DK1931780T3 - Antisense-forbindelser med forøget anti-microrna-aktivitet - Google Patents

Antisense-forbindelser med forøget anti-microrna-aktivitet Download PDF

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DK1931780T3
DK1931780T3 DK06802706.9T DK06802706T DK1931780T3 DK 1931780 T3 DK1931780 T3 DK 1931780T3 DK 06802706 T DK06802706 T DK 06802706T DK 1931780 T3 DK1931780 T3 DK 1931780T3
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aes
mces
modified
antisense compound
nucleosides
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Christine Esau
Eric E Swayze
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Regulus Therapeutics Inc
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    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
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    • C12N2310/31—Chemical structure of the backbone
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
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    • C12N2310/315—Phosphorothioates
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
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    • C12N2310/3341—5-Methylcytosine
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Claims (18)

1. Antisense-forbindelse omfattende bundne substituerede eller usubstituerede 2'-0-alkyl-modificerede nukleosider og fra 3 til 7 interne regioner af bicykliske sukker-modificerede nukleosider, hvor hver interne region omfatter fra 1 til 4 bicykliske sukker-modificerede nukleosider, og hvor hver region af bicykliske sukker-modificerede nukleosider er flankeret på hver side ved fra 1 til 8 substituerede eller usubstituerede 2'-0-alkyl-modificerede nukleosider, og hvor forbindelsen er i stand til at hybridisere med et miRNA og inhibere niveauet, aktivitet eller ekspression af miRNA'et, hvor forbindelsen ikke er Aes mCes Aes Aes Aes mCls Aes mCes mCes Aes Tes Tis Ges Tes mCes Aes mCls Aes mCes Tes mCes mCes Ae ; Aes mCes Aes Aes Aes mCls Aes mCes mCls Aes Tes Tis Ges Tes mCls Aes mCls Aes mCes Tes mCls mCes Ae ; mCes Tes mCls mCes Ae ) Aes mCes Als Aes Aes mCls Aes mCes mCls Aes Tes Tis Ges Tes mCls Aes mCes Als mCes Tes mCls mCes Ae ; Aeo mCeo Alo Aeo Aeo mClo Aeo mCeo mClo Aeo Teo Tlo Geo Teo mClo ΑθΟ mCeo Alo mCeo mClo mCeo Ae; Aes mCes Aes Als Aes mCes Aes mCls mCes Aes Tes Tis Ges Tes mCes Als mCes Aes mCes Tis mCes mCes Ae ; eller Ams mCms As Ams Ams mCls Ams mCms mCls Ams Tms Tis Gms Tms mCls Ams mCms Als mCms Tms mCls mCms Am ; hvor: A betegner adenin; C betegner cytosin; mC betegner 5-methylcytosin; G betegner guanin; T betegner thymin; e betegner 2'-0-methoxyethyl (MOE); m betegner 2'-0-methylribose; I betegner LNA (Locked Nucleic Acids); o betegner phosphodiester; og s betegner phosphorothioat.
2. Antisense-forbindelsen ifølge krav 1, hvor hver af de substituerede eller usubstituerede 2'-0-alkyl modificerede nukleosider har den samme sukkermodifikation og hver af de bicykliske sukker-modificerede nukleosider har den samme bicykliske modifikation.
3. Antisense-forbindelsen ifølge krav 1 eller krav 2, hvor 2'-substituentgruppen af hver af de substituerede eller usubstituerede 2'-0-alkyl modificerede nukleosider er, uafhængigt, -0-(CH2)rCH3, -0-(CH2)2-0-CH3, -0(CH2)2-S-CH3, 0-(CH2)2-0-N(Rm)(Rn) eller C-CH2-C(=0)-N(Rm)(Rn), where j er 0, 1 eller 2 og hver Rm og Rn er, uafhængigt, H, en aminobeskyttelsesgruppe eller substitueret eller usubstitueret C1-C10 alkyl.
4. Antisense-forbindelsen ifølge et hvilket som helst af kravene 1 til 3, hvor det bicykliske sukker af hver bicyklisk sukker-modificeret nukleosid omfatter en 2'-0-CH2-4', eller en 2'-0-(CH2)2-4'-bro.
5. Antisense-forbindelsen ifølge krav 1 med en af formlerne: A5-B1-A5-B1-A4-B1-Αβ, (A-A-B)7(-A)2, (A-A-A-B)5-A3, A5-Bi-A2-Bi-A2-Bi-A2-Bi-Ai-Bi-A3-Bi-A2, A3-B3-A2-B3-A2-B3-An A3-B3-A2-B3-A2-B3-A2-B3-A2, A3-B2-A2-B3-A2-B2-As, As-B2-A2-B3-A2-Β3-Αδ, hvor A er et substitueret eller usubstitueret 2'-0-alkyl-modificeret nukleosid, B er et bicyklisk sukker-modificeret nukleosid, og hvert sænket tal betegner antallet af gentagelser af det foregående nukleosid eller blok af nukleosider.
6. Antisense-forbindelsen ifølge krav 5, hvor hver 2'-substituentgruppe af substituerede eller usubstituerede 2'-0-alkyl-modificerede nukleosider er -0-(CH2)2-0-CH3 og hvert bicyklisk-modificeret nukleosid omfatter en 2'-0-CH2-4'-bro.
7. Antisense-forbindelsen ifølge et hvilket som helst af kravene 1 til 6 omfattende fra 15 til 30 bundne nukleosider.
8. Antisense-forbindelsen ifølge et hvilket som helst af kravene 1 til 7, hvor hver internukleosid-bindings-gruppe er, uafhængigt, en phosphodiester eller et phosphorothioat.
9. Antisense-forbindelsen ifølge krav 8, yderligere omfattende en flerhed af phosphorothioat-internucleosid-bindinger.
10. Antisense-forbindelsen ifølge et hvilket som helst af kravene 1 til 9, yderligere omfattende én eller flere regioner på fra 1 til 4 forskelligt modificerede nukleosider, hvor de forskelligt modificerede nukleosider er forskellige fra de andre nukleosider i antisense-forbindelsen.
11. Antisense-forbindelsen ifølge krav 10, hvor de forskelligt modificerede nukleosider er 2'-deoxynucleosider.
12. Fremgangsmåde til forøgelse af evnen af en substitueret eller usubstitueret 2'-0-alkyl ensartet modificeret antisense-forbindelse til modulering af aktiviteten af miRNA ved inkorporering i antisense-forbindelsen en flerhed af bicyklisk sukker-modificerede nukleosider.
13. Fremgangsmåden ifølge krav 12, hvor 2'-substituentgruppen af hver af de substituerede eller usubstituerede 2'-0-alkyl-modificerede nukleosider er, uafhængigt, -0-(CH2)rCH3, -0-(CH2)2-0-CH3, -0(CH2)2-S-CH3, 0-(CH2)2-0-N(Rm)(Rn) eller 0-CH2-C(=0)-N(Rm)(Rn), hvor j er 0, 1 eller 2 og hver Rm og Rn er, uafhængigt, H, en aminobeskyttelsesgruppe eller substituerede eller usubstituerede Ci-Cio alkyl.
14. Fremgangsmåden ifølge krav 12, hvor det bicykliske sukker af hvert bicyklisk sukker-modificeret nukleosid omfatter en 2'-0-CH2-4'-, eller en 2'-0-(CH2)2-4'-bro.
15. Antisense-forbindelsen ifølge et hvilket som helst af kravene 1 til 11, hvor inhiberingen af niveauet, aktivitet eller ekspression af miRNA'et resulterer i sænket serum cholesterol eller reduceret hepatisk steatose.
16. Farmaceutisk sammensætning omfattende antisense-forbindelsen ifølge et hvilket som helst af kravene 1 til 11 eller 15.
17. Antisense-forbindelsen ifølge et hvilket som helst af kravene 1 til 11 eller 15, eller den farmaceutiske sammensætning ifølge krav 16, til anvendelse i terapi.
18. Antisense-forbindelsen ifølge et hvilket som helst af kravene 1 til 11 eller 15, eller den farmaceutiske sammensætning ifølge krav 16, til anvendelse i sænkning af serumcholesterol eller til anvendelse i behandling af hepatisk steatose.
DK06802706.9T 2005-08-29 2006-08-29 Antisense-forbindelser med forøget anti-microrna-aktivitet DK1931780T3 (da)

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