DK2986729T3 - Målrettet modifikation af rottegenom - Google Patents

Målrettet modifikation af rottegenom Download PDF

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DK2986729T3
DK2986729T3 DK14784879.0T DK14784879T DK2986729T3 DK 2986729 T3 DK2986729 T3 DK 2986729T3 DK 14784879 T DK14784879 T DK 14784879T DK 2986729 T3 DK2986729 T3 DK 2986729T3
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nucleic acid
rat
locus
cell
acid sequence
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Jeffrey D Lee
Alexander O Mujica
Wojtek Auerbach
Ka-Man Venus Lai
David M Valenzuela
George D Yancopoulos
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Regeneron Pharma
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Claims (21)

1. En metode til målrettet modifikation af en genomisk locus af interesse i en pluripotent rottecelle, omfattende: (a) introduktion af en stor målretningsvektor (LTVEC) i den pluripotente rottecelle omfattende en indstiksnukleinsyre flankeret af en 5’-homologiarm, som er komplementær i forhold til en første nukleinsyresekvens ved den genomiske locus af interesse, og en 3’-homologiarm, som er komplementær i forhold til en anden nukleinsyresekvens ved den genomiske locus af interesse, hvor den samlede sum af 5’- og 3’-homologiarmene er mindst 10 kb; og (b) identifikation af en generisk modificeret, pluripotent rottecelle omfattende en målrettet genetisk modifikation ved den genomiske locus af interesse, hvor den målrettede genetiske modifikation kan overføres via kimcellebanen; hvor den pluripotente rottecelle, som skal anvendes til målrettet modifikation af den genomiske locus af interesse, kan skaffes ved at kultivere isolerede embryonale rottestamceller på et feedercellelag, som ikke er modificeret, for at udtrykke leukæmihæmningsfaktor (LIF) med et medium omfattende omkring 50 U/ml til omkring 150 U/ml LIF og en kombination af inhibitorer, som består af en MEK-sti-inhibitor og en GSK3-inhibitor; hvor den pluripotente rottecelle mangler udtrykket af c-Myc; hvor den pluripotente rottecelle danner kugleformede, fritflydende kolonier i kultur; og hvor den modificerede pluripotente rottecelle har en normal karyotype.
2. Metoden ifølge krav 1, hvor den målrettede genetiske modifikation er biallelisk.
3. Metoden ifølge krav 1 eller 2, hvor den pluripotente rottecelle er en embryonal rottestamcelle (ES).
4. Metoden ifølge ethvert af kravene 1-3, hvor den pluripotente rottecelle er karakteriseret ved udtryk af mindst en pluripotensmarker valgt blandt gruppen bestående af Dnmt3L, Eras, Err-beta, Fbxol5, Fgf4, Gdf3, Klf4, Lefl, LIF receptor, Lin28, Nanog, Oct4, Soxl5, Sox2 og Utfl.
5. Metoden ifølge ethvert af kravene 1-3, hvor den pluripotente rottecelle er karakteriseret ved en eller flere af følgende egenskaber: (a) stammer fra en DA-stamme eller en ACI-stamme; (b) mangel af udtryk af en eller flere af pluripotensmarkeme Ecatl og Rexol; (c) mangel af udtryk af en eller flere af mesodermalmarkerne Brachyury og Bmpr2; (d) mangel af udtryk af en eller flere af endodermalmarkerne Gata6, Soxl7 og Sox7; og (e) mangel af udtryk af en eller flere af neuralmarkerne Nestin og Pax6.
6. Metoden ifølge ethvert af kravene 1-5, hvor koncentrationen af LIF i mediet er imellem omkring 75 U/ml til omkring 125 U/ml, helst imellem omkring 90 U/ml til omkring 110 U/ml, og allerhelst omkring 100 U/ml.
7. Metoden ifølge ethvert af kravene 1-6, hvor MEK-sti-inhibitoren er MEK-inhibitor PD0325901 og/eller GSK3-inhibitoren er CHIR99021.
8. Metoden ifølge krav 7, hvor MEK-sti-inhibitoren er MEK-inhibitor PD0325901 i en koncentration på 0,8 μΜ til 1,2 μΜ, og GSK3-inhibitor er CHIR99021 i en koncentration på 2,5 pM til 3,5 pM.
9. Metoden ifølge krav 8, hvor koncentrationen af LIF i mediet er omkring 100 U/ml, MEK-sti-inhibitoren er MEK-inhibitor PD0325901 i en koncentration på omkring 1 pM, og GSK3-inhibitor er CHIR99021 i en koncentration på omkring 3 pM.
10. Metoden ifølge krav 9, hvor mediet omfatter: DMEM/F12-basalmedium i en koncentration på lx; neurobasalmedium i en koncentration på lx; penicillin/streptomycin i en koncentration på 1 %; L-glutamin i en koncentration på 4 mM; 2- mercaptoethanol i en koncentration på 0,1 mM; N2-supplement i en koncentration på lx; B27-supplement i en koncentration på lx; LIF i en koncentration på 100 U/ml; PD0325901 i en koncentration på 1 pM og CHIR99021 i en koncentration på 3 pM.
11. Metoden ifølge ethvert af kravene 1-10, hvor: (a) den samlede sum af 5’- og 3’-homologiarmene for LTVEC er fra omkring 10 kb til omkring 20 kb, fra omkring 20 kb til omkring 40 kb, fra omkring 40 kb til omkring 60 kb, fra omkring 60 kb til omkring 80 kb, fra omkring 80 kb til omkring 100 kb, fra omkring 100 kb til omkring 120 kb eller fra omkring 120 kb til omkring 150 kb; eller (b) den samlede sum af 5’- og 3’-homologiarmene for LTVEC er fra omkring 16 kb til omkring 150 kb.
12. Metoden ifølge ethvert af kravene 1-11, hvor den målrettede genetiske modifikation omfatter: (a) substitution af en endogen rotte-nukleinsyresekvens med en homolog eller en ortholog nukleinsyresekvens; (b) sletning af en endogen rotte-nukleinsyresekvens; (c) sletning af en endogen rotte-nukleinsyresekvens, hvor sletningen rækker fra omkring 5 kb til omkring 10 kb, fra omkring 10 kb til omkring 20 kb, fra omkring 20 kb til omkring 40 kb, fra omkring 40 kb til omkring 60 kb, fra omkring 60 kb til omkring 80 kb, fra omkring 80 kb til omkring 100 kb, fra omkring 100 kb til omkring 150 kb, fra omkring 150 kb til omkring 200 kb, fra omkring 200 kb til omkring 300 kb, fra omkring 300 kb til omkring 400 kb, fra omkring 400 kb til omkring 500 kb, fra omkring 500 kb til omkring 1 Mb, fra omkring 1 Mb til omkring 1,5 Mb, fra omkring 1,5 Mb til omkring 2 Mb, fra omkring 2 Mb til omkring 2,5 Mb eller fra omkring 2,5 Mb til omkring 3 Mb; (d) en exogen nukleinsyresekvens, som rækker fra omkring 5 kb til omkring 10 kb, fra omkring 10 kb til omkring 20 kb, fra omkring 20 kb til omkring 40 kb, fra omkring 40 kb til omkring 60 kb, fra omkring 60 kb til omkring 80 kb, fra omkring 80 kb til omkring 100 kb, fra omkring 100 kb til omkring 150 kb, fra omkring 150 kb til omkring 200 kb, fra omkring 200 kb til omkring 250 kb, fra omkring 250 kb til omkring 300 kb, fra omkring 300 kb til omkring 350 kb eller fra omkring 350 kb til omkring 400 kb; (e) en exogen nukleinsyresekvens omfattende en nukleinsyresekvens, som er homolog eller ortholog i forhold til en endogen rotte-nukleinsyresekvens; (f) en kimær nukleinsyresekvens omfattende en menneske-nukleinsyresekvens og en rotte-nukleinsyresekvens; (g) en betinget allel flankeret positionsspecifikke rekombinase-målsekvenser; eller (h) et reporter-gen, som funktionsegnet er forbundet med et promoter, som er aktivt i en rottecelle.
13. Metoden ifølge ethvert af kravene 1-12, hvor den målrettede genetiske modifikation omfatter: (i) indsætning af en menneske-nukleinsyresekvens, som er homolog eller ortholog i forhold til en rotte-nukleinsyresekvens ved en endogen genomisk locus; (ii) substitution af rotte-nukleinsyresekvensen ved den endogene genomiske locus med den homologe eller orthologe menneske-nukleinsyresekvens; (iii) en kimær nukleinsyresekvens omfattende en menneske-nukleinsyresekvens og en rotte-nukleinsyresekvens; eller (iv) en kombination deraf.
14. Metoden ifølge krav 13, hvor størrelsen af indsætningen eller substitutionen er fra omkring 5 kb til omkring 10 kb, fra omkring 10 kb til omkring 20 kb, fra omkring 20 kb til omkring 40 kb, fra omkring 40 kb til omkring 60 kb, fra omkring 60 kb til omkring 80 kb, fra omkring 80 kb til omkring 100 kb, fra omkring 100 kb til omkring 150 kb, fra omkring 150 kb til omkring 200 kb, fra omkring 200 kb til omkring 250 kb, fra omkring 250 kb til omkring 300 kb, fra omkring 300 kb til omkring 350 kb, fra omkring 350 kb til omkring 400 kb.
15. Metoden ifølge ethvert af kravene 1-14, hvor introduktionstrinnet (a) derudover omfatter introduktion af en nukleinsyre, som koder et nukleasemiddel, som fremmer en homolog rekombination imellem LTVEC og den genomiske locus af interesse i den pluripotente rottecelle.
16. Metoden ifølge krav 15, hvor nukleasemidlet omfatter: (a) en zinkfinger-nuklease; eller (b) en transkriptionsaktivator-lignende effektor-nuklease (TALEN).
17. Metoden ifølge krav 15, hvor nukleasemidlet omfatter et CRISPR/Cas-system omfattende en Cas9-nuklease og en guide-RNA (gRNA), som omfatter en kondenseret crRNA-tracrRNA.
18. Metoden ifølge krav 17, hvor: (a) gRNA omfatter: (i) en kimær RNA af nukleinsyresekvensen af SEQ ID NO: 2; eller (Ii) en kimær RNA af nukleinsyresekvensen af SEQ ID NO: 3; (b) crRNA omfatter SEQ ID NO: 4; SEQ ID NO: 5; eller SEQ ID NO: 6; eller (c) tracrRNA omfatter SEQ ID NO: 7 eller SEQ ID NO: 8.
19. Metoden ifølge ethvert af kravene 1-18, hvor identifikationstrinnet anvender et kvantitativt assay til vurdering af en modifikation af allelen (MOA) ved den genomiske locus af interesse.
20. Metoden ifølge ethvert af kravene 1-19, hvor den målrettede genomiske locus er en interleukin-2-receptor-gamma-locus, en ApoE-locus, en Ragl-locus, en Rag2-locus eller en Rag2/Rag 1 -locus.
21. En metode til målrettet modifikation af en genomisk locus af interesse i en pluripotent rottecelle, omfattende: (a) målretning af en genomisk locus af interesse i en pluripotent rottecelle ifølge metoden i ethvert af kravene 1-20 for at danne en genetisk modificeret, pluripotent rottecelle, hvor indstiksnukleinsyren omfatter en menneske-nukleinsyre; og (b) introduktion af den genetisk modificerede, pluripotente rottecelle i et værtsrotteembryo.
DK14784879.0T 2013-04-16 2014-04-16 Målrettet modifikation af rottegenom DK2986729T3 (da)

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