da transcrição obtida foi efectuada por meio de electroforese desnaturante em gel de poliacrilamida, num gel a 8% com ureia 7 M. Os transcritos de ARN formados na transcrição com extracto nuclear HeLa, em tampão de amostra desnaturante, foram aquecidas durante 10 minutos a 90°C, e 10 μΐ desta mistura foram imediatamente aplicados nos bolsos de amostra acabadas de ser lavados. A electrof orese foi realizada a 40 mA. A quantidade de ARNcs radioactivo formado na transcrição, foi analisada após a electroforese, por meio de um Instant Imager. A fig. 3 mostra o ARN radioactivo de um teste representativo, representado por meio do Instant Imager. Foram aplicadas amostras obtidas das preparações de transcrição seguintes:
Banda 1: sem ADN de matriz, sem ARNcd;
Banda 2: 50 ng de ADN de matriz, sem ARNcd; 14 ΕΡ 1 550 719/ΡΤ
Banda 3 : 50 ng de ADN de matriz, 0,5 pg de ARNcd-YFP; Banda 4 : 50 ng de ADN de matriz, 1,5 pg ARNcd-YFP; Banda 5: 50 ng de ADN de matriz, 3 pg de ARNcd-YFP; Banda 6: 50 ng de ADN de matriz, 5 pg de ARNcd-YFP; Banda 7 : sem ADN de matriz, 1,5 ARNcd-YFP; Banda 8 : 50 ng de ADN de matriz, sem ARNcd; Banda 9 : 50 ng de ADN de matriz, 0,5 pg de ARNcd-CMV5 Banda 10 : 50 ng de ADN de matriz, 1,5 pg de ARNcd-CMV5 Banda 11: 50 ng de ADN de matriz, 3 pg de ARNcd-CMV5; Banda 12 : 50 ng de ADN de matriz, 5 pg de ARNcd-CMV5;
Verificou-se uma nítida diminuição da quantidade de transcrito na presença de ARNcd sequencialmente homólogo, em comparação com a preparação de controlo sem ARNcd assim como, também, com as preparações com ARNcd-YFP sequencialmente não homólogo. O controlo positivo na banda 2 mostra que na transcrição in vitro com extracto nuclear HeLa foi formado um transcrito radioactivo. A preparação serve de comparação com as preparações de transcrição incubadas na presença de ARNcd. As bandas 3 a 6 mostram que a adição de ARNcd-YFP sequencialmente não específico não tem influência na quantidade de transcrito formado. As bandas 9 a 12 mostram que a adição de uma quantidade entre 1,5 e 3 pg de ARNcd-CMV5 sequencialmente específico, conduz a uma diminuição da quantidade de transcrito formado. Para excluir que os efeitos observados não se devem ao ARNcd, mas sim a uma contaminação possivelmente arrastada, sem querer, na produção do ARNcd, realizou-se um outro controlo. ARN de cadeia simples foi transcrito como acima descrito e, a seguir, sujeito ao tratamento com ARNase. Por meio de uma electroforese em gel nativo de poliacrilamida pôde ser demonstrado que o ARNcs tinha sido degradado completamente. Como as preparações de hibridação, esta preparação foi sujeita a uma extracção com fenol e a uma precipitação com etanol e, a seguir, retomada em tampão TE. Desta maneira foi obtida uma amostra que não continha ARN, mas que tinha sido tratada com as mesmas enzimas e tampões que o ARNcd. A banda 8 mostra que a adição desta amostra não tinha nenhuma influência na transcrição. A diminuição de transcrito em caso de adição de ARNcd sequencialmente específico pode, por isso, ser atribuída inequivocamente ao próprio ARNcd. A redução da quantidade de transcrito de um gene na presença de ARNcd num sistema de 15 ΕΡ 1 550 719/ΡΤ transcrição humano, mostra uma inibição da expressão do respectivo gene. Este efeito deve ser atribuído a um novo mecanismo condicionado pelo ARNcd.
Exemplo de realização 2:
Como sistema de teste para estas experiências in vivo, serviu a linha celular murina de fibroblastos NIH3T3, ATCC CRL-1658. Por meio de micro-injecção foi introduzido o gene da YFP nos núcleos celulares. A expressão da YFP foi analisada sob a influência de ARNcd sequencialmente homólogo co-transfectado simultaneamente. Este ARNcd-YFP é homólogo à região 5' do gene da YFP ao longo de um comprimento de 315 pb. A sequência nucleotídica de uma cadeia do ARNcd-YFP é representada na sequência n.° 5. A avaliação sob o microscópio de fluorescência foi realizada 3 horas após a injecção, por meio da fluorescência amarela esverdeada da YFP formada.
Construção do plasmídeo de matriz e produção do ARNcd:
Como matriz para a produção do YFP-ARNcd por meio de transcrição de T7 e SP6 in vitro, foi construído um plasmídeo de acordo com o mesmo princípio que o descrito no exemplo de realização 1. O fragmento génico desejado foi amplificado por meio de PCR utilizando-se o iniciador Eco_T7_YFP de acordo com a sequência 6 e Bam_SP6_YFP de acordo com a sequência 7, e utilizado em analogia com a descrição dada anteriormente para a produção do ARNcd. O ARNcd-YFP obtido é idêntico ao ARNcd utilizado no exemplo de realização 1 como controlo sequencialmente não específico.
Foi produzido um ARNcd ligado ao terminal 3' do ARN quimicamente, através de um grupo de ligação C18, ao terminal 5' do ARN complementar (L-ARNcd) de acordo com a sequência 8. Para este efeito utilizaram-se sintões modificados com pontes de dissulfureto. O sintão 3'-terminal está ligado através do carbono 3' a um grupo de ligação alifático através de uma ponte de dissulfureto, ao suporte sólido. No sintão 5'-terminal do oligorribonucleótido complementar, que é complementar ao sintão 3'-terminal de um dos oligorribonucleótidos, o grupo protector tritilo 5' está ligado através de um outro grupo ligante alifático e uma 16 ΕΡ 1 550 719/ΡΤ ponte de dissulfureto. A seguir à síntese das duas cadeias simples, remoção dos grupos protectores e hibridação dos oligorribonucleótidos complementares, os grupos tiol resultantes chegam a ficar numa vizinhança espacial mútua. Através de oxidação as cadeias simples são ligadas uma à outra através dos seus grupos ligantes alifáticos e uma ponte de dissulfureto. A seguir é realizada uma purificação por meio de HPLC.
Preparação das culturas celulares.
As células foram incubadas em DMEM com 4,5 g/1 de glucose, 10% de soro fetal de vitelo, sob uma atmosfera de 7,5% de CO2 a 37°C, em placas de cultura e transferidas antes de atingirem a confluência. A separação das células foi efectuada com tripsina/EDTA. Para a preparação da micro-injecção, as células foram transferidas para placas de Petri e continuaram a ser incubadas até à formação de microcolónias.
Micro-injecção
Para a micro-injecção, as placas de cultura foram retiradas da incubadora durante cerca de 10 minutos.
Realizou-se uma injecção individual em cerca de 50 núcleos celulares por preparação, dentro de uma zona marcada, utilizando o sistema de micro-injecção AIS da firma Cari Zeiss, Gõttingen, Alemanha. A seguir, as células continuaram a ser incubadas durante mais três horas. Para a micro-injecção foram preparados capilares de vidro de borossilicato da firma Hilgenberg GmbH, Malsfeld, Alemanha, com um diâmetro da ponta inferior a 0,5 pm. A micro-injecção foi realizada com um micromanipulador da firma Narishige Scientific Instrument Lab. Tóquio, Japão. A duração da injecção era de 0,8 segundos, a pressão cerca de 100 hPa. Para a transfecção foi utilizado o plasmídeo pCDNA-YFP, que contém um fragmento BamHI/EcoRI de um comprimento de cerca de 800 pb, com o gene da YFP no vector pcDNA3. As amostras injectadas nos núcleos celulares continham 0,01 pg/μΐ de pCDNA-YFP, assim como vermelho de Texas acoplado a dextrano-70000 em NaCl 14 mM, KC1 3 mM, KPO4 10 mM, pH 7,5. Além disso foram adicionados cerca de 100 pl de ARN com uma concentração de 1 μΜ ou, no caso do L-ARNcd, 375 μΜ. 17 ΕΡ 1 550 719/ΡΤ
As células foram examinadas ao serem excitadas com luz com comprimentos de onda de excitação do vermelho de Texas, 568 nm e, respectivamente, 488 nm no caso da YFP, por meio de um microscópio de fluorescência. Algumas células individuais foram documentadas por meio de uma câmara digital. As figuras 4a-e, mostram o resultado para células NIH3T3. Nas células apresentadas na fig. 4 a foi injectado sense-YFP-ARNcs, na fig. 4 b antisense-YFP-ARNcs, na fig. 4 c ARNcd-YFP, na fig. 4 d nenhum ARN e na fig. 4 e, L-ARNcd.
Em cada um dos casos, o quadro à esquerda mostra a fluorescência de células que foram excitadas com 568 nm. À direita vê-se a fluorescência das mesmas células numa excitação com 488 nm. A fluorescência do vermelho de Texas de todas as células representadas mostra que a solução de injecção foi aplicada com êxito nos núcleos celulares e que células atingidas ainda eram vivas ao cabo de três horas. As células mortas já não mostravam nenhuma fluorescência de vermelho de Texas.
Os quadros à direita das figuras 4 a e 4 b mostram que a expressão da YFP em caso de injecção do ARN de cadeia simples nos núcleos celulares, não foi inibida de forma visível. O quadro direito da fig. 4 c mostra células cuja fluorescência de YFP, após injecção de ARNcd-YFP, já não foi detectável. A fig. 4 d mostra como controlo, células nas quais não tinha sido injectado ARN. Devido à injecção do L-ARNcd, o qual apresenta regiões sequencialmente homólogas ao gene da YFP, a célula representada na fig. 4 e já não mostra uma fluorescência de YFP detectável. Este resultado prova que para uma inibição específica da expressão génica em mamíferos, também podem ser utilizados ARNcd mais curtos no caso das cadeias duplas serem estabilizadas através de ligação química entre as cadeias simples.
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LISTAGEM DE SEQUÊNCIAS <110> Alnylam Europe AG <12 0 > Oligorribonucleótido para a inibição da expressão de um gene previamente definido <130> <140> <141> 453722EH <150> 199 03 713.2 <151> 1999-01-30 <150> 199 56 568.6 <151> 1999-11-24 <160> 8 <170 > Patentln Ver. 2.1 <210 > 1 <211 > 45 <212> ADN <213> Sequência artificial <220> <223> Descrição da sequência artificial: Local de restrição EcoRI, promotor de ARN-polimerase de T7 <400> 1 gg&&ccccss fcscgsctcac cacsãSyCyS tcayâtcccc âyâây 45 <210 > 2 <211 > 50 <212> ADN <213> Sequência artificial <2 2 0 > <223> Descrição da sequência artificial: Local de restrição BamHI, promotor de ARN- polimerase de SP6 <400> 2 21 ΕΡ 1 550 719/ΡΤ gggatccatt taggtgacac tatagaatac ccatgatcgc gtasrtcgata 50 <210> 3 <211> 340
<212> ARN <213> Sequência artificial <220> <223> Descrição da sequência artificial: ARN que corresponde a uma sequência do "positive control DNA" do kit de transcrição in vitro HeLaScribe Nuclear Extract da firma Promega. <400> 3 uuaucacagu uaaauugcua acgcagucag 60 aucgucaucc ucggcaccgu cacccuggau 120 cugccgggcc ucuugcggga uaucguccau 180 cugcuagcgc uauaugcguu gaugceauuu 240 gaccgcuuug gccgccgccc aguccugcuc 300 gcgaucaugg 340 ucagaucucu agaagcuuua augcgguagu gcaccgugua ugaaaucuaa caaugcgeuc gcuguaggca uaggcuuggu uaugccggua uccgacagca ucgccaguca cuauggcgug cuaugcgcac ccguucucgg agcacugucc gcuucgcuac uuggagccac uaucgacuac <210> 4 <211> 363
<212> ADN <213> Sequência artificial <220> <223> Descrição da sequência artificial: ADN que corresponde a uma sequência do "positive control DNA" do kit de transcrição in vitro HeLaScribe Nuclear Extract da firma Promega. <400> 4 tcagatctct agaagcttta atgcggtagt ttatcacagt taaattgcta acgcagccãg 60 gcaccgtgta tgaaatctaa caatgcgctc atcgtcatcc tcggcaccgt caccctggaC 120 gctgtaggca taggcttggt tatgccggta ctgccgggcc tcttgcggga tatcgtccat 180 tccgacagca tcgccagtca ctatggcgtg ctgctagcgc tatatgcgtt gatgcaattt 240 ctatgcgcac ccgttctcgg agcactgtcc gaccgctttg gccgccgccc agbcctgctc 300 gcttcgctac ttggagccac tatcgactac gcgatcatgg cgaccacacc cgtcctgtgg 360 ate 363 22 ΕΡ 1 550 719/ΡΤ <210> 5 <211> 315
<212> ARN <213> Sequência artificial <220> <223> Descrição da sequência artificial: sequência do gene de YFP <400> 5 auggugagca agggcgagga gcuguucacc gggguggugc ccauccuggu cgagcuggac 60 ggcgacguaa acggccacaa guucagcgug uccggcgagg gcgagggcga ugccaccuac 120 ggcaagcuga cccugaaguu caucugcacc accggcaagc ugeccgugcc cuggcccacc 180 cucgugacca cccugaccua cggcgugcag ugcuúcagcc gcuaocccga ocacaugaag 240 cagcacgacu ucuucaaguc cgccaugccc gaaggcuacg uccaggagcg caccaucuuc 300 uucaaggacg acggc 315 <210> 6 <211> 52
<212> ADN <213> Sequência artificial <220>
<223> Descrição da sequência artificial: Local de restrição EcoRI, promotor de ARN-polimerase de T7, região complementar ao gene da YFP <4 0 0 > 6 ggaattctaa tacgactcac tatagggcga atggtgagca agggcgagga gc 52 <210 > 7 <211> 53
<212> ADN <213> Sequência artificial <220>
<223> Descrição da sequência artificial: Local de restrição BamHI, promotor de ARN-polimerase de SP6, região complementar ao gene da YFP <400> 7 gggatccatt taggtgacac tatagaatac gccgtcgtcc ttgaagaaga tgg 53 <210> 8 <211> 21 23
ΕΡ 1 550 719/ΡΤ <212> ARN <213> Sequência artificial <2 2 0 >
<223> Descrição da sequência artificial: ARN que corresponde a uma sequência do gene da YFP <400> 8 ucgagcugga cggcgacgua a 21
Lisboa, 2009-03-05
Claims (28)
- ΕΡ 1 550 719/ΡΤ 1/4 REIVINDICAÇÕES 1. Oligorribonucleótido com estrutura de cadeia dupla (ARNcd), para a inibição da expressão de um gene alvo previamente definido em células de mamífero, sendo que o ARNcd consiste em 15 a 21 pares de bases e uma cadeia do ARNcd apresenta uma região I complementar ao gene alvo a qual consiste em 15 a 21 pares de nucleótidos seguidos, e em que uma região complementar II dentro da estrutura de cadeia dupla é formada por duas cadeias simples de ARN separadas, sendo que a estrutura de cadeia dupla é estabilizada por ligação química das cadeias simples.
- 2. ARNcd de acordo com a reivindicação 1, onde o gene alvo é seleccionado do grupo que se segue: oncogene, gene de citoquina, gene de proteína Id, gene de desenvolvimento, gene da PKR, gene de prião.
- 3. ARNcd de acordo com uma das reivindicações anteriores, onde o ARNcd existe sob a forma embalada em estruturas micelares, de preferência em lipossomas.
- 4. ARNcd de acordo com uma das reivindicações anteriores, onde o ARNcd está incluído em cápsides virais naturais ou em cápsides sintéticas produzidas por via química ou enzimática ou em estruturas daí derivadas.
- 5. ARNcd de acordo com uma das reivindicações anteriores, onde o gene alvo é parte integrante de um vírus.
- 6. ARNcd de acordo com a reivindicação 5, onde o vírus é um vírus patogénico em seres humanos.
- 7. ARNcd de acordo com a reivindicação 5, onde o vírus ou viróide é um vírus patogénico em animais.
- 8. ARNcd de acordo com uma das reivindicações anteriores, onde o ARNcd tem uma estrutura de cadeia dupla em segmentos.
- 9. ARNcd de acordo com uma das reivindicações anteriores, onde os terminais do ARNcd estão modificados para ΕΡ 1 550 719/ΡΤ 2/4 contrariar a degradação nas células de mamífero ou a dissociação nas cadeias simples.
- 10. ARNcd de acordo com uma das reivindicações anteriores, onde a coesão da região complementar II efectuada pelos pares de nucleótidos é aumentada por pelo menos uma, de preferência duas, outras ligações químicas.
- 11. ARNcd de acordo com a reivindicação 10, onde a ligação química é formada por uma ligação covalente ou iónica, por uma ligação de ponte de hidrogénio, por interacções hidrófobas, de preferência interacções de van-der-Waals ou de empilhamento, ou por coordenação de iões metálicos.
- 12. ARNcd de acordo com a reivindicação 10 ou 11, onde a ligação química é estabelecida em pelo menos um, de preferência em ambos os terminais da região complementar II.
- 13. ARNcd de acordo com uma das reivindicações 10 a 12, onde a ligação química é formada por meio de um ou vários grupos de ligação, onde os grupos de ligação são de preferência cadeias de poli(oxifosfinicooxi-1,3-propanodiol) e/ou de polietilenoglicol.
- 14. ARNcd de acordo com uma das reivindicações 10 a 12, onde a ligação química é formada através de análogos de purina utilizados nas regiões complementares II em vez de purinas.
- 15. ARNcd de acordo com uma das reivindicações 10 a 12, onde a ligação química é formada através de unidades de azabenzeno introduzidas nas regiões complementares II. 10 a 12, análogos regiões
- 16. ARNcd de acordo com uma das reivindicações onde a ligação química é formada através de nucleotídicos ramificados utilizados nas complementares II em vez de nucleótidos.
- 17. ARNcd de acordo com uma das reivindicações 10 a 12, onde para o estabelecimento da ligação química é utilizado pelo menos um dos grupos seguintes: azul de metileno; grupos ΕΡ 1 550 719/ΡΤ 3/4 bifuncionais, de preferência bis-(2-cloroetil)amina; N-acetil-N'-(p-glioxilbenzoil)cistamina; 4-tiouracilo; psoraleno.
- 18. ARNcd de acordo com uma das reivindicações 10 a 12, onde a ligação química é formada através de grupos tiofosforilo proporcionados nas extremidades da região de cadeia dupla.
- 19. ARNcd de acordo com uma das reivindicações 10 a 12, onde a ligação química são ligações de hélice tripla proporcionadas nas extremidades da região de cadeia dupla.
- 20. ARNcd de acordo com uma das reivindicações anteriores, onde os nucleótidos do ARNcd estão modificados.
- 21. ARNcd de acordo com uma das reivindicações anteriores, onde pelo menos um grupo 2'-hidroxilo dos nucleótidos do ARNcd na região complementar II está substituído por um grupo químico, de preferência um grupo 2'-amino ou 2'-metilo.
- 22. ARNcd de acordo com uma das reivindicações anteriores, onde pelo menos um nucleótido em, pelo menos, uma cadeia da região complementar II é um "locked nucleotide" com um anel de açúcar modificado quimicamente, de preferência através de uma ponte 2’-O, 4'-C-metileno.
- 23. ARNcd de acordo com uma das reivindicações anteriores, onde o ARNcd está ligado a, associado a, ou envolvido por, pelo menos, uma proteína de invólucro virai proveniente ou derivada de um vírus, ou sintetizada.
- 24. ARNcd de acordo com uma das reivindicações anteriores, onde a proteína de invólucro é uma proteína derivada de poliomavírus.
- 25. ARNcd de acordo com a reivindicação 24, onde a proteína de invólucro contém a proteína virai 1 (VPl) e/ou a proteína virai 2 (VP2) do poliomavírus. ΕΡ 1 550 719/ΡΤ 4/4
- 26. ARNcd de acordo com a reivindicação 24 ou 25, onde, durante a formação de uma cápside ou de uma estrutura do tipo cápside, a partir da proteína de invólucro, um lado fica virado para o interior da cápside ou da estrutura do tipo cápside.
- 27. ARNcd de acordo com uma das reivindicações anteriores, onde o ARNcd é complementar ao transcrito de ARN primário ou processado do gene alvo.
- 28. ARNcd de acordo com uma das reivindicações anteriores, onde as células de mamífero são células humanas. Lisboa, 2009-03-05
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DE19956568A DE19956568A1 (de) | 1999-01-30 | 1999-11-24 | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
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PT02003683T PT1214945E (pt) | 1999-01-30 | 2000-01-29 | Processo e medicamento para a inibicao da expressao de um gene alvo previamente definido |
PT60253895T PT1798285T (pt) | 1999-01-30 | 2000-01-29 | Método e medicamento para a inibição da expressão de um determinado gene |
PT100112176T PT2363479T (pt) | 1999-01-30 | 2000-01-29 | Oligorribonucleótido para a inibição da expressão de um gene previamente definido |
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PT60253895T PT1798285T (pt) | 1999-01-30 | 2000-01-29 | Método e medicamento para a inibição da expressão de um determinado gene |
PT100112176T PT2363479T (pt) | 1999-01-30 | 2000-01-29 | Oligorribonucleótido para a inibição da expressão de um gene previamente definido |
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