DK1214945T4 - Fremgangsmåde og medikament til at hæmme ekspressionen af et defineret målgen - Google Patents
Fremgangsmåde og medikament til at hæmme ekspressionen af et defineret målgen Download PDFInfo
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Description
Opfindelsen angår en fremgangsmåde til at hæmme ekspressionen af et defineret målgen i en celle in vitro. Den angår endvidere et medikament og en anvendelse af dobbeltstrengede oligoribonukleotider.
En sådan fremgangsmåde kendes fra den senere offentliggjorte WO 99/32619. Den kendte fremgangsmåde sigter mod at hæmme ekspressionen af gener i celler fra invertebrater. Hertil er det nødvendigt, at det dobbeltstrengede oligoribo-nukleotid har en med målgenet identisk sekvens med en længde på mindst 50 baser. Med henblik på at opnå en effektiv hæmning er en længde af den identiske sekvens på 300 til 1000 basepar nødvendig. Fremstillingsomkostningerne til et sådant oligoribonukleotid er høje.
Fra WO 99/53050 kendes en fremgangsmåde til at hæmme den fænotypiske ekspression af en nukleinsyre i en eykaryotisk celle. Et kimært RNA-molekyle kan indføres i den eukaryotiske celle. Et dobbeltstrenget RNA (dsRNA) dannes enten i celler ved transkription af i cellerne indførte kimære DNA-molekyler eller indføres i cellerne som enkeltstrenget RNA med hårnålesløjfestruktur. WO 99/15682 angår en fremgangsmåde til at hæmme ekspressionen af en mål-nukleotidsekvens i en plante. Til dette indføres et af DNA eller RNA bestående enkeltstrenget eller dobbeltstrenget nukleinsyrekonstrukt i en celles cytoplasma. Nu kl ein syreko nstruktet koder for en sekvens, der er identisk med målnukleotid-sekvensen eller den dertil komplementære streng. Målnukleotidsekvensen er i den forbindelse tilstede i en første del af planten, medens nukleinsyrekonstruktet indføres i en celles cytoplasma i en anden del af planten.
Ifølge Fire, A., "RNA-triggered gene silencing" TIG september 1999, vol. 15, nr. 9, side 358 til 363 er det usandsynligt, at de simple for ikke-hvirveldyr- og plantesystemer anvendte protokoller er virksomme i pattedyrceller. Pattedyr udviser en heftig reaktion på dsRNA. En komponent i denne reaktion er proteinkinase (PKR). Hvert genspecifikt dsRNA-svar ville i pattedyr skulle finde sted i skyggen af det PKR-inducerede totalsvar eller i celler eller under betingelser, hvor PKR er mindre virksom. Med henblik på at komme uden om en påvirkning fra PKR-systemet foreslås kemiske modifikationer på dsRNA'et, der stadig muliggør en virkning af dsRNA'et ved den genspecifikke interferens uden at udløse PKR-svaret.
De ved aktiveringen af PKR ved hjælp af dsRNA udløste cellulære mekanismer kendes f.eks. fra Clemens, J. A., PKR-A Protein Kinase Regulated by Double-stranded RNA, Int. J. Biochem. Cell Biol. (1997) bind 29, nr. 7, side 945-949. WO 92/19732 beskriver et antisense-agens med topologisk lukket enkeltstrenget struktur. Inden for denne struktur kan der være et selvkomplementært dobbeltstrenget område. Dette område kan virke ved en vekselvirkning med proteiner, der har en affinitet til dette område. WO 98/05770 beskriver et enkeltstrenget antisense-RNA med en hårnålesløjfe-struktur. DE 196 31 919 C2 beskriveret antisense-RNA med særlige sekundærstrukturer, hvor antisense-RNA'et foreligger i form af en vektor, der koder for det. Ved antisense-RNA'et drejer det sig om et RNA-molekyle, der er komplementært til områder af mRNA'et. Ved binding til disse områder fremkaldes en hæmning af genekspressionen. Denne hæmning kan især anvendes til diagnosticering og/eller behandling af sygdomme, f.eks. tumorsygdomme eller virale infektioner. - Antisense-RNA'et skal på ufordelagtig vis indbringes i cellen i en mængde, der er mindst lige så stor som mængden af mRNA'et. Virkningen af den kendte anti-sense-fremgangsmåde er ikke særligt høj.
Fra US 5,712,257 kendes et medikament, der indeholder fejl parret dobbeltstrenget RNA (dsRNA) og biologisk aktive fejlparrede brudstykker af dsRNA i form af et ternært kompleks med et overfladeaktivt middel. Det i den forbindelse anvendte dsRNA består af syntetisk fremstillede nukleinsyreenkeltstrenge uden defineret basesekvens. Enkelstrengene indgår ikke-regulære, såkaldte "ikke-Watson-Crick"-baseparringer med hinanden, således at der dannes fejlparrede dobbeltstrenge. Det kendte dsRNA tjener til at hæmme formeringen af retrovira, såsom HIV. Formering af virusset kan hæmmes, når der indbringes ikke-sekvensspecifikt dsRNA i cellerne. Der sker derved en induktion af interferon, hvorved virusformeringen skal hæmmes. Hhv. den hæmmende effekt og virkningen af denne fremgangsmåde er lille.
Fra Fire, A. et al., NATURE, vol. 391, s. 806 er det kendt, at dsRNA, hvis ene streng sektionsvis er komplementær til en rundorms gen, der skal hæmmes, hæmmer ekspression af dette gen med en høj virkning. Man har den opfattelse, at den særlige virkning af det anvendte dsRNA i rundormens celler ikke beror på antisense-princippet, men muligvis skyldes katalytiske egenskaber ved dsRNA'et eller af dette inducerede enzymer. - Om virkningen af specifikt dsRNA med hensyn til hæmning af genekspressionen, især i pattedyrceller og humane celler, nævnes der intet i denne artikel.
Det er formålet med opfindelsen at eliminere ulemperne ifølge den kendte teknik. Der skal især angives hhv. en mest mulig effektiv fremgangsmåde, medikament og en mest mulig effektiv anvendelse til fremstilling af et medikament, hvormed en særlig virksom hæmning af ekspressionen af et defineret målgen kan fremkaldes.
Dette formål opfyldes med de i krav 1,24 og 48 angivne kendetegn. Fordelagtige udformninger fremgår af kravene 2 til 23, 25 til 47 og 49 til 72.
Ifølge opfindelsen opereres der til at hæmme ekspressionen af et defineret målgen i en pattedyrcelle in vitro med at indføre et 15 til 49 basepar stort oligoribonukleotid med dobbeltstrenget struktur (dsRNA) i pattedyrcellen, idet en streng af dsRNA'et har et område I, der i det mindste segmentvis er komplementært til målgenet og har højst 49 efter hinanden følgende nukleotidpar, og et inden for den dobbeltstrengede struktur komplementært område II dannes af to separate RNA- enkeltstrenge, idet den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II øges ved hjælp af en yderligere kemisk binding, og idet den kemiske binding fremstilles på en ende af det komplementære område II. Oligoribonukleotidet har i det mindste segmentvis en defineret nukleotidsekvens. Den definerede sektion kan være begrænset til det komplementære område I. Det kan imidlertid også være, at det dobbeltstrengede oligoribonukleotid samlet har en defineret nukleotidsekvens. dsRNA'et kan være længere end det til målgenet komplementære område I. Det komplementære område I kan være anordnet på enden eller indkoblet i dsRNA'et. Et sådant dsRNA kan være fremstillet hhv. syntetisk og enzymatisk med gængse fremgangsmåder.
Det har overraskende vist sig, at allerede ved en længde af det komplementære område I på højst 49 basepar kan en virksom hæmning af ekspressionen af målgenet opnås. Passende oligoribonukleotider kan stilles til rådighed med ubetydelige ressourcer.
Især dsRNA med en længde på mere end 50 nukleotidpar inducerer i pattedyrceller og humane celler bestemte cellulære mekanismer, f.eks. den dsRNA-afhængige proteinkinase eller 2-5A-systemet. Det fører til, at den af dsRNA'et med en defineret sekvens bestemte interferenseffekt forsvinder. Derved blokeres pro-teinbiosyntesen i cellen. Især denne ulempe elimineres med den foreliggende opfindelse.
Endvidere er optagelsen af dsRNA med kort kædelængde i cellen eller i cellekernen lettet betydeligt over for dsRNA'er med længere kæder.
Det har vist sig fordelagtigt, at dsRNA foreligger pakket i micellare strukturer, fortrinsvis i liposomer. dsRNA'et kan ligeledes være indesluttet i virale naturlige kapsider eller i på kemisk eller enzymatisk vis fremstillede kunstige kapsider eller deraf afledte strukturer. - De ovenfor nævnte kendetegn muliggør en indslusning af dsRNA'et i definerede målceller.
Det gen, der skal hæmmes, eksprimeres på hensigtsmæssig vis i eukaryotiske celler. Målgenet kan være udvalgt blandt: onkogen, cytokin-gen, id-proteingen, udviklingsgen, priongen. Det kan også eksprimeres i patogene organismer, fortrinsvis i plasmodia. Det kan være en bestanddel af et, fortrinsvis humanpatogent, virus eller viroid. - Den foreslåede fremgangsmåde muliggør fremstillingen af midler til behandling af genetisk styrede sygdomme, f.eks. kræft, virale sygdomme eller Morbus Alzheimer.
Virusset eller viroidet kan også være et dyre- eller plantepatogent virus eller vi riod. I dette tilfælde muliggør fremgangsmåden ifølge opfindelsen også tilvejebringelsen af midler til behandling af dyre- eller plantesygdomme. dsRNA'et kan segmentvis være udformet dobbeltstrenget. Enderne af dsRNA'et kan modificeres for at modvirke en nedbrydning i cellen eller en dissociation ind i enkeltstrengene. En dissociation optræder især ved anvendelse af lavere koncentrationer eller kortere kædelængder. Med henblik på særligt virksomt at hæmme dissociationen kan den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II øges ved hjælp af mindst en yderligere kemisk binding. - Et dsRNA ifølge opfindelsen, hvis dissociation er reduceret, har en højere stabilitet over for enzymatisk og kemisk nedbrydning hhv. i cellen og i organismen.
Den kemiske binding dannes på hensigtsmæssig vis ved en kovalent eller ionisk binding, en hydrogenbrobinding, hydrofobe vekselvirkninger, fortrinsvis van-der-Waals- eller stabelvekselvirkninger, eller ved metal-ionkoordination. Den er ifølge opfindelsen fremstillet på en ende og kan være fremstillet på begge ender af det komplementære område II.
Det har yderligere vist sig fordelagtigt, at den kemiske binding dannes ved hjælp af en eller flere forbindelsesgrupper, idet forbindelsesgrupperne fortrinsvis er poly-(oxyphosphinicooxy-1,3-propandiol)- og/eller polyethylenglycol-kæder. Den kemi ske binding kan også dannes af purinanaloger benyttet i de komplementære områder II i stedet for puriner. Det er endvidere en fordel, at den kemiske binding dannes af azabenzenenheder indført i de komplementære områder II. Den kan desuden dannes af forgrenede nukleotidanaloger benyttet i de komplementære områder II i stedet for nukleotider.
Det har vist sig hensigtsmæssigt, at der til fremstilling af den kemiske binding benyttes mindst en af følgende grupper: methylenblå, bifunktionelle grupper, fortrinsvis bis-(2-chlorethyl)-amin; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamin; 4-thiouracil; psoralen. Endvidere kan den kemiske binding dannes af thiophospho-ryl-grupper anbragt på enderne af det dobbeltstrengede område. Fortrinsvis fremstilles den kemiske binding på enderne af det dobbeltstrengede område ved hjælp af tripelhelix-bindinger.
Den kemiske binding kan på hensigtsmæssig vis induceres ved hjælp af ultraviolet lys. dsRNA’ets nukleotider kan være modificerede. Dette modvirker en aktivering af en af dobbeltstrenget RNA afhængig proteinkinase, PKR, i cellen. På fordelagtig vis er mindst en 2’-hydroxylgruppe af dsRNA'ets nukleotider i det komplementære område II erstattet af en kemisk gruppe, fortrinsvis en 2’-amino- eller en 2’-methylgruppe. Mindst et nukleotid i mindst en streng af det komplementære område II kan også være et såkaldt "locked nucleotide" med en, fortrinsvis ved hjælp af en 2'-0, 4'-C-methylenbro, kemisk modificeret sukkerring. På fordelagtig vis er flere nukleotider "locked nucleotides".
Ifølge en yderligere særligt fordelagtig udformning opereres der med, at dsRNA'et bindes til, associeres med eller omgives af mindst et fra et virus stammende, deraf afledt eller syntetisk fremstillet viralt kappeprotein. Kappeproteinet kan være afledt af polyomavirus. Kappeproteinet kan indeholde polyomavirussets virus-protein 1 (VP1) og/eller virus-protein 2 (VP2). Anvendelsen af sådanne kappeproteiner kendes f.eks. fra DE 196 18 797 A1, hvis beskrivelsesindhold hermed inddrages. - De ovenfor nævnte kendetegn letter væsentligt indføringen af dsRNA'et i cellen.
Ved dannelse af et kapsid eller en kapsidlignende form ud fra kappeproteinet er den ene side fortrinsvis vendt mod det indre af kapsidet eller den kapsidlignende form. Det dannede konstrukt er særligt stabilt. dsRNA'et kan være komplementær til målgenets primære eller processerede RNA-transkript. - Cellen kan være en vertebratcelle eller en menneskelig celle.
Der kan indføres mindst to fra hinanden forskellige dsRNA'er i cellen, idet en streng af hvert dsRNA i det mindste segmentvis er komplementær til i hvert enkelt tilfælde et af mindst to forskellige målgener. Derved er det muligt samtidigt at hæmme ekspressionen af mindst to forskellige målgener. For at undertrykke ekspressionen afen af dobbeltstrenget RNA afhængig proteinkinase, PKR, i cellen er et af målgenerne med fordel PKR-genet. Derved kan PKR-aktiviteten i cellen undertrykkes effektivt.
Ifølge opfindelsen er der videre tilvejebragt et medikament med mindst et 15 til 49 basepar stort oligoribonukleotid med dobbeltstrenget struktur (dsRNA) til at hæmme ekspressionen af et defineret målgen i pattedyrceller, idet en streng af dsRNA'et har et område I, der i det mindste segmentvis er komplementært til målgenet og har højst 49 efter hinanden følgende nukleotidpar, og et inden for den dobbeltstrengede struktur komplementært område II er dannet af to separate RNA-enkeltstrenge, idet den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II øges ved hjælp af en yderligere kemisk binding, og idet den kemiske binding er fremstillet på en ende af det komplementære område II. -Det har overraskende vist sig, at et sådant dsRNA egner sig som medikament til at hæmme ekspressionen af et defineret gen i pattedyrceller. Hæmningen fremkaldes sammenlignet med anvendelsen af enkeltstrengede oligoribonukleo-tider allerede ved koncentrationer, der er mindst en størrelsesorden lavere.
Medikamentet ifølge opfindelsen er højeffektivt. Der må forventes mindre bivirkninger. Det har overraskende vist sig, at allerede ved en længde af det komplementære område I på højst 49 basepar kan en effektiv hæmning af ekspressionen af målgenet opnås. Passende oligoribonukleotider kan stilles til rådighed med få ressourcer.
Genstand for opfindelsen er endvidere en anvendelse af et 15 til 49 basepar stort oligoribonukleotid med dobbeltstrenget struktur (dsRNA) til at fremstille et medikament, idet en streng af dsRNA'et har et område I, der i det mindste segmentvis er komplementært til et defineret målgen i pattedyrceller og har højst 49 efter hinanden følgende nukleotidpar, og et inden for den dobbeltstrengede struktur komplementært område II er dannet af to separate RNA-enkeltstrenge, idet den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II er øget ved hjælp af en yderligere kemisk binding, og idet den kemiske binding er fremstillet på en ende af det komplementære område II. - Overraskende egner et sådant dsRNA sig til fremstilling af et medikament til at hæmme ekspressionen af et defineret gen. Ved en anvendelse af dsRNA fremkaldes hæmningen sammenlignet med anvendelsen af enkeltstrengede oligoribonukleotider allerede ved koncentrationer, der er en størrelsesorden mindre. Anvendelsen ifølge opfindelsen muliggør altså fremstilling af særlige virksomme medikamenter.
Vedrørende fordelagtige udformninger af medikamentet og anvendelsen henvises der til beskrivelse af de forudgående kendetegn.
Efterfølgende forklares eksemplerne nærmere under henvisning til figurerne. Der vises:
Fig. 1 den skematiske afbildning af et plasmid til in wfro-transkription med T7- og SP6-polymerase, fig. 2 RNA efter elektrophorese på en 8% polyacrylamidgel og ethidium- bromidfarvning, fig. 3 en afbildning af radioaktive RNA-transkripter efter elektrophorese på en 8% polyacrylamidgel med 7 M urinstof ved hjælp af en "Instant Imager" og fig. 4 a-e Texas-rød- og YFP-fluorescens i murine fibroblastre. Referenceeksempel 1:
Inhiberingen af transkriptionen blev påvist ved hjælp af sekvenshomologt dsRNA i et in wfro-transkriptionssystem med et kerneekstrakt af humane HeLa-celler. DNA-skabelonen til dette forsøg var det ved hjælp af BamVW lineariserede plasmid pCMV1200.
Fremstilling af skabelonplasmiderne:
Det på fig. 1 viste plasmid blev konstrueret til anvendelse ved den enzymatiske syntese af dsRNA'et. Hertil blev der først gennemført en polymerasekædereaktion (PCR) med det "positive control DNA" i HeLaScribe® Nuclear Extract in vitro transkriptionskittet fra firmaet Promega, Madison, USA som DNA-skabelon. En af de anvendte primere indeholdt sekvensen af et EcoRI-skæringssted og af T7-RNA-polymerase-promotoren ifølge sekvensprotokol nr. 1. Den anden primer indeholdt sekvensen af et EamHI-skæringssted og af SP6-RNA-polymerase-pro-motoren ifølge sekvensprotokol nr. 2. Derudover havde begge primere på deres 3'-ender identiske eller komplementære områder til DNA-skabelonen. PCR blev gennemført ved hjælp af" Taq PCR Core Kits" fra firmaet Qiagen, Hilden, Tyskland efter producentens angivelser. I et volumen på 100 μΙ blev 1,5 mM MgCh, 200 μΜ dNTP ad gangen, 0,5 μΜ primer ad gangen, 2,5 U Taqf-DNA-polymerase og cirka 100 ng "positive control DNA" anvendt som skabelon i PCR-puffere. Efter den initiale denaturering af skabelon-DNA'et ved opvarmning til 94°C i 5 minutter skete amplifikationen i 30 cykler på hver 60 sekunders denaturering ved 94°C, 60 sekunders annealing ved 5°C under den beregnede smeltetemperatur for primer ne og 1,5 - 2 minutters polymerisering ved 72°C. Efter en afsluttende poly-merisering på 5 minutter ved 72°C blev 5 μΙ af reaktionschargen analyseret ved hjælp af agarosegelelektrophorese. Længden af det således amplificerede DNA-fragment udgjorde 400 basepar, idet 340 basepar svarede til det "positive control DNA". PCR-produktet blev oprenset, hydrolyseret med EcoRI og BamYW og efter fornyet oprensning anvendt til ligering med en ligeledes ved hjælp af EcoRI og BamYW hydrolyseret pUC18 vektor. Der skete transformation af E. coli XL1-blue. Det opnåede plasmid (pCMV5) bærer et DNA-fragment, der på 5'-enden flankeres af T7- og på 3'-enden af SP6-promotoren. Ved linearisering af plasmidet med BamYW kan det anvendes in vitro med T7-RNA-polymerasen til run-off-transkriptionen af et 340 nukleotider langt, i sekvensprotokol nr. 3 vist, enkelt-strenget RNA. Lineariseres plasmidet med EcoRI, kan det anvendes til run-off-transkriptionen med SP6-RNA-polymerasen, hvorved den komplementære streng opstår. Svarende til den tidligere viste fremgangsmåde blev også et 23 nukleotider længere RNA syntetiseret. Hertil blev et i sekvensprotokol nr. 4 vist DNA ligeret med pUC18 vektoren via EcoRI og EamHI-skæringsstederne.
Plasmidet pCMV1200 blev konstrueret som DNA-skabelon til in vitro-transkriptio-nen med HeLa-kerneekstrakt. Til dette blev et 1191 bp stort EcoRI/BamH I -fragment af det i HeLaScribe® Nuclear Extract in vitro transkriptionskittet indeholdte positivkontrol-DNA amplificeret ved hjælp af PCR. Det amplificerede fragment omfatter den 828 bp store "umiddelbare tidlige" CMV-promotor og et 363 bp stort transkriberbart DNA-fragment. PCR-produktet blev ligeret med vektoren pGEM-T via "T-overhæng"-ligering. På 5'-enden af fragmentet er der et BamHI-skærings-sted. Plasmidet blev lineariseret ved hjælp af hydrolyse med BamHI og anvendt som skabelon til run-off-transkriptionen. in vitro-transkriotion af de komplementære enkeltstrenae: pCMV5-plasmid-DNA blev lineariseret med EcoRI eller EamHI. Det blev anvendt som DNA-skabelon til en in wiro-transkription af de komplementære RNA-enkelt-strenge med hhv. SP6- og T7-RNA-polymerase. Hertil blev der anvendt "Ribo- probe in vitro Transcription" systemet fra firmaet Promega, Madison, USA. Efter producentens angivelser blev 2 μg lineariseret plasmid-DNA inkuberet 5-6 timer ved 37°C i 100 μΙ transkriptionspuffer og 40 U T7- eller SP6-RNA-polymerase. I tilslutning dertil blev DNA-skabelonen nedbrudt ved tilsætning af 2,5 μΙ RNase-fri DNase RQ1 og inkubation i 30 minutter ved 37°C. Transkriptionschargen blev påfyldt med H2O til 300 μΙ og renset ved phenolekstraktion. RNA'et blev fældet ved tilsætning af 150 μΙ 7 M ammoniumacetat og 1125 μΙ ethanol og opbevaret ved -65°C frem til hybridisering.
Fremstilling af RNA-dobbeltstrenae
Til hybridiseringen blev 500 μΙ af det i ethanol opbevarede og fældede enkeltstrengede RNA udcentrifugeret. Det resulterende pellet blev tørret og optaget i 30 μΙ PIPES-puffer, pH 6,4 i nærvær af 80% formamid, 400 mM NaCI og 1 mM EDTA. 15 μΙ af de komplementære enkeltstrenge blev i hvert enkelt tilfælde sat sammen og opvarmet i 10 minutter til 85°C. I tilslutning dertil blev chargerne inkuberet natten over ved 50°C og afkølet til stuetemperatur.
Ved hybridiseringen blev der kun anvendt tilnærmelsesvis ækvimolære mængder af de to enkeltstrenge. Derved indeholdt dsRNA-præparationerne enkeltstrenget RNA (ssRNA) som kontamination. For at fjerne disse ssRNA-kontaminationer blev chargerne efter hybridiseringen behandlet med de enkeltstrengsspecifikke ribonukleaser RNase A af kvægpankreas og RNase T1 af Aspergillus oryzae. RNase A er en for pyrimidiner speciel endoribonuklease. RNase T1 er en endoribonuklease, der fortrinsvis skærer på 3'-siden af guanosiner. dsRNA er intet substrat for disse ribonukleaser. Til RNase-behandlingen blev der til chargerne i 300 μΙ Tris, pH 7,4, 300 mM NaCI og 5 mM EDTA tilsat 1,2 μΙ RNaseA i en koncentration på 10 mg/ml og 2 μΙ RNaseTI i en koncentration på 290 μΙ/ml. Chargerne blev inkuberet 1,5 time ved 30°C. Derefter blev RNaserne denatureret ved tilsætning af 5 μΙ proteinkinase K i en koncentration på 20 mg/ml samt 10 μΙ 20% SDS og inkubation i 30 minutter ved 37°C. dsRNA'et blev renset ved phenol- ekstraktion og fældet med ethanol. For at kunne kontrollere fuldstændigheden af RNase-fordøjelsen blev to kontrolcharger behandlet med ssRNA analogt med hybridiseringschargerne.
Det tørrede pellet blev optaget i 15 μΙ TE-puffer, pH 6,5 og underkastet en nativ polyacrylamidgelelektrophorese på en 8% gel. Acrylamidgelen blev derefter farvet i en ethidiumbromidopløsning og skyllet i et vandbad. Fig. 2 viser det på en UV-transilluminator synliggjorte RNA. Det på spor 1 påførte sense- og det på spor 2 påførte antisense-RNA viste ved de valgte betingelser en anden vandringsadfærd end det på spor 3 påførte dsRNA af hybridiseringschargen. Det på hhv. spor 4 og 5 påførte RNase-behandlede hhv. sense- og ani/sense-RNA frembragte intet synligt bånd. Dette viser, at de enkeltstrengede RNA'er blev nedbrudt fuldstændigt. Det på spor 6 påførte RNase-behandlede dsRNA af hybridiseringschargen er resistent over for RNase-behandlingen. Det i den native gel sammenlignet med det på spor 3 påførte dsRNA hurtigere vandrende bånd er et resultat af dsRNA, der er fri for ssRNA. Ud over det dominerende hovedbånd optræder der efter RNase-behandlingen svagere, hurtigere vandrende bånd. in WfrO-transpkriptionstest med menneskeligt cellekerneekstrakt:
Med anvendelse af HeLaScribe® Nuclear Extract in vitro transkriptionskittet fra firmaet Promega, Madison, USA blev transkriptionseffektiviteten af det ovenfor angivne, i plasmidet pCMV1200 indeholdte, med "positive control DNA" homologe DNA-fragment bestemt i nærvær af det sekvenshomologe dsRNA (dsRNA-CMV5). Desuden blev påvirkningen fra det ikke-sekvenshomologe, til det "gult fluorescerende protein" (YFP)-gen svarende dsRNA (dsRNA-YFP) undersøgt. Dette dsRNA var fremstillet analogt med det sekvenshomologe dsRNA. Sekvensen af en streng af dette dsRNA fremgår af sekvensprotokol nr. 5. Som skabelon til run-off-transkriptionen fungerede plasmidet pCMV1200. Det bærer den "umiddelbart tidlige" promotor af cytomegalovirus, der genkendes af den eukaryotiske RNA-polymerase II, og et transkriberbart fragment. Transkriptionen skete ved hjælp af HeLa-kerneekstraktet, der indeholder alle nødvendige proteiner til en transkription. Ved tilsætning af [a-32P]rGTP til transkriptionschargen blev der opnået radioaktivt markeret transkript. Det anvendte [a-32P]rGTP havde en specifik aktivitet på 400 Ci/mmol, 10 mCi/ml. Per charge blev der anvendt 3mM MgCI2, 400 μΜ af hver af rATP, rCTP, rUTP, 16 μΜ rGTP, 0,4 μΜ [a-32P]rGTP og alt efter forsøg 1 fmol lineariseret plasmid-DNA og forskellige mængder dsRNA i transkriptionspuffer. Hver charge blev påfyldt med H20 til et volumen på 8,5 μΙ. Chargerne blev blandet forsigtigt. Til at starte transkriptionen blev der tilsat 4 U HeLa-kerneekstrakt i et volumen på 4 μΙ og inkuberet 60 minutter ved 30°C. Reaktionen blev stoppet ved tilsætning af 87,5 μΙ til 30°C opvarmet stop-mix. Med henblik på at fjerne proteinerne blev chargerne tilsat 100 μΙ phenol/chloro-form/isoamylalkohol (25:24:1, v/v/v) mættet med TE-puffer, pH 5,0 og blandet kraftigt 1 minut. Til faseadskillelsen blev der centrifugeret cirka 1 minut ved 12000 rpm, og den øvre fase blev overført til et nyt reaktionskar. Til hver charge blev der tilsat 250 μΙ ethanol. Chargerne blev blandet godt og inkuberet mindst 15 minutter på tøris/methanol. Med henblik på præcipitation af RNA'et blev chargerne centrifugeret 20 minutter ved 12000 rpm og 4°C. Supernatanten blev kasseret. Pellet blev tørret 15 minutter i vakuum og resuspenderet i 10 μΙ H20. Til hver charge blev der tilsat 10 μΙ denatureret prøvepuffer. Adskillelsen af det fri GTP fra det opståede transkript skete ved hjælp af denaturerende polyacrylamid-gelelektrophorese på en 8% gel med 7 M urinstof. De ved transkriptionen med HeLa-kerneekstrakt dannede RNA-transkripter i denaturerende prøvepuffer blev opvarmet 10 minutter til 90°C og 10μΙ deraf straks påført i de friskt skyllede prøvelommer. Elektro-phorese skete ved 40 mA. Mængden af det ved transkriptionen dannede radioaktive ssRNA blev efter elektrophoresen analyseret ved hjælp af en Instant Imager.
Fig. 3 viser det ved hjælp af Instant Imageren viste radioaktive RNA fra en repræsentativ test. Prøver udvundet fra følgende transkriptionscharger blev påført:
Spor 1: uden skabelon-DNA, uden dsRNA; spor 2: 50 ng skabelon-DNA, uden dsRNA; spor 3: 50 ng skabelon-DNA, 0,5 μg dsRNA-YFP; spor 4: 50 ng skabelon-DNA, 1,5 μg dsRNA-YFP; spor 5: 50 ng skabelon-DNA, 3 μg dsRNA-YFP; spor 6: 50 ng skabelon-DNA, 5 μg dsRNA-YFP; spor 7: uden skabelon-DNA, 1,5 dsRNA-YFP; spor 8: 50 ng skabelon-DNA, uden dsRNA; spor 9: 50 ng skabelon-DNA, 0,5 μg dsRNA-CMV5; spor 10: 50 ng skabelon-DNA, 1,5 μg dsRNA-CMV5; spor 11: 50 ng skabelon-DNA, 3 μg dsRNA-CMV5; spor 12: 50 ng skabelon-DNA, 5 μg dsRNA-CMV5.
Der viste sig en tydelig reduktion af mængden af transkript i nærvær af sekvenshomologt dsRNA sammenlignet med kontrolchargen uden dsRNA samt også med chargerne med ikke-sekvenshomologt dsRNA-YFP. Positivkontrollen i spor 2 viser, at der ved in wfro-transkription med HeLa-kerneekstrakt blev dannet radioaktivt transkript. Chargen fungerer som sammenligning med de transkriptions-charger, der var inkuberet i nærvær af dsRNA. Spor 3 til 6 viser, at tilsætning af ikke-sekvensspecifikt dsRNA-YFP ikke har nogen indflydelse på mængden af det dannede transkript. Spor 9 til 12 viser, at tilsætning af en mellem 1,5 og 3 μg liggende mængde sekvensspecifik dsRNA-CMV5 fører til en nedgang i den dannede transkriptmængde. For at udelukke, at de observerede effekter ikke beror på dsRNA'et, men på en muligvis ved fremstillingen af dsRNA'et utilsigtet medført kontamination, blev der gennemført en yderligere kontrol. Enkeltstrengs-RNA blev transkriberet som beskrevet ovenfor og efterfølgende underkastet RNase-behandling. Ved hjælp af nativ polyacrylamidgelelektrophorese kunne det vises, at ssRNA'et var fuldstændigt nedbrudt. Denne charge blev i lighed med hybrodiseringschargerne underkasteten phenolekstraktion og en ethanolfældning og i tilslutning dertil optaget i TE-puffer. På denne måde blev der opnået en prøve, der ikke indeholdt RNA, men var behandlet med de samme enzymer og puffere som dsRNA'et. Spor 8 viser, at tilsætningen af denne prøve ikke har nogen ind flydelse på transkriptionen. Nedgangen i transkriptet ved tilsætning af sekvensspecifikt dsRNA kan derfor entydigt tilskrives selve dsRNA'et. Reduceringen af transkriptionsmængden af et gen i nærvær af dsRNA ved et menneskeligt transkriptionssystem viser en hæmning af ekspressionen af det pågældende gen. Denne effekt skyldes en hidtil ukendt, af dsRNA'et betinget mekanisme.
Udførelseseksempel 2:
Som testsystem for disse in v/Vo-eksperi menter tjente den murine fibroblaster-cellelinie NIH3T3, ATCC CRL-1658. Ved hjælp af mikroinjektion blev YFP-genet indbragt i cellekernerne. Ekspressionen af YFP blev undersøgt under påvirkning fra samtidigt medtransficeret sekvenshomologt dsRNA. Dette dsRNA-YFP er over en længde på 315 bp homologt med YFP-genets 5'-område. Nukleotidsekvensen af en streng af dsRNA-YFP er gengivet i sekvensprotokol nr. 5. Evalueringen under fluorescensmikroskop skete 3 timer efter injektion ved hjælp af den grøngule fluorescens af det dannede YFP.
Konstruktion af skabelonplasmidet oa fremstilling af dsRNA'et:
Som skabelon til fremstillingen af YFP-dsRNA'et ved hjælp af T7- og SP6-in vitro-transkription blev der konstrueret et plasmid efter det samme princip som beskrevet i udførelseseksempel 1. Med anvendelse af primeren Eco_T7_YFP ifølge sekvensprotokol nr. 6 og Eam_SP6_YFP ifølge sekvensprotokol nr. 7 blev det ønskede genfragment amplificeret ved hjælp af PCR og anvendt analogt med ovenstående beskrivelse til at fremstille dsRNA'et. Det opnåede dsRNA-YFP er identisk med det i udførelseseksempel 1 som ikke-sekvensspecifik kontrol anvendte dsRNA.
Der blev fremstillet et dsRNA (L-dsRNA), der på 3'-enden af RNA'et ifølge sekvensprotokol nr. 8 via en C18-linkergruppe er kemisk forbundet med 5'-enden af det komplementære RNA. Hertil blev der anvendt syntoner modificeret med disulfidbroer. Det 3'-terminale synton er bundet til den faste bærer via 3'-kulstoffet med en alifatisk linkergruppe via en disulfidbro. Ved det til det 3'-terminale synton af det ene oligoribnukleotid komplementære 5'-terminale synton af det komplementære oligoribonukleotid er 5'-tritylbeskyttelsesgruppen bundet via en anden alifatisk linker og en disulfidbro. Efter syntese af de to enkeltstrenge, fjernelse af beskyttelsesgrupperne og hybridisering af de komplementære oligoribonukleotider kommer de opstående thiolgrupper i rumligt naboskab med hinanden. Ved oxidation forbindes enkeltstrengene med hinanden via deres alifatiske linkere og en disulfidbro. I tilslutning dertil sker der rensning ved hjælp af HPLC.
Forberedelse af cellekulturerne:
Cellerne blev inkuberet i DMEM med 4,5 g/l glucose, 10% føtalt kvægserum ved 7,5% C02-atmosfære ved 37°C i kulturskåle og passageret før opnåelse af konfluens. Løsnen af cellerne skete med trypsin/EDTA. Til forberedelse af mikroinjektionen blev cellerne overført til petriskåle og inkuberet videre frem til dannelse af mikrokolonier.
Mikroinjektion:
Kulturskålene blev til mikroinjektionen taget ud af inkubatoren i ca. 10 minutter. Der blev injiceret individuelt i ca. 50 cellekerner per charge inden for et markeret område med anvendelse af mikroinjektionssystemet AIS fra firmaet Carl Zeiss, Gottingen, Tyskland. Efterfølgende blev cellerne inkuberet i yderligere tre timer. Til mikroinjektionen blev der forberedt borosilikat-glaskapillærer fra firmaet Hilgenberg GmbH, Malsfeld, Tyskland med en spidsdiameter under 0,5 μίτι. Mikroinjektionen blev gennemført med en mikromanipulator fra firmaet Narishige Scientific Instrument Lab., Tokyo, Japan. Injektionsvarigheden udgjorde 0,8 sekunder, trykket ca. 100 hPa. Til transfektionen blev der anvendt plasmidet pCDNA-YFP, der indeholder et ca. 800 bp stort BamHI/EcoRI-fragment med genet for YFP i vektoren pcDNA3. De i cellerkernerne injicerede prøver indeholdt 0,01 μg/μl pCDNA-YFP samt til dextran-7000 koblet Texas-rød i 14 mM NaCI, 3 mM KCI, 10 mM KPO4, pH 7,5. Supplerende blev der tilsat ca. 100 pi RNA med en koncentration på hhv. 1 μΜ og 375 μΜ i L-dsRNA'ets tilfælde.
Cellerne blev ved excitation med lys af excitationsbølgelængden for Texas-rød, 568 nm, eller for YFP, 488 nm, undersøgt ved hjælp af et flourescensmikroskop. Enkelte celler blev dokumenteret ved hjælp af et digitalt kamara. Fig. 4 a - e viser resultatet for NIH3T3-celler. Ved de på fig. 4 a viste celler er der injiceret sense-YFP-ssRNA, på fig. 4 b antisense-YFP-ssRNA, på fig. 4 c dsRNA-YFP, på fig. 4 d intet RNA og på fig. 4 e L-dsRNA.
Det i hvert enkelt tilfælde venstre felt viser flourescensen af celler, der blev exciteret med 568 nm. Til højre kan flourescensen af de samme celler ses ved excitation med 488 nm. Texas-rød-fluorescensen af alle illustrerede celler viser, at injektionsopløsningen med succes blev applikeret ind i cellekernerne, og ramte celler stadig var levende efter tre timer. Døde celler viste ikke længere nogen Texas-rød-flourescens.
De i hvert enkelt tilfælde højre felter på fig. 4 a og 4 b viser, at ekspressionen af YFP ved injektion af det enkeltstrengede RNA i cellekernerne ikke blev inhiberet synligt. Det højre felt på fig. 4 c viser celler, hvis YFP-fluorescens ikke længere kunne påvises efter injektion af dsRNA-YFP. Fig. 4 d viser som kontrol celler, hvori der ikke var injiceret RNA. Den på fig. 4 e illustrerede celle viser ved injektionen af L-dsRNA, der har sekvenshomologe områder med YFP-genet, en ikke længere påviselig YFP-fluorescens. Dette resultat dokumenterer, at også kortere dsRNA'er kan anvendes til specifik inhibering af genekspressionen i pattedyr, når dobbeltstrengene stabiliseres ved kemisk binding af enkeltstrengene.
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SEKVENSPROTOKOL <110> Kreutzer Dr., Roland
Limmer Dr., Stephan <120> Fremgangsmåde og medikament til at hæmme ekspressionen af et defineret gen <130> 400968 <140> < 141 > <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> DNA <213> Kunstig sekvens <220> <223> Beskrivelse af den kunstige sekvens:
EcoR I -skæri ngssted, T7- RNA-polym erasepromotor <400> 1 ggaattctaa tacgactcac tatagggcga tcagatctct agaag 45 <210> 2 <211> 50
<212> DNA <213> Kunstig sekvens <220> <223> Beskrivelse af den kunstige sekvens:
BamHI-skæringssted, SP6-RNA-polymerasepromotor <400> 2 gggatccatt taggtgacac tatagaatac ccatgatcgc gtagtcgata 50 <210> 3 <211> 340
<212> RNA <213> Kunstig sekvens <220> <223> Beskrivelse af den kunstige sekvens: RNA, der svarer til en sekvens fra det "positive control DNA" i HeLaScribe Nuclear Extract in vitro transkriptionskittet fra firmaet Promega <400> 3 ucagaucucu agaagcuuua augcgguagu uuaucacagu uaaauugcua acgcagucag 60 gcaccgugua ugaaaucuaa caaugcgcuc aucgucaucc ucggcaccgu cacccuggau 120 gcuguaggca uaggcuuggu uaugccggua cugccgggcc ucuugcggga uaucguccau 180 uccgacagca ucgccaguca cuauggcgug cugcuagcgc uauaugcguu gaugcaauuu 240 cuaugcgcac ccguucucgg agcacugucc gaccgcuuug gccgccgccc aguccugcuc 300 gcuucgcuac uuggagccac uaucgacuac gcgaucaugg 340 <210> 4 <211> 363
<212> DNA <213> Kunstig sekvens <220> <223> Beskrivelse af den kunstige sekvens: DNA, der svarer til en sekvens fra det "positive control DNA" i HeLaScribe Nuclear Extract in vitro transkriptionskittet fra firmaet Promega <400> 4 tcagatctct agaagcttta atgcggtagt ttatcacagt taaattgcta acgcagtcag 60 gcaccgtgta tgaaatctaa caatgcgctc atcgtcatcc tcggcaccgt caccctggat 120 gctgtaggca taggcttggt tatgccggta ctgccgggcc tcttgcggga tatcgtccat 180 tccgacagca tcgccagtca ctatggcgtg ctgctagcgc tatatgcggt gatgcaattt 240 ctatgcgcac ccgttctcgg agcactgtcc gaccgctttg gccgccgccc agtcctgctc 300 gcttcgctac ttggagccac tatcgactac gcgatcatgg cgaccacacc cgtcctgtgg 360 atc 363 <210> 5 <211> 315
<212> RNA <213> Kunstig sekvens <220> <223> Beskrivelse af den kunstige sekvens: Sekvens fra YFP-genet <400> 5 auggugagca agggcgagga gcuguucacc gggguggugc ccauccuggu cgagcuggac 60 ggcgacguaa acggccacaa guucagcgug uccggcgagg gcgagggcga ugccaccuac 120 ggcaagcuga cccugaaguu caucugcacc accggcaagc ugcccgugcc cuggcccacc 180 cucgugacca cccugaccua cggcgugcag ugcuucagcc gcuaccccga ccacaugaag 240 cagcacgacu ucuucaaguc cgccaugccc gaaggcuacg uccaggagcg caccaucuuc 300 uucaaggacg acggc 315 <210> 6 <211> 52
<212> DNA <213> Kunstig sekvens <220> <223> Beskrivelse af den kunstige sekvens:
EcoR I -skæri ngssted, T7- RNA-polym erasepromotor, komplementært område til YFP-genet <400> 6 ggaattctaa tacgactcac tatagggcga atggtgagca agggcgagga gc 52 <210> 7 <211> 53
<212> DNA <213> Kunstig sekvens <220> <223> Beskrivelse af den kunstige sekvens:
BamHI-skæringssted, SP6-RNA-polymerasepromotor, komplementært område til YFP-genet <400> 7 gggatccatt taggtgacac tatagaatac gccgtcgtcc ttgaagaaga tgg 53 <210> 8 <211> 21
<212> RNA <213> Kunstig sekvens <220> <223> Beskrivelse af den kunstige sekvens: RNA, der svarer til en sekvens fra YFP-genet <400> 8 ucgagcugga cggcgacgua a 21
Claims (72)
- PAT E NT K RAV1. Fremgangsmåde til at hæmme ekspressionen af et defineret målgen i en pattedyrcelle in vitro, idet et 15 til 49 basepar stort oligoribonukleotid med dobbeltstrenget struktur (dsRNA) indføres i pattedyrcellen, hvor en streng af dsRNA'et har et område I, der i det mindste segmentvis er komplementært til målgenet og har højst 49 efter hinanden følgende nukleotidpar, og et inden for den dobbeltstrengede struktur komplementært område II dannes af to separate RNA-enkeltstrenge, idet den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II øges ved hjælp af en yderligere kemisk binding, og idet den kemiske binding fremstilles på en ende af det komplementære område II.
- 2. Fremgangsmåde ifølge krav 1, hvor dsRNA'et indesluttes i micellare strukturer, fortrinsvis i liposomer.
- 3. Fremgangsmåde ifølge et af de ovenstående krav, hvor målgenet eksprimeres i eukaryotiske celler.
- 4. Fremgangsmåde ifølge et af de ovenstående krav, hvor målgenet er udvalgt blandt: onkogen, cytokin-gen, id-proteingen, udviklingsgen, priongen.
- 5. Fremgangsmåde ifølge et af de ovenstående krav, hvor målgenet er en bestanddel af et virus eller vi roid.
- 6. Fremgangsmåde ifølge krav 5, hvor virusset er et humanpatogent virus eller viroid.
- 7. Fremgangsmåde ifølge krav 5, hvor virusset eller viroidet er et dyre-patogent virus eller viroid.
- 8. Fremgangsmåde ifølge et af de ovenstående krav, hvor enderne af dsRNA'et modificeres for at modvirke en nedbrydning i cellen eller en dissociation ind i enkeltstrengene.
- 9. Fremgangsmåde ifølge et af de ovenstående krav, hvor den af nukleotid-parrene fremkaldte sammenhæng af det komplementære område II øges ved hjælp af en yderligere kemisk binding.
- 10. Fremgangsmåde ifølge et af de ovenstående krav, hvor den kemiske binding dannes ved en kovalent eller ionisk binding, en hydrogenbro-binding, hydrofobe vekselvirkninger, fortrinsvis van-der-Waals- eller stabelvekselvirkninger, eller ved metal-ionkoordination.
- 11. Fremgangsmåde ifølge et af de ovenstående krav, hvor den kemiske binding dannes ved hjælp af en eller flere forbindelsesgrupper, idet forbindelsesgrupperne fortrinsvis er poly-(oxyphosphinicooxy-1,3-propan-diol)- og/eller polyethylenglycol-kæder.
- 12. Fremgangsmåde ifølge et af de ovenstående krav, hvor den kemiske binding dannes af purinanaloger benyttet i de komplementære områder II i stedet for puriner.
- 13. Fremgangsmåde ifølge et af de ovenstående krav, hvor den kemiske binding dannes af azabenzenenheder indført i de komplementære områder II.
- 14. Fremgangsmåde ifølge et af de ovenstående krav, hvor den kemiske binding dannes af forgrenede nukleotidanaloger benyttet i de komplementære områder II i stedet for nukleotider.
- 15. Fremgangsmåde ifølge et af de ovenstående krav, hvor der til fremstilling af den kemiske binding benyttes mindst en af følgende grupper: methylenblå; bifunktionelle grupper, fortrinsvis bis-(2-chlorethyl)-amin; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamin; 4-thiouracil; psoralen.
- 16. Fremgangsmåde ifølge et af de ovenstående krav, hvor den kemiske binding dannes af thiophosphoryl-grupper anbragt på enderne af det dobbeltstrengede område.
- 17. Fremgangsmåde ifølge et af de ovenstående krav, hvor mindst en 2’-hydroxylgruppe af dsRNA’ets nukleotider i det komplementære område II er erstattet af en kemisk gruppe, fortrinsvis en 2’-amino- eller en 2’-methyl-gruppe.
- 18. Fremgangsmåde ifølge et af de ovenstående krav, hvor mindst et nukleotid i mindst en streng af det komplementære område II er en "locked nucleotide" med en, fortrinsvis ved hjælp af en 2’-0, 4’-C-methylenbro, kemisk modificeret sukkerring.
- 19. Fremgangsmåde ifølge et af de ovenstående krav, hvor dsRNA’et bindes til, associeres med eller omgives af mindst et fra et virus stammende, deraf afledt eller syntetisk fremstillet viralt kappeprotein.
- 20. Fremgangsmåde ifølge et af de ovenstående krav, hvor dsRNA’et er komplementær til målgenets primære eller processerede RNA-transkript.
- 21. Fremgangsmåde ifølge et af de ovenstående krav, hvor cellen er en menneskelig celle.
- 22. Fremgangsmåde ifølge et af de ovenstående krav, hvor mindst to fra hinanden forskellige dsRNA’er indføres i cellen, idet en streng af hvert dsRNA i det mindste segmentvis er komplementær til i hvert enkelt tilfælde et af mindst to forskellige målgener.
- 23. Fremgangsmåde ifølge et af de ovenstående krav, hvor et af målgenerne er PKR-genet.
- 24. Medikament med mindst et 15 til 49 basepar stort oligoribonukleotid med dobbeltstrenget struktur (dsRNA) til at hæmme ekspressionen af et defineret målgen i pattedyrceller, idet en streng af dsRNA'et har et område I, der i det mindste segmentvis er komplementært til målgenet og har højst 49 efter hinanden følgende nukleotidpar, og et inden for den dobbeltstrengede struktur komplementært område II er dannet af to separate RNA-enkeltstrenge, idet den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II øges ved hjælp af en yderligere kemisk binding, og idet den kemiske binding er fremstillet på en ende af det komplementære område II.
- 25. Medikament ifølge krav 24, hvor dsRNA'et foreligger pakket i micellare strukturer, fortrinsvis i liposomer.
- 26. Medikament ifølge et af kravene 24 eller 25, hvor målgenet kan eksprime-res i eukaryotiske celler.
- 27. Medikament ifølge et af kravene 24 til 26, hvor målgenet er udvalgt blandt: onkogen, cytokin-gen, id-proteingen, udviklingsgen, priongen.
- 28. Medikament ifølge et af kravene 24 til 27, hvor målgenet kan eksprimeres i patogene organismer, fortrinsvis i plasmodia.
- 29. Medikament ifølge et af kravene 24 til 28, hvor målgenet er en bestanddel af et virus eller vi roid.
- 30. Medikament ifølge krav 29, hvor virusset er et humanpatogent virus eller viroid.
- 31. Medikament ifølge krav 29, hvor virusset eller viroidet er et dyrepatogent virus eller viroid.
- 32. Medikament ifølge et af kravene 24 til 31, hvor enderne af dsRNA'et er modificeret for at modvirke en nedbrydning i cellen eller en dissociation ind i enkeltstrengene.
- 33. Medikament ifølge et af kravene 24 til 32, hvor den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II er øget ved hjælp af en yderligere kemisk binding.
- 34. Medikament ifølge et af kravene 24 til 33, hvor den kemiske binding er dannet ved en kovalent eller ionisk binding, en hydrogenbrobinding, hydrofobe vekselvirkninger, fortrinsvis van-der-Waals- eller stabelveksel-virkninger, eller ved metal-ionkoordination.
- 35. Medikament ifølge et af kravene 24 til 34, hvor den kemiske binding er dannet ved hjælp af en eller flere forbindelsesgrupper, idet forbindelsesgrupperne fortrinsvis er poly-(oxyphosphinicooxy-1,3-propandiol)- og/eller polyethylenglycol-kæder.
- 36. Medikament ifølge et af kravene 24 til 35, hvor den kemiske binding er dannet af purinanaloger benyttet i de komplementære områder II i stedet for puriner.
- 37. Medikament ifølge et af kravene 24 til 36, hvor den kemiske binding er dannet af azabenzenenheder indkoblet i de komplementære områder II.
- 38. Medikament ifølge et af kravene 24 til 37, hvor den kemiske binding er dannet af forgrenede nukleotidanaloger benyttet i de komplementære områder II i stedet for nukleotider.
- 39. Medikament ifølge et af kravene 24 til 38, hvor der til fremstilling af den kemiske binding benyttes mindst en af følgende grupper: methylenblå; bifunktionelle grupper, fortrinsvis bis-(2-chlorethyl)-amin; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamin; 4-thiouracil; psoralen.
- 40. Medikament ifølge et af kravene 24 til 39, hvor den kemiske binding er dannet af thiophosphoryl-grupper tilvejebragt på enderne af det dobbeltstrengede område.
- 41. Medikament ifølge et af kravene 24 til 40, hvor mindst en 2’-hydroxyl-gruppe af dsRNA’ets nukleotider i det komplementære område II er erstattet af en kemisk gruppe, fortrinsvis en 2’-amino- eller en 2’-methylgruppe.
- 42. Medikament ifølge et af kravene 24 til 41, hvor mindst et nukleotid i mindst en streng af det komplementære område II er en "locked nucleotide" med en, fortrinsvis ved hjælp af en 2’-0, 4’-C-methylenbro, kemisk modificeret sukkerring.
- 43. Medikament ifølge et af kravene 24 til 42, hvor dsRNA’et bindes til, associeres med eller omgives af mindst et fra et virus stammende, deraf afledt eller syntetisk fremstillet viralt kappeprotein.
- 44. Medikament ifølge et af kravene 24 til 43, hvor dsRNA’et er komplementær til målgenets primære eller processerede RNA-transkript.
- 45. Medikament ifølge et af kravene 24 til 44, hvor cellen er en menneskelig celle.
- 46. Medikament ifølge et af kravene 24 til 45, hvor der heri er indeholdt mindst to fra hinanden forskellige dsRNA'er, idet en streng af hvert dsRNA i det mindste segmentvis er komplementær til i hvert enkelt tilfælde et af mindst to forskellige målgener.
- 47. Medikament ifølge krav 46, hvor et af målgenerne er PKR-genet.
- 48. Anvendelse af et 15 til 49 basepar stort oligoribonukleotid med dobbeltstrenget struktur (dsRNA) til at fremstille et medikament, idet en streng af dsRNA'et har et område I, der i det mindste segmentvis er komplementært til et defineret målgen i pattedyrceller og har højst 49 efter hinanden følgende nukleotidpar, og et inden for den dobbeltstrengede struktur komplementært område II er dannet af to separate RNA-enkeltstrenge, idet den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II er øget ved hjælp af en yderligere kemisk binding, og idet den kemiske binding er fremstillet på en ende af det komplementære område II.
- 49. Anvendelse ifølge krav 48, hvor dsRNA'et foreligger pakket i micellare strukturer, fortrinsvis i liposomer.
- 50. Anvendelse ifølge et af kravene 48 eller 49, hvor målgenet kan eksprime-res i eukaryotiske celler.
- 51. Anvendelse ifølge et af kravene 48 til 50, hvor målgenet er udvalgt blandt: onkogen, cytokin-gen, id-proteingen, udviklingsgen, priongen.
- 52. Anvendelse ifølge et af kravene 48 til 51, hvor målgenet kan eksprimeres i patogene organismer, fortrinsvis i plasmodia.
- 53. Anvendelse ifølge et af kravene 48 til 52, hvor målgenet er en bestanddel af et virus eller viroid.
- 54. Anvendelse ifølge krav 53, hvor virusset er et humanpatogent virus eller viroid.
- 55. Anvendelse ifølge krav 53, hvor virusset eller viroidet er et dyrepatogent virus eller viroid.
- 56. Anvendelse ifølge et af kravene 48 til 55, hvor enderne af dsRNA'et er modificeret for at modvirke en nedbrydning i cellen eller en dissociation ind i enkeltstrengene.
- 57. Anvendelse ifølge et af kravene 48 til 56, hvor den af nukleotidparrene fremkaldte sammenhæng af det komplementære område II er øget ved hjælp af en yderligere kemisk binding.
- 58. Anvendelse ifølge et af kravene 48 til 57, hvor den kemiske binding er dannet ved en kovalent eller ionisk binding, en hydrogenbrobinding, hydrofobe vekselvirkninger, fortrinsvis van-der-Waals- eller stabelveksel-virkninger, eller ved metal-ionkoordination.
- 59. Anvendelse ifølge et af kravene 48 til 58, hvor den kemiske binding er dannet ved hjælp af en eller flere forbindelsesgrupper, idet forbindelsesgrupperne fortrinsvis er poly-(oxyphosphinicooxy-1,3-propandiol)- og/eller polyethylenglycol-kæder.
- 60. Anvendelse ifølge et af kravene 48 til 59, hvor den kemiske binding er dannet af purinanaloger benyttet i de komplementære områder II i stedet for puriner.
- 61. Anvendelse ifølge et af kravene 48 til 60, hvor den kemiske binding er dannet af azabenzenenheder indført i de komplementære områder II.
- 62. Anvendelse ifølge et af kravene 48 til 61, hvor den kemiske binding er dannet af forgrenede nukleotidanaloger benyttet i de komplementære områder II i stedet for nukleotider.
- 63. Anvendelse ifølge et af kravene 48 til 62, hvor der til fremstilling af den kemiske binding benyttes mindst en af følgende grupper: methylenblå; bifunktionelle grupper, fortrinsvis bis-(2-chlorethyl)-amin; N-acetyl-N'-(p-glyoxyl-benzoyl)-cystamin; 4-thiouracil; psoralen.
- 64. Anvendelse ifølge et af kravene 48 til 63, hvor den kemiske binding er dannet af thiophosphoryl-grupper anbragt på enderne af det dobbeltstrengede område.
- 65. Anvendelse ifølge et af kravene 48 til 64, hvor mindst en 2’-hydroxyl-gruppe af dsRNA’ets nukleotider i det komplementære område II er erstattet af en kemisk gruppe, fortrinsvis en 2’-amino- eller en 2’-methylgruppe.
- 66. Anvendelse ifølge et af kravene 48 til 65, hvor mindst et nukleotid i mindst en streng af det komplementære område II er en "locked nucleotide" med en, fortrinsvis ved hjælp af en 2’-0, 4’-C-methylenbro, kemisk modificeret sukkerring.
- 67. Anvendelse ifølge et af kravene 48 til 66, hvor dsRNA’et bindes til, associeres med eller omgives af mindst et fra et virus stammende, deraf afledt eller syntetisk fremstillet viralt kappeprotein.
- 68. Anvendelse ifølge et af kravene 48 til 67, hvor dsRNA’et er komplementær til målgenets primære eller processerede RNA-transkript.
- 69. Anvendelse ifølge et af kravene 48 til 68, hvor cellen er en menneskelig celle.
- 70. Anvendelse ifølge et af kravene 48 til 69, hvor der anvendes mindst to fra hinanden forskellige dsRNA'er, idet en streng af hvert dsRNA i det mindste segmentvis er komplementær til i hvert enkelt tilfælde et af mindst to forskellige målgener.
- 71. Anvendelse ifølge krav 70, hvor et af målgenerne er PKR-genet.
- 72. Anvendelse ifølge et af kravene 48 til 71, hvor medikamentet kan injiceres i blodbanen eller interstitium i den organisme, der skal behandles.
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