HRP20211563T1 - Pripravci koji sadrže sintetske polinukleotide koji kodiraju proteine srodne crispr-u i sintetske sgrna, te postupci njihove uporabe - Google Patents
Pripravci koji sadrže sintetske polinukleotide koji kodiraju proteine srodne crispr-u i sintetske sgrna, te postupci njihove uporabe Download PDFInfo
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- HRP20211563T1 HRP20211563T1 HRP20211563TT HRP20211563T HRP20211563T1 HR P20211563 T1 HRP20211563 T1 HR P20211563T1 HR P20211563T T HRP20211563T T HR P20211563TT HR P20211563 T HRP20211563 T HR P20211563T HR P20211563 T1 HRP20211563 T1 HR P20211563T1
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- synthetic polynucleotide
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- 108091033319 polynucleotide Proteins 0.000 title claims 58
- 102000040430 polynucleotide Human genes 0.000 title claims 58
- 239000002157 polynucleotide Substances 0.000 title claims 58
- 108090000623 proteins and genes Proteins 0.000 title claims 26
- 238000000034 method Methods 0.000 title claims 10
- 239000000203 mixture Substances 0.000 title claims 9
- 108091033409 CRISPR Proteins 0.000 title claims 5
- 102000004169 proteins and genes Human genes 0.000 title claims 5
- 108091027544 Subgenomic mRNA Proteins 0.000 claims 36
- 239000002777 nucleoside Substances 0.000 claims 12
- 210000004027 cell Anatomy 0.000 claims 11
- 150000002632 lipids Chemical class 0.000 claims 11
- 125000003835 nucleoside group Chemical group 0.000 claims 11
- 239000002105 nanoparticle Substances 0.000 claims 9
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims 8
- 230000004048 modification Effects 0.000 claims 8
- 238000012986 modification Methods 0.000 claims 8
- 230000000295 complement effect Effects 0.000 claims 7
- 239000012636 effector Substances 0.000 claims 7
- 238000013518 transcription Methods 0.000 claims 7
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- 238000009472 formulation Methods 0.000 claims 6
- 108020003589 5' Untranslated Regions Proteins 0.000 claims 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims 4
- UVBYMVOUBXYSFV-XUTVFYLZSA-N 1-methylpseudouridine Chemical compound O=C1NC(=O)N(C)C=C1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UVBYMVOUBXYSFV-XUTVFYLZSA-N 0.000 claims 4
- UVBYMVOUBXYSFV-UHFFFAOYSA-N 1-methylpseudouridine Natural products O=C1NC(=O)N(C)C=C1C1C(O)C(O)C(CO)O1 UVBYMVOUBXYSFV-UHFFFAOYSA-N 0.000 claims 4
- 238000010354 CRISPR gene editing Methods 0.000 claims 4
- 102100027188 Thyroid peroxidase Human genes 0.000 claims 4
- 101710113649 Thyroid peroxidase Proteins 0.000 claims 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims 4
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims 4
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims 4
- 229940045145 uridine Drugs 0.000 claims 4
- 101001130171 Homo sapiens L-lactate dehydrogenase C chain Proteins 0.000 claims 3
- 102100031357 L-lactate dehydrogenase C chain Human genes 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 238000002347 injection Methods 0.000 claims 3
- 239000007924 injection Substances 0.000 claims 3
- 238000001361 intraarterial administration Methods 0.000 claims 3
- 238000007912 intraperitoneal administration Methods 0.000 claims 3
- 238000001990 intravenous administration Methods 0.000 claims 3
- 239000002773 nucleotide Substances 0.000 claims 3
- 125000003729 nucleotide group Chemical group 0.000 claims 3
- 230000008685 targeting Effects 0.000 claims 3
- 238000002560 therapeutic procedure Methods 0.000 claims 3
- 108091023045 Untranslated Region Proteins 0.000 claims 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims 2
- 239000003125 aqueous solvent Substances 0.000 claims 2
- 239000012752 auxiliary agent Substances 0.000 claims 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims 2
- 238000000338 in vitro Methods 0.000 claims 2
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- 239000007927 intramuscular injection Substances 0.000 claims 2
- 238000010254 subcutaneous injection Methods 0.000 claims 2
- 239000007929 subcutaneous injection Substances 0.000 claims 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims 2
- RVHYPUORVDKRTM-UHFFFAOYSA-N 1-[2-[bis(2-hydroxydodecyl)amino]ethyl-[2-[4-[2-[bis(2-hydroxydodecyl)amino]ethyl]piperazin-1-yl]ethyl]amino]dodecan-2-ol Chemical compound CCCCCCCCCCC(O)CN(CC(O)CCCCCCCCCC)CCN(CC(O)CCCCCCCCCC)CCN1CCN(CCN(CC(O)CCCCCCCCCC)CC(O)CCCCCCCCCC)CC1 RVHYPUORVDKRTM-UHFFFAOYSA-N 0.000 claims 1
- LRFJOIPOPUJUMI-KWXKLSQISA-N 2-[2,2-bis[(9z,12z)-octadeca-9,12-dienyl]-1,3-dioxolan-4-yl]-n,n-dimethylethanamine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCC1(CCCCCCCC\C=C/C\C=C/CCCCC)OCC(CCN(C)C)O1 LRFJOIPOPUJUMI-KWXKLSQISA-N 0.000 claims 1
- HXVVOLDXHIMZJZ-UHFFFAOYSA-N 3-[2-[2-[2-[bis[3-(dodecylamino)-3-oxopropyl]amino]ethyl-[3-(dodecylamino)-3-oxopropyl]amino]ethylamino]ethyl-[3-(dodecylamino)-3-oxopropyl]amino]-n-dodecylpropanamide Chemical compound CCCCCCCCCCCCNC(=O)CCN(CCC(=O)NCCCCCCCCCCCC)CCN(CCC(=O)NCCCCCCCCCCCC)CCNCCN(CCC(=O)NCCCCCCCCCCCC)CCC(=O)NCCCCCCCCCCCC HXVVOLDXHIMZJZ-UHFFFAOYSA-N 0.000 claims 1
- KPPPLADORXGUFI-KCRXGDJASA-N 4-amino-1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(1-hydroxyethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O[C@@H]1[C@H](O)[C@@H](C(O)C)O[C@H]1N1C(=O)N=C(N)C=C1 KPPPLADORXGUFI-KCRXGDJASA-N 0.000 claims 1
- 229930024421 Adenine Natural products 0.000 claims 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims 1
- 108010003272 Hyaluronate lyase Proteins 0.000 claims 1
- 102000001974 Hyaluronidases Human genes 0.000 claims 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 101150077103 TPO gene Proteins 0.000 claims 1
- 108091036066 Three prime untranslated region Proteins 0.000 claims 1
- NRLNQCOGCKAESA-KWXKLSQISA-N [(6z,9z,28z,31z)-heptatriaconta-6,9,28,31-tetraen-19-yl] 4-(dimethylamino)butanoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCC(OC(=O)CCCN(C)C)CCCCCCCC\C=C/C\C=C/CCCCC NRLNQCOGCKAESA-KWXKLSQISA-N 0.000 claims 1
- 229960000643 adenine Drugs 0.000 claims 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 230000006907 apoptotic process Effects 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 239000011258 core-shell material Substances 0.000 claims 1
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- 239000003995 emulsifying agent Substances 0.000 claims 1
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Chemical compound CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 claims 1
- 230000014509 gene expression Effects 0.000 claims 1
- 210000003494 hepatocyte Anatomy 0.000 claims 1
- 229960002773 hyaluronidase Drugs 0.000 claims 1
- 238000007918 intramuscular administration Methods 0.000 claims 1
- 239000007951 isotonicity adjuster Substances 0.000 claims 1
- -1 lipidoids Substances 0.000 claims 1
- 239000002479 lipoplex Substances 0.000 claims 1
- 239000002502 liposome Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 150000007523 nucleic acids Chemical group 0.000 claims 1
- 150000003833 nucleoside derivatives Chemical class 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
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- 238000007920 subcutaneous administration Methods 0.000 claims 1
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
- C12N9/22—Ribonucleases RNAses, DNAses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
- A61K48/0066—Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C12N15/90—Stable introduction of foreign DNA into chromosome
- C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
- C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- C12N2310/00—Structure or type of the nucleic acid
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Claims (14)
1. Sintetski polinukleotid, pri čemu je uridin 100 % zamijenjen 1-metilpseudouridinom, gdje sintetski polinukleotid sadrži prvo područje spojenih nukleozida, gdje navedeno prvo područje kodira protein srodan CRISPR-u kojeg se bira iz skupine koju čine proteini srodni CRISPR-u koji imaju bilo koje od aminokiselinskih sekvenci SEQ ID NO 61, 7, 8, 9, 62, 63, 64 ili 65 ili ih kodiraju bilo koje od nukleinskokiselinskih sekvenci SEQ ID NO 1-6 ili 110-112.
2. Sintetski polinukleotid u skladu s patentnim zahtjevom 1, pri čemu sintetski polinukleotid sadrži najmanje dvije modifikacije, pri čemu poželjno:
(a) najmanje dvije modifikacije se nalaze na jednom ili više nukleozida i/ili na okosničnoj spojnici između nukleozida; ili
(b) najmanje dvije modifikacije se nalaze i na nukleozidu i na okosničnoj spojnici; ili
(c) najmanje jedna modifikacija se nalazi na okosničnoj spojnici; ili
(d) jedna ili više okosničnih spojnica su modificirane zamjenom jednog ili više atoma kisika; ili
(e) najmanje jedna modifikacija se sastoji u zamjeni najmanje jedne okosnične spojnice fosforotioatnom spojnicom; ili
(f) najmanje jedna modifikacija se nalazi na jednom ili više nukleozida; ili
(g) jedna ili više modifikacija su na šećeru jednog ili više nukleozida; ili
(h) najmanje jedna modifikacija se nalazi na jednoj ili više nukleobaza koje se bira iz skupine koju čine citozin, gvanin, adenin, timin i uracil.
3. Postupak koji uključuje sintetski polinukleotid u skladu s bilo kojim od patentnih zahtjeva 1 ili 2, poželjno:
(a) dodatno sadrži farmaceutski prihvatljivo pomoćno sredstvo, gdje poželjnije dodatno sadrži farmaceutski prihvatljivo pomoćno sredstvo kojeg se bira iz skupine koju čine otapalo, vodeno otapalo, nevodeno otapalo, disperzijski mediji, razrjeđivač, disperzija, suspenzijsko pomagalo, površinski aktivno sredstvo, izotonično sredstvo, sredstvo za ugušćivanje ili emulgiranje, konzervans, lipid, lipidoidi, liposom, lipidna nanočestica, nanočestice tipa jezgra-ljuska, polimer, lipopleks, peptid, protein, stanica, hijaluronidaza, te njihove mješavine;
(b) dodatno sadrži lipid kojeg se bira između DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, 98N12-5, C12-200, DLin-MC3-DMA, reLNP, PLGA, PEG, PEG-DMA i PEGiliranih lipida i njihovih mješavina; ili
(c) dodatno sadrži lipidnu nanočesticu.
4. In vitro postupak proizvodnje proteina srodnog CRISPR-u koji se sastoji u stavljanju stanice ili tkiva u kontakt sa sintetskim polinukleotidom u skladu s patentnim zahtjevom 1 ili postupku u skladu s patentnim zahtjevom 3.
5. Sintetski polinukleotid u skladu s patentnim zahtjevom 1 ili postupak u skladu s patentnim zahtjevom 3, namijenjeni uporabi u terapijskom postupku u kojem se proizvodi protein srodan CRISPR-u, gdje se navedeni postupak sastoji u primjeni na organizmu sintetskog polinukleotida ili postupka, pri čemu se poželjno sintetski polinukleotid:
(a) primjenjuje u ukupnoj dnevnoj dozi između 1 pg i 1 mg;
(b) primjenjuje u jednoj dozi;
(c) primjenjuje u više od jedne doze;
(d) primjenjuje prenatalnom primjenom, neonatalnom primjenom i postnatalnom primjenom;
(e) primjenjuje oralno, injekcijom, očnom primjenom, ili intranazalnom primjenom; ili
(f) primjenjuje injekcijom, gdje se navedenu injekciju bira iz skupine koju čine intravenska, intraarterijska, intraperotonealna, intradermalna, supkutana i intramuskularna.
6. Sintetski polinukleotid u skladu s patentnim zahtjevom 1, namijenjen uporabi u terapijskom postupku moduliranja transkripcije gena od interesa u stanici koji se sastoji u stavljanju stanice u kontakt sa sintetskim polinukleotidom u skladu s patentnim zahtjevom 1 i sintetskom sgRNA u uvjetima dovoljnim za moduliranje transkripcije gena od interesa, gdje prvo područje sintetskog polinukleotida dodatno sadrži polinukleotidnu sekvencu koji kodira efektorsku domenu i sekvencu prvog područja sgRNA komplementaran genu od interesa;
pri čemu je sintetska sgRNA sintetska sgRNA koja cilja na gen od interesa, pri čemu je u navedenoj sintetskoj sgRNA uridin 100 % zamijenjen 1-metilpseudouridinom, gdje sgRNA sadrži:
(a) prvo područje od 20-25 spojenih nukleozida komplementarno bilo kojem od lanaca 5’ UTR gena od interesa, pri čemu poželjno prvo područje sadrži ciljnu sekvencu kao što je opisano u SEQ ID NO:91, 92, 93 ili 94; i
(b) drugo bočno područje koje se nalazi na 3’ kraju navedenog prvog područja koje sadrži navodeću RNA okosničnu sekvencu kakva se nalazi u SEQ ID NO:90, pri čemu poželjno:
(i) sintetski polinukleotid i sintetska sgRNA nisu isti polinukleotid;
(ii) sintetski polinukleotid je sintetski polinukleotidi u skladu s bilo kojim od patentnih zahtjeva 1 ili 2;
(iii) gen od interesa se bira iz skupine koju čine VEGF, TPO, te LDHC;
(iv) sintetski polinukleotid u skladu s patentnim zahtjevom 1 sadrži sekvencu miR specifičnu za stanicu; ili
(v) gen od interesa je VEGF, a stanica je stanica U-97MG, stanica HEK293, primarni ljudski hepatocit ili stanica HepG2, gdje se postupak sastoji u stavljanju stanice u kontakt s jednim od sintetskih polinukleotida u skladu s patentnim zahtjevom 1 ili 2 i jednom od sgRNA u uvjetima dovoljnim za moduliranje transkripcije gena VEGF.
7. Sintetski polinukleotid u skladu s patentnim zahtjevom 1, namijenjen uporabi u terapijskom postupku moduliranja transkripcije gena od interesa kod subjekta koji se sastoji u primjeni na subjektu prve doze sintetskog polinukleotida u skladu s patentnim zahtjevom 1 i druge doze sintetske sgRNA u uvjetima dovoljnim za moduliranje transkripcije gena od interesa, gdje prvo područje sintetskog polinukleotida dodatno sadrži polinukleotidnu sekvencu koja kodira efektorsku domenu i sekvencu prvog područja sgRNA komplementarnu genu od interesa,
pri čemu je sintetska sgRNA sintetska sgRNA koja cilja na gen od interesa, pri čemu je u navedenoj sintetskoj sgRNA uridin 100 % zamijenjen 1-metilpseudouridinom, gdje sgRNA sadrži:
(a) prvo područje od 20-25 spojenih nukleozida komplementarno bilo kojem od lanaca 5’ UTR gena od interesa, pri čemu poželjno prvo područje sadrži ciljnu sekvencu kao što je opisano u SEQ ID NO:91, 92, 93 ili 94; i
(b) drugo bočno područje koje se nalazi na 3’ kraju navedenog prvog područja koje sadrži navodeću RNA okosničnu sekvencu kakva se nalazi u SEQ ID NO:90,
pri čemu poželjno:
(i) sintetski polinukleotid je sintetski polinukleotidi u skladu s patentnim zahtjevom 2;
(ii) subjekt je čovjek;
(iii) sintetski polinukleotid i/ili sintetska sgRNA su formulirani u formulaciju lipidnih nanočestica;
(iv) sintetski polinukleotid je formuliran u formulaciju lipidnih nanočestica, a sgRNA nije formulirana u formulaciju lipidnih nanočestica;
(v) gen od interesa se bira iz skupine koju čine VEGF, TPO, te LDHC;
(vi) sintetski polinukleotid u skladu s patentnim zahtjevom 1 sadrži sekvencu miR specifičnu za stanicu; ili
(vii) gen od interesa je TPO, a subjekt je miš, gdje se postupak sastoji u primjeni na mišu 0,0005/mg/kg-0,5 mg/kg sintetskog polinukleotida koji sadrži SEQ ID NO:51 i 0,0005/mg/kg-0,5 mg/kg sgRNA koja sadrži prvo područje koje sadrži sekvencu komplementarnu jednom lancu 5’ UTR gena TPO.
8. Sintetski polinukleotid namijenjen uporabi u skladu s patentnim zahtjevom 7, pri čemu:
(a) prva doza je 0,0005/mg/kg do 0,5 mg/kg sintetskog polinukleotida; i/ili
(b) druga doza je između 0,0005/mg/kg i 0,5 mg/kg sgRNA; i/ili
(c) sintetski polinukleotid i sgRNA se primjenjuje zajedno ili se primjenjuje odvojeno; i/ili
(d) sintetski polinukleotid i/ili sgRNA se primjenjuje u jednoj dozi ili u više doza; i/ili
(e) sintetski polinukleotid i/ili sgRNA se primjenjuje jednom dnevno ili više nego jednom dnevno; i/ili
(f) sintetski polinukleotid i/ili sgRNA se primjenjuje prenatalno, neonatalno, postnatalno, oralno, očno, intranazalno, i/ili intravenskom, intraarterijskom, intraperotonealnom, intradermalnom, supkutanom ili intramuskularnom injekcijom.
9. Sintetski polinukleotid u skladu s patentnim zahtjevom 1, namijenjen uporabi u postupku liječenja bolesti kod subjekta koji se sastoji u primjeni na subjektu prve doze sintetskog polinukleotida u skladu s patentnim zahtjevom 1 i druge doze sintetske sgRNA u uvjetima dovoljnim za moduliranje transkripcije gena od interesa, gdje prvo područje sintetskog polinukleotida dodatno sadrži polinukleotidnu sekvencu koja kodira efektorsku domenu i sekvencu prvog područja sgRNA komplementarnu jednom lancu gena od interesa 5’ UTR, pri čemu je eksprimiranje gena povezano s bolešću;
pri čemu je sintetska sgRNA sintetska sgRNA koja cilja na gen od interesa, pri čemu je u navedenoj sintetskoj sgRNA uridin 100 % zamijenjen 1-metilpseudouridinom, gdje sgRNA sadrži:
(a) prvo područje od 20-25 spojenih nukleozida komplementarno bilo kojem od lanaca 5’ UTR gena od interesa, pri čemu poželjno prvo područje sadrži ciljnu sekvencu kao što je opisano u SEQ ID NO:91, 92, 93 ili 94; i
(b) drugo bočno područje koje se nalazi na 3’ kraju navedenog prvog područja koje sadrži navodeću RNA okosničnu sekvencu kakva se nalazi u SEQ ID NO:90, pri čemu poželjno:
(i) bolest je rak, a gen je gen za apoptozu ili senescenciju;
(ii) sintetski polinukleotid je sintetski polinukleotidi u skladu s patentnim zahtjevom 2;
(iii) subjekt je čovjek;
(iv) sintetski polinukleotid i/ili sintetska sgRNA su formulirani u formulaciju lipidnih nanočestica;
(v) sintetski polinukleotid je formuliran u formulaciju lipidnih nanočestica, a sgRNA nije formulirana u formulaciju lipidnih nanočestica;
(vi) gen od interesa se bira iz skupine koju čine VEGF, TPO, te LDHC; ili
(vii) sintetski polinukleotid u skladu s patentnim zahtjevom 1 sadrži sekvencu miR.
10. Sintetski polinukleotid namijenjen uporabi ili sintetska sgRNA u skladu s patentnim zahtjevom 9, pri čemu:
(a) prva doza je 0,0005/mg/kg do 0,5 mg/kg sintetskog polinukleotida; i/ili
(b) druga doza je između 0,0005/mg/kg i 0,5 mg/kg sgRNA; i/ili
(c) sintetski polinukleotid i sgRNA se primjenjuje zajedno ili se primjenjuje odvojeno; i/ili
(d) sintetski polinukleotid i/ili sgRNA se primjenjuje u jednoj dozi ili u više doza; i/ili
(e) sintetski polinukleotid i/ili sgRNA se primjenjuje jednom dnevno ili više nego jednom dnevno; i/ili
(f) sintetski polinukleotid i/ili sgRNA se primjenjuje prenatalno, neonatalno, postnatalno, oralno, očno, intranazalno, i/ili intravenskom, intraarterijskom, intraperotonealnom, intradermalnom, supkutanom ili intramuskularnom injekcijom.
11. Sintetski polinukleotid u skladu s patentnim zahtjevom 1, pri čemu prvo područje:
(i) kodira SEQ ID NO: 61;
(ii) dodatno kodira efektorsku domenu;
(iii) dodatno kodira efektorsku domenu koju se bira iz skupine koju čine KRAB, VP64, p65AD, te Mxi;
(iv) dodatno kodira KRAB ili VP64 kao što je opisano u Tablici 6; ili
(v) dodatno kodira efektorsku domenu i sadrži nukleotidnu sekvencu koja se bira iz skupine koju čine efektorske domene opisane u Tablici 6.
12. Sintetski polinukleotid u skladu s patentnim zahtjevom 1, pri čemu sintetski polinukleotid sadrži prvo bočno područje koje se nalazi na 5’ kraju navedenog prvog područja koje sadrži sekvencu spojenih nukleozida koja se bira iz skupine koju čine sekvence 5’ netranslatiranog područja (UTR) SEQ ID NO 71, 72, te 15-18; pri čemu prvo bočno područje može sadržavati SEQ ID NO:71.
13. Sintetski polinukleotid u skladu s patentnim zahtjevom 1, pri čemu sintetski polinukleotid sadrži drugo bočno područje koje se nalazi na 3’ kraju navedenog prvog područja koje sadrži sekvencu spojenih nukleozida koja se bira iz skupine koju čine sekvence 3’ netranslatiranog područja (UTR) SEQ ID NO 81, 82, te 19-35; pri čemu drugo bočno područje može:
(i) sadrži SEQ ID NO:81;
(ii) sadrži SEQ ID NO:82;
(iii) dodatno sadrži 3’repni niz spojenih nukleozida;
(iv) dodatno sadrži poli-A rep;
(v) dodatno sadrži poli-A rep duljine 80 do 140 nukleotida; ili
(vi) dodatno sadrži poli-A rep dug 100 nukleotida.
14. Sintetski polinukleotid u skladu s patentnim zahtjevom 1, pri čemu sintetski polinukleotid:
(i) je modificirani RNA polinukleotid;
(ii) pripada sekvenci koja se bira između SEQ ID NOS:51-56;
(iii) dodatno sadrži strukturu najmanje jedne 5’ kape;
(iv) sadrži najmanje jedan 5’-metilcitidin;
(v) je uglavnom pročišćen; ili
(vi) se proizvodi postupkom transkripcije in vitro ili se koristi postupak kemijske sinteze.
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EP3019619A2 (en) | 2016-05-18 |
DK3019619T3 (da) | 2021-10-11 |
SI3019619T1 (sl) | 2021-12-31 |
JP7019233B2 (ja) | 2022-02-15 |
EP3019619B1 (en) | 2021-08-25 |
WO2015006747A2 (en) | 2015-01-15 |
ES2896755T3 (es) | 2022-02-25 |
CY1124740T1 (el) | 2022-07-22 |
JP2022115896A (ja) | 2022-08-09 |
WO2015006747A3 (en) | 2015-04-23 |
JP2022164843A (ja) | 2022-10-27 |
PT3019619T (pt) | 2021-11-11 |
JP2020108379A (ja) | 2020-07-16 |
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EP3971287A1 (en) | 2022-03-23 |
PL3019619T3 (pl) | 2022-01-10 |
US11027025B2 (en) | 2021-06-08 |
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