DK3161128T3 - Fremgangsmåder og sammensætninger til målrettede gentiske modifikationer og fremgangsmåder til anvendelse heraf - Google Patents
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Claims (15)
1. Fremgangsmåde til modificering af et genomisk mållocus på et Y-kromosom i en celle, hvilken fremgangsmåde omfatter: (a) tilvejebringelse af cellen omfattende det genomiske mållocus på Y-kromosomet, hvor det genomiske mållocus omfatter et genkendelses sted for et nukleasemiddel, og hvor cellen er i en kultur, der omfatter et DMEM-basemedium; (b) indføring i cellen af: (i) nukleasemidlet, hvor nukleasemidlet inducerer et enkelt- eller dobbeltstrenget brud ved genkendelsesstedet; og (ii) et stor målrettet vektor, der omfatter et indsætningspolynukleotid flankeret af første og anden homologiarme svarende til første og andet målsteder placeret inde i det genomiske mållocus, hvor den samlede sum af den første homologiarm og den anden homologiarm er mindst 10 kb, og hvor den målrettede vektor undergår homolog rekombination med det genomiske mållocus; og (c) identificiering af mindst én celle, der i sit genom omfatter indsætningspolynukleotidet integreret ved at det genomiske mållocus, hvor integration af indsætningspolynukleotidet indfører en genetisk modifikation, der omfatter deletion af en endogen nukleinsyresekvens og udskiftning med en exogen nukleinsyresekvens ved det genomiske mållocus, hvor cellen ikke er frembragt ved anvendelse af en fremgangsmåde, der involverer modificering af menneskers genetiske kimlinjeidentitet eller involverer anvendelse af et humant human embryo til industrielle eller kommercielle formål, og hvor fremgangsmåden ikke er en fremgangsmåde til behandling af menneske- eller dyrekroppen ved terapi.
2. Fremgangsmåde ifølge krav 1, hvor den totale sum af den første homologiarm og den anden homologiarm er mindre end 150 kb.
3. Fremgangsmåde ifølge krav 1 eller 2, hvor cellen er en pattedyrecelle, eventuelt hvor pattedyrecellen er fra en gnaver, og eventuelt hvor gnaveren er en rotte eller en mus.
4. Fremgangsmåde ifølge et hvilket som helst af kravene 1-3, hvor cellen er en pluripotent celle, eventuelt hvor den pluripotente celle er en induceret pluripotent stam- (iPS) celle eller en ikke-human embryostam- (ES) celle, eventuelt hvor den ikke-humane ES-celle er en gnaver-ES-celle, en rotte-ES-celle eller en muse-ES-celle.
5. Fremgangsmåde ifølge krav 4, hvor cellen er en muse-ES-celle.
6. Fremgangsmåde ifølge et hvilket som helst af kravene 1-5, hvor nukleasemidlet er: (a) en zinkfingernuklease (ZFN); (b) en Transcription Activator-Like Effector Nuclease (TALEN); (c) en meganuklease; (d) et Clustered Regularly Interspaced Short Palindromic Repeats- (CRISPR) associeret (Cas) protein og et guide-RNA (gRNA), eller (e) et mRNA, der koder for en nuklease.
7. Fremgangsmåde ifølge krav 6, hvor nukleasemidlet er Cas-proteinet og gRNA’et, hvor Cas-proteinet er Cas9, og hvor gRNA’et omfatter: (a) et CRISPR-RNA (crRNA), der er målrettet genkendelsesstedet, hvor genkendelsesstedet er umiddelbart flankeret af en PAM- (Protospacer Adjacent Motif) sekvens; og (b) et transaktiverende CRISPR-RNA (tracrRNA).
8. Fremgangsmåde ifølge et hvilket som helst af kravene 1-7, hvor indsætningspolynukleotidet er fra ca. 5 kb til ca. 200 kb, fra ca. 200 kb til ca. 250 kb, fra ca. 250 kb til ca. 300 kb, fra ca. 300 kb til ca. 350 kb eller fra ca. 350 kb til ca. 400 kb i længden.
9. Fremgangsmåde ifølge et hvilket som helst af kravene 1-8, hvor indsætningspolynukleotidet omfatter en konditionel allel, et polynukleotid, der koder for en selektionsmarkør, en nukleinsyre flankeret af stedsspecifikke rekombinationsmålsekvenser eller et reportergen operativt bundet til en promoter, hvor reportergenet koder for et reporterprotein valgt fra gruppen bestående af LacZ, mPlum, mCherry, tdTomato, mStrawberry, J-Red, DsRed, mOrange, mKO, mCitrine, Venus, YPet, forbedret gult fluorescerende protein (EYFP), Emerald, forbedret grønt fluorescerende protein (EGFP), CyPet, cyanfluorescerende protein (CFP), Cerulean, T-Sapphire, luciferase, alkalisk phosphatase og en kombination deraf.
10. Fremgangsmåde ifølge et hvilket som helst af kravene 1-9, hvor modifikationen omfatter en domæneombytning, en exonombytning, en intronombytning, en ombytning af regulatorisk sekvens, en genombytning eller en kombination deraf.
11. Fremgangsmåde ifølge et hvilket som helst af kravene 1-10, hvor den deleterede endogene nukleinsyresekvens ligger i intervallet fra ca. 5 kb til ca. 10 kb, fra ca. 10 kb til ca. 20 kb, fra ca. 20 kb til ca. 40 kb, fra ca. 40 kb til ca. 60 kb, fra ca. 60 kb til ca. 80 kb, fra ca. 80 kb til ca. 100 kb, fra ca. 100 kb til ca. 150 kb, eller fra ca. 150 kb til ca. 200 kb, fra ca. 200 kb til ca. 300 kb, fra ca. 300 kb til ca. 400 kb, fra ca. 400 kb til ca. 500 kb, fra ca. 500 kb til ca. 1 Mb, fra ca. 1 Mb til ca. 1,5 Mb, fra ca. 1,5 Mb til ca. 2 Mb, fra ca. 2 Mb til ca. 2,5 Mb eller fra ca. 2,5 Mb til ca. 3 Mb.
12. Fremgangsmåde ifølge et hvilket som helst af kravene 1-11, hvor den deleterede endogene nukleinsyresekvens er mindst 500 kb.
13. Fremgangsmåde ifølge et hvilket som helst af kravene 1-12, hvor modifikationen omfatter en udskiftning af en endogen nukleinsyresekvens med en homolog eller en ortolog nukleinsyresekvens.
14. Fremgangsmåde ifølge et hvilket som helst af kravene 1-13, hvor det genomiske mållocus på Y-kromosomet er .S'rv-genet, f//y-genet, Eif2s3y-genet, /Y/.vdv-genet, Ubely-genet, Yspy-genet, Usp9y-genet, Z/'\7-genet, Z/v2-genet, eller området, der omfatter Kdm5d-, Eif2s3y-, Tspy-, Uty-, Ddx3y- og Usp9y-generne.
15. Fremgangsmåde ifølge et hvilket som helst af kravene 1-13, hvor det genomiske mållocus på Y-kromosomet omfatter Sry-genet.
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